Onemorestep

I have been experimenting with thyroid medication and have found it can alter my immune function and visuals. I would be interested to see your responses to ketotifen and cimetidine (they do opposite things to th1/th2; prior is duel suppressor and latter is duel enhancer)

One hypothesis I can come up with is you are sensitive to glutamate now— many of us are. If you have a co disorder— such as mild mcas or histamine intolerance, this can lead to increases glutamate in the brain. (I won’t go into the specifics but histamine —> many steps —>neuronal glutamate release). one thing you can try is a low histamine diet for a few weeks. I follow the one on mastcell360.com Use dao supplements. I use seeking health. Try a mast cell stabilizer such as ketotifen (a supplement site I use, americanresearchlabs, sells it without prescription). claritin ready tabs, the one with fewest ingredients. just my two cents. I really cannot think of any other reasons except for insulin receptor wonky shit that also involves cytokine release.

Full text here Components of the stress system such as norepinephrine (NE) and glucocorticoids appear to mediate a Th2 shift, while serotonin (5-HT) and melatonin might mediate a Th1 shift. Some antidepressants would occur affecting these systems, acting on neurotransmitter balance (especially the 5-HT/NE balance) and expression levels of receptor subtypes, which in turn affect cytokine production and relative Th1/Th2 balance.

If you have hppd for that long and it continues to get worse, you likely have another condition as well. Hppd usually stabilizes within the first few months and then proceeds to get better— until recovery or plateau. 1) mold 2) lyme, bartonella, babesia, 3) candida 4) sibo/sifo These are things I would look into that can exacerbate or mimic hppd enough that people end up here through self diagnosed symptoms.

Something interesting about cannabis is it increases the likelihood of fungal infection 3.5x. zoloft is a biofilm disruptor for candida, a common infection of the gut for chronic cannabis users. It can cause exacerbation of all hppd symptoms.

Sounds like mcas to me

I have taken dihydromyricetin. Works well for hangovers lol.

This is a complicated question— more than you might think. The lay answer— not particularly recommended. Anecdotally, older antihistamines such as hydroxyzine or Benadryl cause reactions in people with hppd. The flares can be quite serious. but then what about the non sedating? Claritin seems well tolerated. H2 is more complex, as it effects the immune system. At this point, I am convinced there is a subset of people with hppd that have it due to pathogenic infection— lyme, bartonella, even sibo that cause visual and emotional symptoms that might lead them to this website. Hppd isn’t very easily or well diagnosed by physicians, and most are self diagnosed. h2 antagonists alter the bodies own signaling foe cytokine release, without going into too much detail. It’s possible to see flares with it because of that. For sleep, Gabapentin, melatonin (if tolerated; may cause depression), making sure you haven’t developed sleep apnea (I have since hppd). I was able to tolerate trazadone after I got hppd. That was a godsend. Do your own research, but I found that the negative reports are out there but are not permanent in their effects. I have found kava can work well too. Do not take with trazadone, you will create a drug in your brain mcpp in your brain normally with trazadone but it is quickly turned into a different metabolite. But when co infested with kava, you suppress the enzyme that turns mcpp into whatever it turns into. the effects of mcpp are unpleasant. I experienced this interaction firsthand and while it didn’t do anything permanent I was well recovered from hppd at the time and it still made my skin feel as if it was on fire. best of luck hall

I have been a member of this forum for a long time. Recently, diagnosed with extreme bartonella and lyme. Third type of lyme infection based off of antibodies. been doing lots of reading on tick diseases and looking between the lines with hppd, mast cell diseases, inflammatory conditions, immune conditions, eye inflammation (not detectable through regular eye exams), gut issues like sibo— there is something to your logic i recommend you get a full panel done by igenx, tlab inc, and galaxy labs. They will be able to help you figure out if you have lyme or other tick born disease states.

question: in what scenario does a brains astrocytes become so over reactive they cannot shut off? Chronic mast cell activation mtorc1 inhibition (mtorc1 activation critical for astrocyte "deactivation" and to "turn off" mast cells) cb1: antagonization: CB1 receptor blockade with rimonabant attenuated mTORC1 overactivation How could this occur?

https://pubmed.ncbi.nlm.nih.gov/31420305/

https://www.jbc.org/article/S0021-9258(20)31733-6/fulltext

im open to any idea that involves infection-- whether it be viral, bacterial, fungal, or parasitic. Hallucinogens are immune suppressing drugs. Strong ones. They leave the doors open and if you have the wrong guest at that door at just the wrong moment....

How did it go?

I think it does. I just find it difficult to believe that there isn’t at the least some mast cell disregulation going on. I wrote a lot about mtorc1 and lsd and how it relates to excessive microglia/astrocyte glutamate activation/release. The intermediary between those two, mTorc1 and the microglia/astrocyte could be mast cells as mtorc1 appears to play a role in the regulation on mast cells which in turn can have very deleterious effects involving interleukins and chemokines and glutamate overload and just a whole clusterfuck of weird neurological brain states. does that mean go take some antihistamines or mast cell stabilizers and shit and you’ll be healed? a sad analogy for you… —you put out your house fire with water. You don’t rebuild your house with it, though. off to find some wood I write about it in a post here: and continue the research here: feel free to hop on in and post things if you come across anything relevant good vibes, oms

The following is a big dump of info I need to sort into a coherent train of though outside of just my brain lol...: keywords: Mast cell degranulation 5ht2a microglia astrocyte mTORC1 MMP3 Histamine AMPA NMDA Interleukin1-b (and more...) Endocannabinoid CB1 Pre Frontal Cortex PFC retinal ganglion cell (RGC) cytokine chemokine Little is known about the signals downstream of PI3K which regulate mast cell homeostasis and function following FcepsilonRI aggregation and Kit ligation. In this study, we investigated the role of the mammalian target of rapamycin complex 1 (mTORC1) pathway in these responses. In human and mouse mast cells, stimulation via FcepsilonRI or Kit resulted in a marked PI3K-dependent activation of the mTORC1 pathway, as revealed by the wortmannin-sensitive sequential phosphorylation of tuberin, mTOR, p70S6 kinase (p70S6K), and 4E-BP1. In contrast, in human tumor mast cells, the mTORC1 pathway was constitutively activated and this was associated with markedly elevated levels of mTORC1 pathway components. Rapamycin, a specific inhibitor of mTORC1, selectively and completely blocked the FcepsilonRI- and Kit-induced mTORC1-dependent p70S6K phosphorylation and partially blocked the 4E-BP1 phosphorylation. In parallel, although rapamycin had no effect on FcepsilonRI-mediated degranulation or Kit-mediated cell adhesion, it inhibited cytokine production, and kit-mediated chemotaxis and cell survival. Furthermore, Rapamycin also blocked the constitutive activation of the mTORC1 pathway and inhibited cell survival of tumor mast cells. These data provide evidence that mTORC1 is a point of divergency for the PI3K-regulated downstream events of FcepsilonRI and Kit for the selective regulation of mast cell functions. Specifically, the mTORC1 pathway may play a critical role in normal and dysregulated control of mast cell homeostasis. https://www.researchgate.net/publication/5498643_Activation_and_Function_of_the_mTORC1_Pathway_in_Mast_Cells What Are Microglia? Microglial cells are the antigen presenting cells of the CNS and are key mediators of neuroinflammation (Kettenmann et al., 2011). They have a role in surveillance and phagocytosis of cellular debris (Sierra et al., 2013) and maintenance of brain function and are thought to regulate many processes including neurogenesis, synaptic plasticity and synaptic pruning (Aloisi, 2001; Tremblay et al., 2010; Ji et al., 2013; Schafer and Stevens, 2013; Zhan et al., 2014; Wu et al., 2015; Bar and Barak, 2019). They are derived from primitive myeloid progenitor cells and migrate into the CNS during embryogenesis, appearing before E8 in mice and 4.5–5 weeks in humans (Lichanska and Hume, 2000; Ginhoux et al., 2010), and increase in numbers rapidly from E16 onward in mice (Swinnen et al., 2013) and are functionally heterogeneous (Smolders et al., 2019; Mendes and Majewska, 2021). Microglial progenitors infiltrate the CNS before the vasculature is maturely formed, either migrating though the ventricular walls or through the meninges (Ginhoux et al., 2010; Swinnen et al., 2013; Reemst et al., 2016). Migration and distribution may also be further regulated by direct neuronal-microglial interactions though the chemokine CX3CL1, otherwise known as Fractalkine, and its corresponding receptor expressed on the microglia (Paolicelli et al., 2011). They then disperse in non-uniform manner, comprising 0.5–16.6% of the cell population depending on the region of the adult brain (Lawson et al., 1992) and differentiate to help regulate neurodevelopment, monitoring and maintaining synapses in the healthy, uninjured brain (Aloisi, 2001; Bar and Barak, 2019). We would direct readers to some excellent review articles on the role of microglia on neurodevelopment (Cowan and Petri, 2018; Coomey et al., 2020; Thion and Garel, 2020). Microglia and Neuroinflammation Increased microglial-mediated neuroinflammation has been seen in numerous NDDs, including ASD (Morgan et al., 2010; Tetreault et al., 2012; Suzuki et al., 2013; Gupta et al., 2014; Lee et al., 2017), schizophrenia (Garey, 2010; Sellgren et al., 2019; Chini et al., 2020), ADHD (Anand et al., 2017), and TS (Lennington et al., 2016). Microglia in the developing brain are also sensitive to external perturbations such as maternal infections (Smolders et al., 2015; Bernstein et al., 2016; Rosin et al., 2021a; Rosin et al., 2021b). Microglia are thought to initiate an immune response to protect the brain, but altered microglial activity has also been implicated in disorders of neurodevelopment and neurodegeneration through an upregulation of neuroinflammation (Kettenmann et al., 2011; Salter and Stevens, 2017). The precise mechanisms how a microglial bias toward pro- or anti-inflammatory cytokine production can affect neurodevelopment and pathological states remains incompletely understood. As further outlined below histamine has been shown to trigger both anti-inflammatory and pro-inflammatory responses from the microglia (Biber et al., 2007; Zhang et al., 2020). An appreciation of the role of the microglia in neuroinflammation and neurodevelopment and their regulation by histamine is therefore an exciting prospect into understanding the pathophysiology of a range of neurodevelopmental disorders. Histamine’s Regulation of Microglia Microglia have been shown to express all four subsets of histamine receptor (Dong et al., 2014a; Haas and Panula, 2016; Zhang et al., 2020), which can differentially affect their behavior. For example,Frick et al. (2016) undertook one of the first in vivo studies on the role of histamine in microglial activation. The group used immunohistochemistry to assess the effect of either histamine deficiency (Hdc KO mouse model) or histamine stimulation in wild type mice on microglia. Histamine was shown to regulate microglia via the H4 receptor. Hdc KO mice have a normal number of microglia but with reduced ramifications, reduced insulin-like growth factor-1 (IGF-1) expression and reduced expression of H4 receptor that may indicate impairment in histaminergic regulation of microglia. Similar findings occurred by selective removal of histaminergic neurons in the TMN of the hypothalamus. IGF-1 expressing microglia are induced by cytokines released from T helper 2 cells, which may be neuroprotective, promoting neurogenesis. Furthermore, the pro-inflammatory microglial response to challenge with lipopolysaccharide (LPS) was greater in Hdc KO mice. This may indicate that a genetic predisposition such as histamine deficiency may increase the brain’s vulnerability to pro-inflammatory insults in neuropsychiatric disorders such as TS. Indeed exogenous histamine was able to reduce LPS induced inflammation in the hippocampus (Saraiva et al., 2019). Interestingly, in vitro studies have shown both pro- and anti-inflammatory effects of histamine on microglial function (Biber et al., 2007). For example, histamine can reduce pro-inflammatory cytokine production such as IL-1β in response to mediators such as LPS as well modulate overall microglial motility (Ferreira et al., 2012). This may indicate an anti-inflammatory function of histamine on the microglia. However, in contrast to this, microglial secretion of the pro-inflammatory cytokines TNF-α and IL-6 is triggered by histaminergic stimulation of the H1 and H4 receptors (Dong et al., 2014a; Zhu et al., 2014). Specifically, Zhang et al. (2020) found that histamine could induce microglial activation and the production of the pro-inflammatory cytokines TNF-α and IL-1β that was partially negated with H1 and H4 receptor antagonists and stimulated with H1 and H4 receptor agonists. On the other hand, H2 and H3 receptor antagonists led to significant increases in TNF-α and IL-1β, and H2 and H3 receptor agonists significantly increased the release of the anti-inflammatory cytokine interleukin-10 (IL-10). This is further supported by both Chen et al. (2020) who found that H2 and H3 receptor agonism inhibited laparotomy- or LPS-induced microglial activation, pro-inflammatory cytokine production and cognitive decline and by Fang et al. (2020) whereby H4 receptor antagonism reduced microglial activation and TNF-α release in a rat model of Parkinson’s disease. Along with histamine’s ability to induce microglial activation and the subsequent release of both anti- and pro-inflammatory factors, it can also promote phagocytosis via H1 receptor activation and the production of reactive oxygen species (Rocha et al., 2016) and prostaglandin E2 (Lenz et al., 2018). Overall, these findings highlight the pleiotropic nature of the microglia in mediating their immune response and suggest potential roles for histamine in regulating microglial-mediated inflammation. What remains poorly studied though, is which sources of histamine within the CNS may contribute to both microglia-mediated neuroinflammation and altered neurodevelopment. What Are Astrocytes? Astrocytes are the most numerous cell type found within the CNS, forming complex networks with neuronal and non-neuronal cells alike. They are dynamic cells that have a wide range of functions and are fundamental for brain homeostasis (Nedergaard et al., 2003; Escartin et al., 2021). During early neurodevelopment, astrocytes have a trophic effect, facilitating the generation and migration of neuronal cells, facilitating synaptogenesis and the creation and maintenance of neuronal circuits (Ricci et al., 2009). One astrocyte can communicate with multiple neurons, with most of these structures being tripartite in nature; structural units formed of pre- and postsynaptic components of two neurons and an astrocyte (Araque et al., 1999; Halassa et al., 2007; Cavaccini et al., 2020). They can sense and respond to changes in the local microenvironment (e.g., local neurotransmitters) to control neuronal signaling (Wahis et al., 2021) and protect neurons from oxidative damage and neuronal injury. They are also important in energy metabolism (Brown and Ransom, 2007; Parra-Abarca et al., 2019), ionic homeostasis (Olsen et al., 2015), blood flow regulation (Howarth, 2014) and the formation of the blood brain barrier and can release gliotransmitters such as adenosine triphosphate (ATP), glutamate and D-serine (Parpura et al., 1994; Zhang et al., 2003; Volterra and Meldolesi, 2005; Hamilton and Attwell, 2010). Astrocytes and Neuroinflammation There is a growing evidence to suggest that astrocytes can modulate the immune system within the CNS and are important in regulating neuroinflammation (Rothhammer and Quintana, 2015). We have already discussed that neuroinflammatory processes can have both protective or detrimental effects on the developing brain. So too can astrocytic activation (Cekanaviciute and Buckwalter, 2016). Astrocyte activation can lead to the release of trophic factors such neurotrophin-3 (NT-3), glial cell line-derived neurotrophic factor (GDNF) and BDNF (Jurič et al., 2011; Thomsen et al., 2017). These growth-promoting molecules promote neuronal survival and GDNF has also been shown to inhibit microglial activation (Ossola et al., 2011; Rocha et al., 2012) resulting in a dampening down of neuroinflammation. Conversely, astrocytic activation can also lead to pro-inflammatory cytokine release, alongside increased concentrations of chemokines and reactive oxygen species and microglial activation (Sochocka et al., 2017) resulting in increased excitotoxicity, apoptosis and neurodegeneration. The mechanisms underlying the induction of a specific neuroinflammatory process remains poorly understood. Recent cutting-edge approaches have started to describe key target molecules important for the interactions between astrocytes and microglia in these neuroinflammatory processes (Clark et al., 2021). It is hoped that improved understanding of astrocyte-microglia cross-talk may then reveal new potential therapeutic targets for modulation that could be relevant in an array of neurodevelopmental disorders. Histamine’s Regulation of Astrocytes The H1, H2, and H3 receptors are expressed on astrocytes (Jurič et al., 2016) (see Figure 2), though H3 receptor expression may be restricted to certain brain regions and may vary depending on the species that is studied (Karpati et al., 2018). Our current understanding of how astrocytes can respond to histaminergic activity in the brain originated over three decades ago (Hosli and Hosli, 1984; Hosli et al., 1984) and continue to be investigated. For example, Karpati et al. (2018) employed the human astrocytoma cell line 1321N1 to better establish the underlying mechanism and found that histamine can interact with astrocytic histamine receptors resulting in glutamate release in an H1 receptor-dependent and concentration-dependent manner suggesting that histamine can form part of neuron-astrocyte communications. There is less data available if and how histaminergic activity might influence astrocytic immunomodulation. Some studies have shown that histamine can act synergistically with pro-inflammatory cytokines such as IL-1 (Lipnik-Stangelj and Carman-Krzan, 2006) and IL-6 (Lipnik-Štangelj and Čarman-Kržan, 2005; Ales et al., 2008) to modulate astrocytic release of neurotrophins such as NGF. For example, Xu et al. (2018) investigated the role of histamine on astrocytic neuromodulation and neuroprotection. They found that histamine selectively upregulated the expression of H1, H2, and H3 receptors, stimulated the synthesis of astrocytic GDNF and inhibited the production of pro-inflammatory cytokines, TNF-α and IL-1β in a concentration-dependent manner. The increased production of neurotrophic factors likely highlights an important mechanistic role in CNS recovery from injury by promoting neuronal survival and synaptogenesis (Lipnik-Stangelj and Carman-Krzan, 2004; Jurič et al., 2011; Xu et al., 2018). We have already discussed that released GDNF can inhibit microglial activation in vivo and in vitro, thereby revealing a possible interaction between these glial cells in modifying (microglial-mediated) neuroinflammation (Rocha et al., 2012; Zhang et al., 2014). In addition see also recent findings suggestive of purinergic signaling from astrocytes to microglia upon histaminergic stimulation (Xia et al., 2021). Moreover, changes in astrocyte-neuronal crosstalk have been implicated in the development of mental disorders, including depression, ASD and schizophrenia (Roman et al., 2020). However, to our knowledge, there are no studies that have investigated the specific role of histamine in directly modulating astrocytic behavior contributing to neurodevelopmental disorders. Mast Cells as a Non-neuronal Source of Histamine Mast cells are immune cells derived from hematopoietic precursors, originating within the bone marrow from CD34+/CD117+ pluripotent progenitors (Gilfillan et al., 2011). They then mature within the microenvironment of various tissues, including the vascular endothelium and the brain, where they participate in both innate and adaptive immune responses, even in the absence of antigen presentation (Dong et al., 2014b). Mast cells in general express H1 and H4 receptors, which have been implicated in the pathophysiology of peripheral type 1 hypersensitivity reactions and increased histamine and cytokine generation, respectively (Thangam et al., 2018) and guide chemotaxis (Hofstra et al., 2003; Halova et al., 2012). However, their expression in brain mast cells has yet to be confirmed. Mast cells are located in perivascular regions within close vicinity of neurons, especially in the hypothalamus, the pineal and pituitary glands (Theoharides, 2017), velum interpositum below the hippocampus (Panula et al., 2014), the meninges (Reuter et al., 2001; Galli et al., 2005a) and are able to cross the normal blood brain barrier (Silverman et al., 2000). The ability to traverse the blood brain barrier may be accentuated further by disease states affecting its integrity which can intimately be linked to mast cell activation and contribute to neuroinflammation and neurotoxicity (Theoharides et al., 2012), including during periods of neurodevelopment. Approximate mast cell numbers in the developing rodent brain have recently been described and are mainly localized to the pia mater and the thalamus. Within the pia mater, mast cells are most numerous during early development, with approximately 3,500 seen at birth, peaking at approximately 5,000 at postnatal day 11. Numbers then decline to approximately 1,500 at P15, though the remaining mast cells become more concentrated in the pia that overlies the anterior thalamus. The total numbers of mast cell within the pia then reach adult levels of approximately 50 by P30. Within the thalamus, around 140 mast cells are seen at P8, which then steadily increases to reach adult values of 1,500 at P30 (Khalil et al., 2007; Panula et al., 2014). Mast cells produce a range of mediators, some of which are preformed, whereas others are synthesized upon activation. These mediators include the biogenic amines histamine and serotonin, cytokines, specifically IL-1, IL-6, TNF-α, interferon-γ (IFN-γ), TGF-β, enzymes such as phospholipases, chymase, and mast cell proteases and tryptase, lipid mediators such as leukotrienes and prostaglandins, growth factors, nitric oxide, heparin, ATP and neuropeptides (Johnson and Krenger, 1992; Skaper et al., 2001; Dong et al., 2014b). Despite their small numbers they can affect numerous processes in the brain that have a potentially underestimated impact on neuroinflammation (see Figure 2). Preformed mediators may be released from secretory granules within seconds, followed by de novo formation of lipid mediators, cytokines and chemokines (Galli et al., 2005b; Nelissen et al., 2013; Silver and Curley, 2013). Mast cells are a heterogeneous cell type, with wide variation in mediator synthesis and release and a wide response in signaling pathways (Dong et al., 2014b) some of which seems to depend on histamine synthesis by mast cells itself (Ohtsu et al., 2001). Mast cells are an important source of histamine in the brain, with up to 50% of brain histamine levels in rodents attributable to the presence of mast cells (Yamatodani et al., 1982). This was established using high-performance liquid chromatography in mast cell deficient (KitW/Wv) mice compared to controls at 2–4 months after birth (Yamatodani et al., 1982). Such mice have reduced c-kit tyrosine kinase-dependent signaling, leading to impaired mast cell development and survival (Kitamura et al., 1978; Grimbaldeston et al., 2005). These mice are profoundly deficient in mast cells, with adult mice containing no detectable mast cells across numerous anatomical sites by 6–8 weeks of age (Kitamura et al., 1978). Mast Cell Interactions With Microglia Mast cells are a non-neuronal source of histamine that can be released upon degranulation. We have already discussed the role of histamine-mediated microglial activation and the release of the pro-inflammatory cytokines IL-6 and TNF-α in vitro via H1 and H4 receptors and MAPK and PI3K/AKT pathway activation (Dong et al., 2014a). Other implicated pathways include the complement 5a receptor and chemokine receptor 4/12 (CXCr4 and CXCL12) (Dong et al., 2014a) and the chemoattractant, C-C Motif Chemokine Ligand 5 (CCL5) (Hendriksen et al., 2017). We can therefore see an array of in vitro evidence for bidirectional interactions between mast cells and microglia in regulating neuroinflammation some of which are highlighted below (see also Figure 2).Dong et al. (2017) provided the first data on in vivo mast cell-microglial interactions, demonstrating that activation of brain mast cells by injecting the mast cell degranulator, C48/80 directly into the hypothalamus triggered microglial activation and the release of the pro-inflammatory cytokines, IL-6 and TNF-α. In turn, this was opposed by mast cell stabilization using sodium cromoglycate. Indeed, this resulted in a decrease in pro-inflammatory cytokines and reduced expression of the innate immune protein, toll-like receptor 4 (TLR4), and H1 and H4 receptors on the microglia. In turn, there was no effect on microglial activation in mast-cell deficient KitW–sh/W/–sh mice. Similar to the KitW/Wv mice discussed previously, these mice have reduced c-kit tyrosine kinase-dependent signaling, leading to impaired mast cell development and survival (Kitamura et al., 1978; Grimbaldeston et al., 2005). However, the specific mutation used is thought to lead to fewer developmental abnormalities that the KitW/Wv model while still retaining the desired mast cell deficiency (Yamazaki et al., 1994; Grimbaldeston et al., 2005). The findings by Dong et al. (2017) are important not only in confirming an interaction between mast cells and microglia in vivo, but also in highlighting the importance of mast cell degranulation for this interaction. Given that mast cell activation may be the first responder to injury (Jin et al., 2009b), and not the microglia, inhibition of mast cell activation may inhibit the pro-inflammatory cascade and therefore protect against neuroinflammation. What remains poorly understood is the contribution and role of histamine, if any, in this interaction. However, as the altered microglial expression of the H1 and H4 receptors depends on the activation state of mast cells (Dong et al., 2017) this may be suggestive that mast cell sources of histamine, not just neuronal sources, are crucial in the initiation of neuroinflammation. Mast Cell Interactions With Astrocytes and Neurons As well as mast cell-microglial interactions, there is some emerging evidence that mast cells may have direct interactions with CNS neurons and astrocytes as outlined below. Indeed, mast cells tend to co-localize with neurons (Skaper et al., 2012; Silver and Curley, 2013) or even to strongly adhere to neurons (Hagiyama et al., 2011). Neuronal release of neuropeptides such as NGF, neurotensin and substance P have been shown to bind directly bind to mast cells, altering their activation state (Kulka et al., 2008). Conversely, mast cells may also communicate with neurons via transgranulation, whereby mast cell granules can be inserted into adjacent neurons that alters neuronal responsiveness to its microenvironment (Wilhelm et al., 2005) (see Figure 3). Kempuraj et al. (2019) investigated such interactions in a mouse model of Parkinson’s disease. They found that mouse mast cell protease-6 and 7 induced the release of interleukin 33 (IL-33) from astrocytes and a mixed culture of glia and neuronal cells. This suggested that mast cells might interact with astrocytes and neurons to accelerate neuroinflammation and neurodegeneration. Kim et al. (2010) investigated the signaling pathways of activated mast cells and their interaction with astrocytes in experimental allergic encephalomyelitis. This was used as a model for the chronic demyelinating disease, multiple sclerosis. Co-culturing of mast cells with astrocytes led to increased release of histamine, leukotrienes and pro-inflammatory cytokines. It does so via enhanced expression of CD40L on mast cells, which is the natural ligand for CD40 expressed on astrocytes. This CD40-CD40L may therefore be important in chronic disease associated with neuroinflammation. Lenz et al. (2018) investigated the role of mast cells, and specifically histamine released from mast cell degranulation on neuronal development in the preoptic area of the hypothalamus. This is a crucial brain region in determining sexual behavior. Mast cell activation with the estrogen steroid hormone, estradiol, was found to stimulate microglial activation, subsequent prostaglandin release which was associated with increased dendritic spine density and the dendritic spine protein, spinophilin, as well as more masculinized sexual behavior. A small number of mast cells therefore had a profound effect on overall brain development and resultant behavior. To our knowledge, there are no further studies that have investigated the effect of mast cell activation and non-neuronal histamine directly on the CNS in vivo. However, bi-directional communication was recently demonstrated between mast cells and neurons in the skin (Zhang et al., 2021), which may demonstrate a role in the mediation of epidermal and dermal inflammation. Mast cell sources of histamine have also been implicated in the pathophysiology of neuropathic pain (Rosa and Fantozzi, 2013). https://www.frontiersin.org/articles/10.3389/fnins.2021.680214/full 2. Overview and activation of MCs Although the role of MCs is overlooked compared with microglia, MCs remain an important factor in the immune signaling pathway (29). MCs, the effector cells of the innate immune system, are derived from hematopoietic stem cells and multifunctional antigen-presenting cells and have a pivotal role in immunoglobulin type E (IgE)-associated allergic and inflammation-associated diseases (35). Despite their low numbers in most organs, MCs are present in both healthy and disease states. MCs are the first line of defense against invading pathogens and are distributed in almost all organs and vascularized tissues (36). Blood MCs express CD34 and contain cytoplasmic granules filled with heparin and histamine, the latter of which is released after binding to IgE. Unlike other myeloid-derived cells, tissue MCs have a hematopoietic developmental lineage (37,38). During MC development, immature lineage progenitors enter the circulation and are recruited to peripheral tissues by endothelial cells, regulating the appearance of granules with proteases (37,38). Human MCs may be classified into mucosal and connective tissue types according to the type of proteases present in their cytoplasmic granules; the mucosal type contains tryptase, whereas the connective tissue type contains both tryptase and chymase (39). MCs act as first responders and environmental ‘sensors’ to interact with other cellular elements involved in physiological and immune responses, promoting the neuroinflammation process (40). MCs are present in various areas of the brain and meninges. Although less distributed in the brain, they are generally found in the subthalamic nucleus, choroid plexus and the parenchyma of the hypothalamic region (41). The pathogenic roles of MCs were indicated to extend from allergic disease to autoimmune diseases and carcinogenesis (42-47). The most common way through which MCs perform their function is degranulation. The activation of the inflammatory process results in a rapid release of MC granules into the interstitium. MC granules contain pre-formed and newly synthesized reactive chemicals known as MC mediators. These mediators include histamine, tryptase, chymase, interleukin families, tumor necrosis factor-α (TNF-α), serotonin, heparin, proteoglycans, vascular endothelial growth factor (VEGF), prostaglandins, leukotrienes, chemokines and growth factors, several of these are unique to MCs (42,48). Studies have indicated that MC degranulation may cause cognitive dysfunction (49). Large-scale MC degranulation may cause fatal anaphylaxis; however, most physiological functions of MCs, including regulation of inflammatory processes, occur without complete degranulation (50). MCs are phenotypically and functionally heterogeneous. The pathways and results of MC activation are multifaceted. In addition to IgE, MCs may also be activated through a number of other stimuli, including trauma, other immunoglobulins, complements, toll-like receptors (TLRs), neuropeptides, cytokines, chemokines and other inflammatory products, causing mast cell activation and leading to the selective release of mediators and/or stimulating T-cell proliferation, differentiation and migration (51,52). A characteristic of MC physiology that has been overlooked is that MCs are able to secrete mediators via differential or selective release without significant degranulation. This process may be regulated by the action of distinct protein kinases on a unique phosphoprotein (53). MCs undergo changes in the core of the electron-dense granules but without overt degranulation, a process that has been termed as activation, intragranular activation or piecemeal degranulation (54). MCs are essential for the pathogenesis of numerous inflammatory diseases, but this effect may only be achieved if MCs release selective mediators without degranulation, which may otherwise cause allergic reactions (52). Under normal circumstances, the brain does not express IgE receptor (FcεRI), since the brain does not display any allergic reactions and IgE does not cross the blood-brain barrier (BBB) under normal conditions (55). The ways in which the mediators are secreted depend on the given stimuli and microenvironmental conditions. For instance, serotonin may be selectively released without histamine or arachidonic acid metabolites (56). The combination of TLR4 and mast cells does not cause degranulation but results in the secretion of inflammation-associated mediators. TLR4 binds to the co-receptors CD14 and MD-2 expressed by MCs. Subsequently, activation by myeloid differentiation primary response protein MyD88 innate immune signal transduction adaptor results in activation of interleukin (IL) receptor-associated kinase family members and pyruvate dehydrogenase kinase isoform 1, mitogen-activated protein kinases (MAPKs) p38 and JNK and to phospholipase A2(57). TLR4 also binds to lipopolysaccharides (LPS) and induces TNF-α release without degranulation (58). LPS induces secretion of IL-5, IL-10 and IL-13 but not granulocyte-macrophage colony-stimulating factor, IL-1 or leukotriene C4 (LTC4) (58). The selective release of IL-6 occurs in the MC response to LPS, provided the presence of the PI3K inhibitor wortmannin or stem cell factors (59). Corticotropin-releasing hormone (CRH) was demonstrated to stimulate the selective release of VEGF without degranulation and histamine or tryptase release from the human leukemic mast cell line HMC-1 and human umbilical cord blood-derived mast cells (60). Neurotensin (NT) induces expression of CRH receptor (CRHR)-1 on MCs and NT and CRH are released under stress via NT-CRH crosstalk (61). IL-1 stimulates human MCs to selectively release IL-6 without degranulation, via a unique process utilizing 40-80 nm vesicles unrelated to the length of secretory granules (800-1,000 nm) (62). IL-33 may serve as a potent activator of MCs and was reported to promote MC survival, maturation, migration and adhesion, and to selectively produce a variety of pro-inflammatory cytokines, including IL-4, IL-5, IL-6, IL-8 and IL-13 and chemokines including macrophage inflammatory protein-1α and monocyte chemoattractant protein 1 (MCP-1) (63,64). IL-33 enhances the role of the pro-inflammatory peptide substance P in stimulating human MCs to secrete high levels of VEGF and TNF via the interaction of neurokinin 1 and ST2 receptors without concomitant secretion of tryptase (65). In the presence of stem cell factor, IL-33 may also induce TNF production in MCs via a MAPK-activated protein kinases 2 and 3, ERK1/2- and PI3K-dependent pathways (66). Understanding the selective release of mediators may explain how MCs participate in numerous biological processes and how they are capable of exerting both immunostimulatory and immunosuppressive effects. 3. MC-glia crosstalk Microglia and MCs are the two most important cell types mediating and regulating neuroinflammation in the brain. There is a close association between MCs and glial cells. MCs are generally clustered near the glia in neuroinflammatory conditions to recruit and activate other inflammatory cells, where neuroinflammation already occurs in the brain. The contribution of MCs and glia to neuroinflammation is strongly influenced by the likelihood of their crosstalk and pathological exacerbation (29). MCs may interact with microglia and astrocytes via the complement system, proteases, TLRs and chemokines. MCs may participate in the migration and activation of glia, thereby affecting the release of inflammatory mediators. The expression of ligand-receptor pairings may be upregulated under inflammatory conditions, facilitating chemotactic actions through contact between MC and glia (27). For instance, C5a, the chemoattractant anaphylatoxin peptide and its receptor CD88 are upregulated in the glia of inflammatory CNS tissues (67-69). Complementary expression of the C5a receptor on activated MCs produces an intense chemoattractant signal to the C5a peptide and intense crosstalk between C5a and TLR4, which also has a role in neuroinflammation (67-69). TLRs are a major class of pattern recognition receptors involved in innate immunity. TLRs are associated with groups of pathogens recognized by innate immune system cells, including microglia and MCs, and act as a bridge between non-specific and specific immunity (70). Upregulation of C-C motif chemokine 5 (CCL5; also known as RANTES) by MC activation leads to a pro-inflammatory response in microglia, releasing IL-6 and CCL5, which in turn promotes chemokine expression in MC (71). IL-33 is an activator of MCs and IL-33 release from astrocytes may activate brain MCs and microglia (72). The binding of IL-33 to MC receptors leads to the secretion of IL-6, IL-13 and MCP-1 to regulate microglia activity. Furthermore, IL-33 may be stimulated from microglia pre-activated with pathogen-associated molecular patterns via TLRs (73,74). Together, MC protease and matrix metalloproteinase (MMP) activate p38, ERK1/2, MAPKs and transcription factors including NF-κB in astrocytes, microglia and MCs (75). IL-6 and TNF-α released from microglia upregulate protease-activated receptor 2 (PAR2) expression in MCs, causing MC activation and TNF-α release (76). MC tryptase may induce the release of pro-inflammatory mediators such as TNF-α, IL-6 and reactive oxygen species (ROS) via the PAR2/MAPK/NF-κB signaling pathway and activation of PAR2 receptors on MCs, which then contributes to the development of microglia-mediated inflammation in the brain (77). IL-6 induces IL-13 release from MCs, affecting the expression of TLR2/TLR4. Furthermore, TNF-α upregulates PAR2 expression in MCs and enhances PAR2-mediated MC activation and degranulation (78-80). C-X-C chemokine receptor type 4 (CXCR4; also known as stromal cell-derived factor 1) is an MC chemotaxin and studies have indicated that CXCR4 is upregulated in hypoxia and ischemia, promoting the migration and activation of microglia (81). In addition to microglia, astrocytes sharing a perivascular localization with MCs maintain the viability of MCs. Astrocytes express histamine receptors and release cytokines/chemokines through Rho-family GTPases/Ca2+-dependent protein kinase C isoforms, MAPK, NF-κB and signal transducer and activator of transcription 1 (82-84). These trigger MC degranulation and enhance CD40L and CD40 surface expression, leading to further inflammation (82-84). Both microglia and astrocytes express histamine receptor H1 (HRH1), HRH2 and HRH3 and MCs may affect the activity of microglia and astrocytes through these receptors (85,86). An in vitro study has indicated that MC proteases may induce demyelination and apoptosis of oligodendrocytes, while myelin promotes MC degranulation (87). Several experiments have confirmed the relationship between MCs and glia. Co-culture of microglia and HMC-1 cells revealed that activated HMC-1 cells stimulate the activation of microglia and subsequent production of pro-inflammatory factors TNF-α and IL-6(88). MC degranulator compound 48/80 induces microglia activation and inflammatory cytokine production, triggering an acute brain inflammatory response. However, the MC stabilizer cromolyn inhibits this effect, reduces inflammatory cytokines and inhibits the MAPK, AKT and NF-κB signaling pathways. Furthermore, cromolyn inhibits HRH1, HRH4, protease activity, PAR2 and TLR4 in microglia (49,89). Incubation of astrocytes and neurons with 1-methyl-4-phenylpyridinium, glia maturation factor (GMF), mouse MC protease-6 (MMCP-6) and MMCP-7 increased PAR-2 expression, suggesting contact between MCs and astrocytes (90). 4. MC-neuron interactions The connection between MCs and neurons mainly occurs through peripheral interactions. A number of studies have revealed the association between MCs and neurons in CNS neuroinflammation. In the brain, the co-localization of MCs and neurons provides a basis for neuroimmunological interactions. Cell adhesion molecule-1 (CADM1), expressed by mature hippocampal neurons, may have an important role in the development of MC neuron interactions (91). In the CNS, MC-derived products may enter adjacent neurons to insert their granular contents, a process known as granulation. In this way, MCs change the internal environment of neurons, presenting a novel form of neuroimmunological interaction (92). In addition, MCs express a series of neurotransmitter receptors, which may be directly activated, enhanced [neurokinin 1 receptor (NK1R), NK2R, NK3R and VIP receptor type 2] or inhibited (acetylcholine receptor) (93,94). Furthermore, it was reported that activated MCs enhanced excitotoxic damage to 60% when co-cultured with hippocampal neurons. In N-methyl-D-aspartate receptor-mediated synaptic neurotransmission, MC-derived histamine directly increases the death of hippocampal neurons (95). Tryptase released by MCs may directly activate proteinase-activated receptors on neurons and MC-derived TNF-α has a vital role in neuronal development, cell survival, synaptic plasticity and ionic homeostasis in the CNS (96). These MC-neuron interactions are thought to be involved in the pathogenesis of numerous neuroinflammatory diseases. 5. MCs and the HPA axis The association between chronic stress and neuroinflammation has been confirmed by numerous studies. MCs have a vital role in the mechanism of brain damage caused by chronic stress on the brain. A variety of psychological and physiological stresses may lead to changes in the expression, distribution and activity of MCs in the CNS. Stress and pro-inflammatory cytokines activate the HPA axis, thus leading to an increase in CRH and arginine vasopressin release from the paraventricular nucleus of the hypothalamus. HPA axis activation also enhances the expression of CRH receptors, vascular permeability and MC activation (97). CRH released from MCs activates MCs and glia in the CNS in an autocrine and paracrine manner in the context of stress and neuroinflammation (98). In turn, activation of CNS MCs activates the HPA axis. MCs are located near CRH-positive neurons in the median eminence and are closely linked to corticotropin-releasing factor receptors, which may be activated by CRH (99). This may be closely associated with the meningeal vasodilation and increased secretion of cytokines during meningeal inflammation in migraines (46). Cao et al (100) indicated that intravesical stress, CRH, MC activation and VEGFs have a crucial role in the stress-induced deterioration of inflammation, which may provide insight into the mechanism of brain stress. MC activation and CRH release increase BBB permeability, leading to further brain damage and contributing to chronic neuroinflammation in the brain (60,101). Microglia express CRH receptors and activation of microglia by CRH leads to the release of harmful inflammatory mediators in psychiatric diseases, such as AD and pain (102,103). Human MCs synthesize and secrete CRH and express functional CRH receptors (CRHR1 and CRHR2) (104). CRHR1-mediated activation of microglia induces microglia proliferation, TNF-α release and activation of MAPK. CRHR1 also mediates stress-induced MC degranulation (105). CRH release from activated MCs may also activate glial cells in neurodegenerative diseases such as AD (103,106). Stressful conditions, including trauma or hypoxia, also activate peripheral MCs, which in turn activate CRH and substance P pathways, leading to BBB leakage and glial activation, causing further neuroinflammation and neurodegeneration (107). CRH concentrations are higher in brain regions prone to developing a pathology of AD (108). Elevated cortisol levels and HPA axis dysfunction are implicated in chronic stress, which releases amyloid beta (Aβ) that causes and/or worsens AD (109). CRHR1 antagonists have been indicated to decrease stress-mediated oxidative damage, prevent cognitive damage and loss of dendritic cells and reduce Aβ deposition in the brain (110). These results confirm the correlation between CRH and AD. Other neuropeptides, including NT, may work with CRH to enhance MC activation and release of excessive inflammatory mediators under stress (61). CRH may enhance VEGF release from human MCs and induce FcεRI expression in MCs, and this effect may be blocked by the natural flavone luteolin (111). CRH is also implicated in the pathogenesis of PD. Emotional chronic stress, which is closely associated with CRH, enhances glial activation and aggravates neuronal death through inflammation in the substantia nigra of the brain of patients with PD (107). Furthermore, observations in animal models of PD indicate that stress-induced striatal damage may subsequently worsen motor symptoms (112). 6. MCs and the BBB The BBB is composed of functional cerebral blood vessels, which create a stable CNS environment and protect brain parenchymal cells from harmful substances in the immune cells and blood. The BBB consists of tightly connected endothelial junctions and several intact transmembrane proteins, including claudin and occludin, that ensure its integrity. The basal lamina, which is part of the extracellular matrix, connects the endothelial cells of the BBB to adjacent cell layers (113). BBB destruction involves the accumulation of multiple vascular and neurotoxic molecules within the brain parenchyma, decreased cerebral blood flow and hypoxia (114). MCs are present in the dura mater and meninges, as well as on the cerebral side of the BBB, and MCs are in contact with the distal ends of the astrocytes (115). MCs may cross the BBB and blood-spinal cord barrier when the barrier is damaged by CNS pathologies. Inflammatory factors released by MC activation, including histamine, tryptase, chymotrypsin and TNF-α, may regulate BBB permeability (116). Furthermore, TNF-α induces the expression of intercellular adhesion molecule 1 (ICAM-1) and allows leukocytes to enter the affected tissues in the brain (117). The me chanism by which MCs destroy the BBB and promote basal layer degradation may involve vascular activity and matrix degradation components of MCs. MCs affect the integrity of the BBB through MMPs, whose enzymatic activity may be regulated by tissue MMP inhibitors. These include histamine and protease chymase, trypsin and cathepsin G (118). Cathepsin G activates MMPs, which degrade most of the protein components of the neurovascular matrix (118). In cerebral ischemic disease, MC degranulation increases, and brain MCs affect the activation of acute microvascular gelatinases (MMP-2 and -9) by releasing proteases to affect BBB destruction. In addition, elevated levels of VEGF may cause BBB rupture, vascular leakage and edema, which in turn causes stroke (119,120). This process extravasates glutamate and albumin, activates astrocytes, alters K+ homeostasis in the brain parenchyma and leads to excessive neuronal excitation and inflammatory cell entry (119,120). In experimental autoimmune encephalomyelitis (EAE), activation of meningeal MCs leads to TNF-α production and early neutrophil recruitment (121). This promotes local BBB destruction, allowing initial immune cells to enter the CNS and aggravate neuroinflammation (121). An in vitro study revealed that TNF-α induces downregulation of tight junction proteins occludin, claudin-5 and vascular endothelial-cadherin via an increase in ROS, which leads to increased paracellular permeability (122). IL-6 participates in the effect of TNF-α on endothelial monolayers. TNF-α upregulates the expression of ICAM-1 and vascular cell adhesion molecule-1 on brain microvascular endothelial cells (123). ICAM-1 is involved in leukocyte adhesion to the endothelium and its upregulation and leukocyte-mediated BBB breakdown are one of the pathological mechanisms and characteristics of various brain inflammatory diseases, including MS (123). Brain MCs may induce post-operative cognitive dysfunction by destabilizing the BBB and acute stress may cause BBB breakdown by activating MCs (88,124). In addition to cerebral ischemia, BBB destruction has also been detected in dementia, motor neuron disease, MS, AD and other neuropsychiatric disorders (125-128). Substance P, which is released following traumatic brain injury or under stress, activates MCs and glia, releasing neuroinflammatory mediators and increasing BBB permeability (129). The release of CRH from MCs contributes to the subsequent release of various neuroinflammatory and neurotoxic mediators, leading to BBB rupture and glial cell activation, chronic neuroinflammation in the brain and causing autism (130). Cromoglycate, a MC-stabilizing agent, reversed BBB destruction, brain edema and neutrophil recruitment post-ischemia by inhibiting MC activation in a stroke model (131). https://www.spandidos-publications.com/10.3892/etm.2020.8789 In summary, the results presented here are the first to reveal the function of MMP3 in the BBB and suggest that it has an essential role in the brain microvasculature that differs from its function in other vessels. We have shown that MMP3 increases BBB permeability by upregulating the ERK signaling pathway, which subsequently reduces TJ and AJ protein abundance in BMVECs. Oxidative stress often leads to impairment of BBB. Since the BBB is the primary regulator of exchange between the peripheral blood and the brain, our observations likely have important implications for treating neuroinflammatory conditions and other CNS disorders involving the endothelial MMP3 pathway. https://www.hindawi.com/journals/omcl/2021/6655122/ 4.1. Mast Cells: Guardians of Homeostasis in the Brain Although they are often described in the context of pathology and disease, mast cells are likely important regulators of homeostasis, since mast cell mediators can have both beneficial and harmful effects depending on the context in which they are deployed. This may also be the case in the brain. For example, activated mast cells rapidly release a series of immunomodulatory molecules, such as histamine and TNF-α. In organotypic slice cultures and primary rat astrocyte-neuron co-cultures, exogenously added histamine was shown to protect hippocampal neurons against glutamate-induced excitotoxicity [63]. Neuroprotection was mediated by increased expression of astrocytic glutamate transporter-1 (GLT-1), probably due to reduction in extracellular glutamate levels. Mast cell-derived proteases and proteoglycans also might provide neuroprotection [64]. In a mouse model of ischemic injury, TNF-α was shown to promote the survival of hippocampal and striatal neurons, probably acting via its receptor (tumor necrosis factor receptor 2 (TNFR2)) [65]. The protective or detrimental effects of TNF-α might depend on the concentration and duration of release as well as receptor binding (TNFR1 vs TNFR2) [66]. Intracerebral mast cell secrete proteases, vasoactive molecules such as nitric oxide, lipid mediators, histamine, gonadotropin-releasing hormone and TNF-α which can increase BBB permeability by breaking down the tight junctions between brain endothelial cells [67]. Thus in pathological situations, mast cells appear to operate in a feed-forward mechanism; loss of BBB integrity might activate meningeal mast cells to recruit inflammatory cells to the CNS, leading to a vicious cycle of neuroinflammation [68]. These findings suggest that the beneficial or detrimental effects of mast cells to brain health might be dependent on several factors, including levels and time of cytokine release and the magnitude of the initial insult. A growing number of recent studies have shown that under pathological conditions, microglia activates a defense program and transition from the ‘homeostatic state’ into the ‘disease-associated’ state and during disease progression might “lose control” and transition into a ‘neurodegenerative-disease state’ and become dysfunctional and destructive to the CNS [50,77]. Microglia from each disease-associated state express a unique transcriptional signature [78,79]. Whether microglia exacerbate or inhibit disease progression is still being actively debated, with both beneficial and detrimental roles ascribed to these cells in neurodegeneration [80]. Under pathological state, microglia continuously release excessive amounts of pathogenic pro-inflammatory mediators, excitatory amino acids (e.g., glutamate), complement activation products, proteolytic enzymes and RNOS, which, in turn, generates oxidative stress [84]. Exposure of in vitro neuronal-glia cultures to glutamate resulted in oxidative stress and neurotoxicity [85]. Microglia respond to misfolded β-amyloid by producing RNOS, notably superoxide anions via the NADPH oxidase. These reactive species can be inactivated by extracellular SOD to produce hydrogen peroxide, which can be further detoxified by the antioxidant defense systems, namely SOD, GPX, PRX, and HO [82]. Superoxide can also react rapidly with nitric oxide to produce peroxynitrite, a potent oxidizing and nitrating agent [86]. Interestingly, NADPH oxidase activity is increased in activated microglia in early stage AD patients as compared to age-matched controls [87]. Mast cells and microglia are found in close proximity to each other in the CNS, facilitating active communication. Mast cells likely use their surface receptors, adhesion molecules and ‘mast cell mediators’ to engage in a complex cross-talk with other brain-resident cells, which could be both unidirectional and bidirectional. Increasing evidence suggests that the initiation and propagation of neuroinflammation relies on the interactions between these cell types. Mast cells also express several costimulatory and inhibitory surface molecules that allows them to communicate with other immunocompetent cells, such as T-cells and B-cells, positioning them as a main bridge between innate and adaptive immunity [37,100]. Activated brain mast cells release histamine that can cause phenotypic changes and activation of microglial cells [101]. Exogenously added histamine triggered activation of cultured primary cortical microglia, murine N9 microglia and hippocampal organotypic slice cultures to secrete TNF-α and IL-6 and RNOS [102,103]. Although histamine stimulated microglial cell motility in control microglia, histamine inhibited microglial migration and IL-1β release in LPS-stimulated microglia, suggesting a dual role of histamine in modulating microglia-induced inflammatory responses [102,104]. Histamine exerts its functions by signaling through four types of G-protein coupled receptors, namely Histamine 1 receptor (H1R), H2R, H3R, and H4R, which are expressed on innate immune cells, neurons and endothelial cells [105]. In these cultures, the anti-inflammatory effects of histamine were mediated by activation of H4R which involved α5β1 integrin, p38 and protein kinase B (AKT) signaling to restrain exacerbated microglial responses in neuroinflammation [102]. All four types of histamine receptors are expressed by microglial cells and can modulate microglia-mediated neuroinflammation [104]. Rocha SM et. al., directly injected histamine into the substantia nigra of mice and studied its effects on microglial activity and dopaminergic neuron survival [106]. In accordance with other studies, histamine induced microglial activation and dopaminergic neuronal toxicity via H1R activation, probably through NADPH oxidase dependent oxidative stress signaling pathways and microglia phagocytosis. Altogether, these studies show that histamine per se triggers a pro-inflammatory response and under inflammatory conditions, histamine activates an anti-inflammatory response, dampens microglial-induced inflammation and is associated with neuroprotection. Similar to peripheral mast cells, brain mast cells are also known to secrete proteases, such as tryptase. Exposure of primary microglia to mast cell-derived tryptase stimulated microglia to subsequently secrete TNF-α and IL-6 and RNOS. These effects were mediated by protease-activated receptor-2 (PAR-2) signaling via activation of mitogen-activated protein (MAP) kinase (Erk and p38) and NF-kappa B (NF-kB) pathways [68]. Furthermore, PAR-2 activation induces the expression of ATP-sensitive ionotropic P2X4 receptors on microglia and exposure to ATP leads to secretion of BDNF, a potent trophic factor [107]. The presence of functional P2X4 receptors are also expressed by human mast cell lines [108]. Since mast cells play a pivotal role in neuroinflammation, it is important to determine the exact molecular mechanisms employed by activated mast cells and microglia and their role in disease progression. Mast cell-derived pro-inflammatory cytokines such as CCL2, TNF-α and IL1β can also influence microglia activation. To recapitulate in vitro mast cell-glia-neuron crosstalk during neuroinflammation, mast cells were cocultured with mixed cultures of neuron and glia or enriched cultures of neurons or astroglia and challenged with MPP+ or GMF or mast cell proteases [109]. Mast cells cocultured with glia had increased production of CCL2 and IL-33, highlighting the importance of mast cell-glia coupling and their role in neuroinflammation [110]. Increased CCL2 levels have been demonstrated in AD patients which is associated with accelerated cognitive decline and AD progression [111]. CCL2 expression altered β-amyloid phagocytosis, supporting the notion that microglial phagocytosis could be regulated by mast cells [112]. Although there is no direct evidence of CCL2 expression in the brain of PD patients, increased serum levels of CCL2 have been reported [113]. Recently, two polymorphisms have been reported in the promoter region of CCL2 which are associated with an increased risk of PD [114]. The exact role of CCL2-CCR2 axis in regulating mast cells and microglia in neurodegenerative diseases is still not well understood. Mast cell degranulation has been shown to activate microglia. Stereotaxic injection of a mast cell degranulation compound 48/80 (C48/80) and activator of the mas-related G protein-coupled receptor Mrgpr [115] in the hypothalamus of rats induced mast cell degranulation, production of pro-inflammatory cytokines and microglia activation [103]. These effects were mediated by activation of MAP kinase and AKT pathways and an increased protein expression of H1R, H4R, PAR-2 and TLR4 on microglial cells. Treatment with a mast cell stabilizer disodium cromoglycate (cromolyn), inhibited microglial activation and downstream signaling, suggesting mast cell involvement. Most importantly, C48/80 had no effect on microglial activation in mast cell-deficient Kitw-sh/w-sh mice. These data support the notion that stabilization of brain mast cells during neuroinflammation could be a new therapeutic strategy to restrain microglial hyperactivity. Tranilast has been used to inactivate the NLR family pyrin domain containing 3 (NLRP3) inflammasome, yet is also used as an anti-allergy medication as a “mast cell stabilizer” [116] suggesting that its effect in the brain may also modulate mast cell functions via the inflammasome. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865982/ TNF released by microglia has an important role in regulating synaptic plasticity [110]. Specifically, it controls a process called synaptic scaling, i.e., the adjustment of synaptic strength in response to prolonged changes in the electrical activity of neurons [110,111]. Indeed, a reduction of glutamate transmission increases microglial TNF release, which promotes the expression of AMPA glutamate receptors in neurons. Conversely, increased extracellular glutamate concentration inhibits TNF release from microglia, additional glutamate receptor expression, and declines neuronal activity [111–113]. The increase of AMPA receptor GluR1 subunit expression does not occur at mRNA level, but this is controlled by TNF at post-transcriptional level [114]. Subsequent studies revealed that TNF facilitates the trafficking and membrane insertion of AMPA receptors at the neuron surface, which are crucial for the homeostatic synaptic plasticity. Specifically, hippocampal neurons exposed to TNF increase surface expression of GluR1 subunit through modulation of NF-κB and acid sphingomyelinase pathways [115]. TNF not only controls homeostatic synaptic activity, but also induces neurotoxicity via autocrine/paracrine loops involving other endogenous mediators. First, TNF activates TNFR1 on microglia, amplifying its production and release [95]. Second, microglia-derived TNF activates TNFR1 expressed on astrocytes, allowing glutamate release from the glial cells. This, in turn, activates its specific receptors, including the metabotropic mGluR2 receptor on microglia, potentiating microglial TNF production and affecting synaptic transmission [110]. ATP, released by microglia concurrently with TNF, contributes to TNF-mediated neuronal damage by inducing a prolonged activation of microglial P2X7 receptor and release of both IL-1β and TNF inflammatory cytokines. In addition, both microglial TNF and ATP trigger adjacent astrocytes to release additional ATP, that amplifies microglia response and promotes astroglial release of glutamate, aggravating neuronal dysfunction [110]. Moreover, TNF mediates neuronal death by increasing extracellular levels of the excitotoxic transmitter glutamate and excessive AMPA receptor activation via downregulation of the astrocytic glutamate transporter EAAT2/GLT1 [116]. The effects of TNF on N-methyl-D-aspartate receptors (NMDARs) trafficking are less characterized. However, it has been demonstrated that, in hippocampal neurons, TNF increases the expression of the NR1 subunit of NMDAR and its specific clustering into lipid rafts [117]. Accordingly, treatment of human neuronal cultures with competitive (2-APV) and noncompetitive (MK-801) NMDA receptor antagonists reduced the glutamate neurotoxicity induced by TNF [118]. https://www.mdpi.com/2073-4409/9/10/2145/pdf Interleukin-1β Causes Anxiety by Interacting with the Endocannabinoid System 1. increase in IL-1b proinflammatory cytokine 2 decrease in cb1 recebtor binding 3. decreases CB1R's (gabaA) synapse binding in striatum 4. causes behavioral manifestations closely resembling anxious-depressive symptoms in humans, including anhedonia, reduced exploratory behaviors, social withdrawal, fatigue, and sleep disturbances 5. This entire process requires "intact function of the transient receptor potential vanilloid 1 (TRPV1)" to work. ----- IL-1beta, but not IL-10 or tumour necrosis factor (TNF)-alpha, down-regulated the surface expression and Ser831 phosphorylation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1. Agents that block IL-1beta receptor activity abolished these effects. In contrast, no change in the surface expression of the N-methyl-d-aspartate (NMDA) receptor subunit NR1 was observed. The inhibition of NMDA receptor activity or depletion of extracellular calcium blocked IL-1beta effects on GluR1 phosphorylation and surface expression. NMDA-mediated calcium influx was also regulated by IL-1beta. These findings suggest that IL-1beta selectively regulates AMPA receptor phosphorylation and surface expression through extracellular calcium and an unknown mechanism involving NMDA receptor activity. Interleukin-1 beta modulates AMPA receptor expression and phosphorylation in hippocampal neurons -- Losing Connections, Losing Memory: AMPA Receptor Endocytosis as a Neurobiological Mechanism of Forgetting https://www.jneurosci.org/content/36/29/7559 ---] Functional role of the endocannabinoid system and AMPA/kainate receptors in 5-HT2A receptor-mediated wet dog shakes. AMPA/kainate receptors play a role in the mediation of 5-HT2A receptor activity, whereas the endocannabinoid system may act as a regulatory buffer system during periods of elevated activity, but not under basal conditions. https://www.sciencedirect.com/science/article/abs/pii/S0014299905004334 The prefrontal cortex (PFC) plays a key role in many high-level cognitive processes. It is densely innervated by serotonergic neurons originating from the dorsal and median raphe nuclei, which profoundly influence PFC activity. Among the 5-HT receptors abundantly expressed in PFC, 5-HT2A receptors located in dendrites of layer V pyramidal neurons control neuronal excitability and mediate the psychotropic effects of psychedelic hallucinogens, but their impact on glutamatergic transmission and synaptic plasticity remains poorly characterized. Here, we show that a 20-min exposure of mouse PFC slices to serotonin or the 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) produces a long-lasting depression of evoked AMPA excitatory postsynaptic currents in layer V pyramidal neurons. DOI-elicited long-term depression (LTD) of synaptic transmission is absent in slices from 5-HT2A receptor-deficient mice, is rescued by viral expression of 5-HT2A receptor in pyramidal neurons and occludes electrically induced long-term depression. Furthermore, 5-HT2A receptor activation promotes phosphorylation of GluA2 AMPA receptor subunit at Ser880 and AMPA receptor internalization, indicating common mechanisms with electrically induced LTD. These findings provide one of the first examples of LTD gating under the control of a G protein-coupled receptor that might lead to imbalanced synaptic plasticity and memory impairment following a nonphysiological elevation of extracellular serotonin. Sustained Activation of Postsynaptic 5-HT2A Receptors Gates Plasticity at Prefrontal Cortex Synapses - ---- Seven days post-intervention, there was still significantly higher SV2A density in hippocampus (+9.24%) and PFC (+6.1%) whereas there were no longer any differences in 5-HT2AR density. Our findings suggest that psilocybin’s antidepressive actions are linked to increased persistent synaptogenesis and possibly also to an acute decrease in 5-HT2AR density. A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT2A Receptor Density in the Pig Brain THE EYE: Research more** A retinal ganglion cell (RGC) is a type of neuron located near the inner surface (the ganglion cell layer) of the retina of the eye. A retinal ganglion cell function and output can be influenced by retinal glia that include Müller cells that span the tissue (and provide critical ionic, metabolic and modulatory of support for neurons, [68]), protoplasmic astrocytes that line the inner limiting membrane (ILM) and (in vascularized retinas) control the permeability of the blood-retina barrier, and microglia, which represent the resident immune cells [69]. Whilst organization of retinal circuits represents a key determinant of visual information processing, the physiological state of every cell type is dynamically altered through activity-dependent and neurodegeneration-driven changes in calcium homeostasis, functional and structural connectivity across and between retinal laminae [67,69,70]. ---- sleepy..... so much turkey...

Just wanted to throw out there that feeling of “neuropathy” in the hands and feet along with muscle fasciculations are signs of mast cell activation syndrome. MCAS can be triggered by drugs. it has a wide range of symptoms— localized and/or systemic. visual snow is common in mast cell patients. feeling “butterflies” (anxiety) in the abdomen. mast cells are most prevalent in areas that come into contact with the outside world. Hands, feet, face, groin. there are also neuro mast cells

Hey Lucas! Nice to hear from ya. what antihistamines have you taken? off the top of my head: the nofap, fasting, and antihistamines are common things that help people with mast cell issues. antihistamine drugs are reported to worsen hppd. If antihistamine drugs help you, this may be a sign you have mast cell issues, or histamine issues, or mast cell issues caused by hppd, or it has nothing to do with mast cells. But the thing about mast cell— usually a bad reaction is a sign of reacting to a FILLER. I have seen zero mentioning or attempts to take supplements or prescription drugs without fillers. Why would we try? No one told us maybe we shouldn’t. but let’s be real. We play science here. Well taking a drug that has 10 different fillers in it is not a solid experiment. Good reaction or bad— all you have proved is a reaction/no reaction to the drug AND all the other shit in it. as I mentioned— certain fillers can make me feel terrified. I haven’t been able to find any antihistamine on here market except for Claritin that doesn’t have a ton of shit in it. Claritin ready tabs have like… mint, cornstarch, some artificial sweetener. That’s all. Vs other otc drugs have things like sodium L sulfate. That’s in shampoo too btw. masturbation, or orgasm in general, involves histamine release— histamine, which is one of the mediators releases by mast cells, is involved in emotional regulation, cognition, wakefulness, sleep cycles— you name it. cars tend to have a lot of things in them that activate mast cells. 1) offgassing plastics. Many people with mast cell issues (myself included) have chemical sensitivities. The plastics, foams, and chemicals in cars (especially new cars) can trigger the cascade. This cascade could be felt immediately or (like with myself usually) within 24 hours. it was impossible for me to understand the link between plastics and my disease state until I was in a tent and tried to offgas a cheap foam mattress. It went poorly. This was before I knew what mcas was and didn’t know to avoid it. This time the reaction was so intense I was able to link the two—object and feeling— together. I mean… one can’t be blamed for assuming their environment is safe? I had no idea I was reacting to things. 2) older vehicles and public vehicles (such as busses!) can harbor MOLD. Apart from being a known hppd relapse trigger, mast cell patients often have mold sensitivities or had their mast cell disease begin with mold. It’s easy to think you are reacting to the bus. Or the shaking. But let me propose some other things: the other people. The colognes and perfumes they wear. The laundry they use. If they use a moldy front loading laundry machine. The deodorant they use. If they smoke. What they track in and leave on the bus from their shoes. The water issues and mold that grows on busses. The foam in the seats. there is probably more but that’s just throwing a few things out there. If you notice fluctuations in your hppd I encourage you to write down EVERYTHING you have come into contact with in the last few hours. Even 24 hourS. Its not perfect in terms of identifying things in your environment that may exacerbate your symptoms but it’s a start. mast cell diseases are interesting. I the case of MCAS, it is thought to have a genetic link that is triggered by a chemical, emotional, or physical trauma (drugs, death/loss of close friend or relative, surgery). It can be localized to the point of trauma (physical: surgery point, chemicals ingested and then impacting gut mast cells, drugs that activate neuronal mast cells) or it can be systemic. mast cells tend to be located primarily in the brain, hands, feet, groin, and face. Histamine is one of about 2000 mediators released by mast cells. It is responsible for a slew of effects but not all. Antihistamines help but they do not cure it. Fillers in the antihistamines tend to hurt. If hppd does have a mast cell component to it, unfortunately, since no one has also listed the fillers for the supplements they try on this site it makes it hard to accurately assess if something does or does not hurt. for instance, doxepine and mertazapine tend to anecdotally worsen hppd. But no one has tried these drugs without the excipients. im blathering— but thank you for responding btw clonazepam is a very effective mast cell stabilizer— as are all benzodiazepines. They are just shitty because of the addiction issues.

Not necessarily. In fact, if you’ve had an excitotoxic event from histamine causing excessive glutamate, while lowering the histamine will help solve the root problem it will likely cause your now low glutamate issue to worsen. Hope that makes sense. Even so— it may help. It would have to be free of excipients and cross the BBB readily and also be highly targeted to just the h1,2,3,4 receptors. The subject would basically have to be living in the middle of a desert with no known mast cell triggers (such as man made plastics etc) and would need to be eating no triggers as well. Then you might know if it helped. But histamine is just one of the many many manyyyy things mast cells release to cause issues. it’s been eye opening for me to discover I have reacted poorly to so many supplements/drugs because of excipients and not the actual drug. Anyways, it does fit in nicely to astrocyte/glial theory. Either way, if Dr Laurence Afrin is correct about the prevalence/predisposition in the public for this then a subset of hppd patients probably develop mcas due to the extreme stress and trauma of it. I feel if it is no a question of mcas causing hppd, what is the prevalence of mcas in hppd sufferers? It is hard to prove the prior but the latter seems more a question of how many (if no all) not if. unfortunately, if this is highly activated neural mast cells it would be extraordinary difficult to scientifically prove it. It’s hard enough when they’re flipping out in the body to see bio markers. back to the question— Claritin rapid dissolving tablets helped my brain fog and mood substantially. It seems a short term solution, however. the neuro immune changes that probably occur with lsd/psilocybin probably shouldn’t be ignored in our quest for answers. I hope more time and research elucidates more on that front.

I had private messages with someone who greatly benefited from it. They felt they were asd and that might have something to do with it. It seems to be quite the supplement I took it as well. The first time it made me irritable foe two months after taking my last tiny dose. It did allow me to sleep soundly for the first time in Hearst second time I flew into a rage but kept dosing. Irritability went away within a few days. I couldn’t discern much effect but it felt… healthy. I stopped because I lost the vial and haven’t reordered haha. just beware of the anger component if you get that. AFAIK it was a strange response. It did pass quite fast though. best of luck to you all.

My friend with hppd says propofol takes away their anxiety for days. But only tried it once for biopsy of stomach. I believe propofol is a mast cell stabilizer

There is an assumption here that thc, nicotine, or hemp is the culprit of your relapse state. In reality, there are dozens if not hundreds of factors that could correlate with it. what was in the blunt wrap? Did you go into a gas station to get it? Did that gas station have mold? Was the car you drove in new? Old? People experience different biological stressors in both scenarios. were you under stress at the time? this is just a few diff scenarios where you start to wonder. what was the supply chain like for the products you ingested? Did they come into contact with mycotoxins? Or did they contain chemicals you may be sensitive to and do not know? the world is more strange than you might believe. It’s difficult to imagine that it’s not what effects you… it’s what doesn’t effect you?

He has entered the nether.

Hello fellow perma trippers! I am increasingly becoming suspicious about the involvement in mast cells in the etiology of hppd— whether it is the initial problem or it is something that many have added on after onset. Mast cell activation disorder is something I’ve had most of my life (if not all of it, genetically it can be inherited but not activated until an environmental trigger (this includes emotional trauma and chemical lbs entering the body (this includes drugs)). I have also had slight perception issues for as long as I can remember. People talk a lot about… well everything on this forum. Hppd is so incredibly highly specific. No one can seem to figure out what is safe and what isn’t. Since I’ve started to tackle my other health issues, I’ve come to realize the way we interact with our world is way way more complicated that I ever really could have imagined. I mean, currently, I can “smell” polyurethane foam and emotionally be in a state of fear for hours. Gasoline fumes too. I say smell because that’s the easiest way to explain— in reality it is my mast cells degranulating and releasing a huge amount of chemicals. These mast cells are in the body and in the brain. The effects on the bodies mast cells can translate into the functioning of the brains. Speaking of the brain— since we all get a bit obsessive with it here— I cannot stress enough how connected your body is to it. Literally . But in terms of what can happen in your noggin when these mast cells go nuts Neural Histamine overload causes the microglial/astrocytes to prime up. They start releasing large amounts of glutamate-damaging themselves and nearby cells. They can get stuck in this state too. There were so many times I took xyz supplement and thought I had a bad reaction to the supplement. Then I realize it was an “inactive ingredient” or I was traveling and the days I had bad reactions I was staying in musty hotels or flying on airplanes. Once I started to look at the total chemical intake into my body I was shocked. There are so many. Hundreds upon hundreds of “safe” chemicals. I recently met with the top doctor in the world on mast cell. I asked him about these visual issues and he said he often has patients who complain about visual symptoms—especially visual snow. There a million more connections. Aggregations of hppd by mold, aggravation of hppd by emotional stress, aggravation of hppd over time in the absence of drug use after triggering event (people with mast cell activation often don’t realize it’s the food additive they ate or the mold in the wall that grew this year or the filler in the supplement they took). The craziest thing about mast cell disease states is they can be highly localized. Therefore, the general “effects” of mast cell disorder are extremely person to person specific. Some get it in their gut— and they get diagnosed with its. Some get it on their skin and they are diagnosed with dandruff. Some get it in their brain? Eyes? And get diagnosed with visual snow. When you start looking at mast cells you start to see a creepy and ominous prescience in the etiology of hppd. But you could also probably argue this one way or the other until th cows come home. I would think it is safe to say that hppd is a spectrum disorder. The effects of it are highly specific—person to person— in symptom variability and intensity. The responses to medications are even more variable. There are generalized rules about what makes good worse and those things are almost always in line with those who have mast cell dysfunction. I don’t think you even NEED to have visuals to have hppd. I think that’s just a variable symptom in a larger disease state. Some people have no cognitive symptoms and only visual. some people—and I’ve noticed them wander in here as knowledge about the existence hppd becomes more widespread—have only cognitive symptoms and no visuals. Some people develop one after the other. Inflammatory states in the brain OR body could cause issues with visual distortion. The thing about spectrums too— is they can seemingly change the way an entire disease or state of being looks depending on severity. Autism spectrum “disorder” is a great example of this. You could appear “dumb” (nonverbal etc) or you could appear incredibly intelligent but “odd” and without understanding of that you wouldn’t know that those two subtypes are related to each other. (There’s a lot of interesting stuff about mast cells and autism too hehe). So we have similarities in theories about hppd and microglial/astrocyte activation. We have similar triggers. There is an association between waxing and waning disease states over time. There is the worsening of disease state over time without “apparent” triggers by the authors (ie no additional drug use). There’s a lot to look at and compare. It’s really quite fascinating. Did I mention the top doctor in the country, if n t world, on mast cell disease believes the prevalence rate of this could be as high as 18% of the population? But it’s hard to say because the immediate and downstream effects can be localized or generalized. Ever been told to not masterbate and that helps hppd? Take a look at what’s been going on over at the pois forums about mast cells. Fasting? Mast cells. Don’t drink alcohol? Mast cells Don’t smoke weed? Well apart from smoke itself being a mast cell activator don’t get me started on the clusterfuck of a non scientific experiment that cannabinoids are rn. B/c they come from a plant. From pesticides (mast cell) to terrible supply chain cleanliness, to mold, to blah blah it’s just the worst. You can’t even assume that cannabinoids make hppd worse because no one is taking PURE cannabinoids. The best bet for that test will be companies like willow biosciences supplying 99.99% pure cannabinoids. To give an example of how sensitive mast cell can make you to things— I got a food delivery and brought the bags inside. Within three hours I felt like I was on lsd. I come into contact with any mold? I feel like I’m on lsd. Anyway you could probably write a book on the back and forth between why or why not with is one. Confirmation bias is always real. But it’s what I’m hedging my bets on. From sleep disturbances, to medication sensitivities, to exercise intolerances, to visual distortions, to brain fog, to eye/muscle twitching, to “random” changes in disease severity, to weight gain, to weight loss, to decreasing symptoms during stress free time, to “keep calm And carry on mentality” leading healing (form of psych mcas therapy), to sensitivities to MOLD (this could even have been the trigger— are you sure it was the hallucinogens? Or was it the mold you didn’t know about? Or was it the two things combined together… did you have a simple virus at the time? Did you have bacterial or fungal overgrowth?), to lack of any of these symptoms or combinations of any of these symptoms, to the fandoms “IM CURED” posts where someone found SOMETHING (whether it be Keppra or propofol (both effects mast cells)—it just all SCREAMS mast cell disorder. And not just for hppd. For so many other disorders. Does this mean that testing the mast cells treats the symptoms of hppd? Not necessarily. Primary start points for disease states don’t necessarily correlate with the therapies for the downstream disorders those primary points create. But it certainly is a good place to start. (In fact, should there be a component of glutamate overload here caused via histamine, lowering histamine via therapies could create a more disassociated state by lowering the total glutamate (while it may be high in levels) over a now lessened amount of receptors… I have a lot of brain fog of late; here’s to hoping that made sense) I hope this non spell checked free write without references, which has been on my mind for some time, helps relieve some suffering somewhere. God knows we all have had enough of it, here. I hope to lazily add to this post as I see more links between this theory and hppd. Or perhaps it fades into the oblivion of the internet… Or maybe it’s ….!!! Much love, OMS

It does not surprise me that some might. Inflammatory conditions in the brain can cause all of those symptoms.