H3R antagonist against neuroinflammation 2022 mice study

pattismith

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https://doi.org/10.1016/j.expneurol.2021.113870


Thioperamide attenuates neuroinflammation and cognitive impairments in Alzheimer's disease via inhibiting gliosis


Highlights

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Thioperamide suppresses glial activation and neuroinflammation in AD.
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Thioperamide ameliorates Aβ deposition and cognitive impairments in AD.
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Thioperamide activates cAMP/PKA/CREB pathway in AD.
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Thioperamide-mediated effects are abolished by CREB inhibitor.

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disease, which characterized by deposition of amyloid-β (Aβ) plaques, neurofibrillary tangles, neuronal loss, and accompanied by neuroinflammation. Neuroinflammatory processes are well acknowledged to contribute to the progression of AD pathology.

Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release vianegative feedback way. Recently, studies show that H3R are highly expressed not only in neurons but also in microglia and astrocytes.

H3R antagonist has been reported to have anti-inflammatory efficacy. However, whether inhibition of H3R is responsible for the anti-neuroinflammation in glial cells and neuroprotection on APPswe, PSEN1dE9 (APP/PS1 Tg) mice remain unclear.

In this study, we found that inhibition of H3R by thioperamide reduced the gliosis and induced a phenotypical switch from A1 to A2 in astrocytes, and ultimately attenuated neuroinflammation in APP/PS1 Tg mice.

Additionally, thioperamide rescued the decrease of cyclic AMP response element-binding protein (CREB) phosphorylation and suppressed the phosphorylated P65 nuclear factor kappa B (p-P65 NF-κB) in APP/PS1 Tg mice. H89, an inhibitor of CREB signaling, abolished these effects of thioperamide to suppress gliosis and proinflammatory cytokine release. Lastly, thioperamide alleviated the deposition of amyloid-β (Aβ) and cognitive dysfunction in APP/PS1 mice, which were both reversed by administration of H89.

Taken together, these results suggested the H3R antagonist thioperamide improved cognitive impairment in APP/PS1 Tg mice viamodulation of the CREB-mediated gliosis and inflammation inhibiting, which contributed to Aβ clearance. This study uncovered a novel mechanism involving inflammatory regulating behind the therapeutic effect of thioperamide in AD.
 

pattismith

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HI @pattismith......is there any indication of how long this neuroinflammatory condition can last? Can it be used for other illnesses, or is that still unknown? Yours, Lenora.
H3R antagonists has gained interest these past years since Pitolisant got agreement for Narcolepsy.

Many scientific articles talk about their potential application in neuropsychiatric diseases (Autism, ADHD, Schizophrenia, Depression, Alzheimer, Hypersomnia, Restless Legs...) but also in demyelinating diseases like Multiple Sclerosis and ALS.

The H3Rs are important modulators of numerous central control mechanisms22.

Therefore, blockade of inhibitory histamine H3 auto-receptors reinforces histaminergic neurotransmission, while antagonism of H3 hetero-receptors accelerates the corticolimbic liberation of acetylcholine, norepinephrine, glutamate, dopamine, serotonin and gamma-aminobutyric acid (GABA)7,9,12
The positive effect on neuroinflammation had been explored in a few studies, but it's reasonable to expect it can benefit to many brain diseases.

In this autism mouse study for example, it's interesting to note that the H3R antagonist protects against neuroinflammation too:

2018

Abstract

Autistic spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in social communication and restricted/repetitive behavior patterns or interests.

Antagonists targeting histamine H3 receptor (H3R) are considered potential therapeutic agents for the therapeutic management of different brain disorders, e.g., cognitive impairments.

....

The results showed that VPA-exposed mice exhibited significantly lower sociability and social novelty preference compared to VPA-exposed mice that were pretreated with DL77 (10 or 15 mg/kg, i.p.).

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Furthermore, pretreatment with DL77 (10 or 15 mg/kg, i.p.) modulated oxidative stress status by increasing GSH and decreasing MDA, and it attenuated the proinflammatory cytokines IL-1β, IL-6 and TNF-α exacerbated by lipopolysaccharide (LPS) challenge, in VPA-exposed mouse brain tissue.



Taken together, these results provide evidence that modulation of brain histaminergic neurotransmission, such as by subchronic administration of the H3R antagonist DL77, may serve as an effective pharmacological therapeutic target to rescue ASD-like behaviors in VPA-exposed animals, although further investigations are necessary to corroborate and expand these initial data.
 

pattismith

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It took me some time to understand the histamine function in brain as a neurotransmitter, and the role of the brain histamine receptor H3R, so I found a nice figure to explain it.

This receptor is found in presynaptic neurons, and when activated by histamine, blocks the release of all the other neurotransmitters, even the histamine release!

So if you block the H3R, you have a brain histaminergic effect, as well as gabaergic+dopaminergic+cholinergic...etc!

What a potent class of drug!


1638686454142.png



Current Enlightenment About Etiology and Pharmacological Treatment of Autism Spectrum Disorder | Semantic Scholar
 
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Oliver3

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In my unscientific way, I've been telling my doc for years that this is histadelia....do you think this might work for us
 

pattismith

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In my unscientific way, I've been telling my doc for years that this is histadelia....do you think this might work for us
I don't know much about histadelia... But I just read it's high histamine in blood.

Blood histamine is not supposed to go through the blood brain barrier, so I don't know if peripheral histamine can reach some brain histamine receptor... Is it a validated theory?
 

Oliver3

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I don't know much about histadelia... But I just read it's high histamine in blood.

Blood histamine is not supposed to go through the blood brain barrier, so I don't know if peripheral histamine can reach some brain histamine receptor... Is it a validated theory?
It's just another way of saying mcas in my eyes. But that was the old term I found. Janice jonela did work on the 80s with it. I noticed early that vit c and flavonoids stopped my anxiety. I told the docs. Of course, the said it was sugar..but only flavonoids did it, stopped my anxiety. That's what got me interested.
Don't forget , the blood brain barrier is likely leaky with us.
Mcas us more common in eds. I think eds cones first, everything else grows in those foundation.
I really hope they can find a gene that crispr can repair. I just feel that would resolve, or at least prevent other cases
 

pattismith

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It's just another way of saying mcas in my eyes. But that was the old term I found. Janice jonela did work on the 80s with it. I noticed early that vit c and flavonoids stopped my anxiety. I told the docs. Of course, the said it was sugar..but only flavonoids did it, stopped my anxiety. That's what got me interested.
Don't forget , the blood brain barrier is likely leaky with us.
Mcas us more common in eds. I think eds cones first, everything else grows in those foundation.
I really hope they can find a gene that crispr can repair. I just feel that would resolve, or at least prevent other cases
if you have a mast cell activation with high blood histamine, H3R antagonist might not be indicated (it's a brain histaminergic drug)
 

Oliver3

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if you have a mast cell activation with high blood histamine, H3R antagonist might not be indicated (it's a brain histaminergic drug)
I understand, but aren't we supposed to have leaky blood brain barriers, plus could the sane pathology be at play in the brain anyways?