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Nelotanserin As 5HT Inverse Agonist To Treat Lewy Body Dementia

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    What Is Nelotanserin?

    Nelotanserin for alzheimer's
    Source: Wikipedia

    Nelotanserin is a potent 5-HT2A inverse agonist, a moderately potent 5-HT2C partial inverse agonist and a weak 5-HT2B inverse agonist, with IC50s of 1.7, 79, 791 nM in IP accumulation assays, according to medchemexpress.com. The drug was originally developed by Arena Pharmaceuticals to tackle insomnia.

    The Story Of Nelotanserin As A Dementia Drug

    In May 2015, Vivek Ramaswarmy acquired Nelotanserin from Arena Pharmaceuticals for $4 million dollars. Nelotanserin was slated as an insomnia drug, but Vivek Ramaswarmy thought it could be useful for symptomatic treatment in a type of dementia called Lewy Body Dementia or LBD. 

    Patients with Lewy Body Dementia may present with visual hallucinations and rapid eye movement behavior disorder, and Nelotanserin was seen as a novel drug to solve this problem. 

    What Were The Research Outcomes From Nelotanserin?

    Nelotanserin for alzheimer's

    The case of Nelotanserin was no different from that of Intepirdine, the other failed drug by Vivek Ramaswarmy. Unfortunately, in around late 2017 – 2018, development of Nelotanserin was halted after it missed the primary endpoint in a phase 2 trial in patients with Lewy body dementia. 

    A later study in 2021 showed Nelotanserin did not significantly help Rapid eye movement sleep behaviour disorder (RBD) in Lewy body dementia (LBD) and Parkinson’s disease dementia (PDD).

    Sleep Disorder Precedes Neurodegeneration

    Ambra Stefani (MD) of the Medical University of Innsbruck in Austria explains that neurodegeneration is commonly linked to sleep disorders, due to the brain’s loss of ability to control sleep.

    While many of us may think that neurodegenerative conditions like Alzheimer’s disease will also result in sleep disorders, there is evidence that shows the opposite to be true.

    According to Dr Stefani, sleep disorders often precede neurodegeneration. This is true for Alzheimer’s disease – see the Youtube Video below:

    Why Nelotanserin Could Still be Useful for Alzheimer’s?

    We know from research that: 

    1. Slow-wave sleep contributes to cerebral amyloid-beta clearance
    2. REM sleep decreases amyloid-beta levels
    3. We are able to use cortisol nocturnal fluctuations as a marker of clearance efficiency. 

    Although a drug like Nelotanserin is meant to treat sleep disorder, there is potential that this drug, by increasing sleep efficiency, may also help with clearance of amyloid-beta.

    By targeting the 5-HT2A receptor, which is involved in the regulation of sleep-wake cycles, Nelotanserin may help to improve sleep quality and reduce the severity of RBD symptoms in Alzheimer’s patients. This, in turn, could potentially have a positive impact on the overall management of Alzheimer’s disease.

    Pimavanserin As Treatment For Alzheimer’s

    Pimavanserin As Treatment For Alzheimer’s​
    Source: Deciphering an interplay of proteins associated with amyloid β 1-42 peptide and molecular mechanisms of Alzheimer’s disease - ResearchGate

    Another 5HT2A receptor inverse agonist, Pimavanserin, displays a very strong potential in treating Alzheimer’s. This time, it works by suppressing beta-amyloid production, implying that it can prevent the APP processing pathway to become amyloidogenic. 

    “Amyloid‐β (Aβ) peptide aggregation into soluble oligomers and insoluble plaques is a precipitating event in the pathogenesis of Alzheimer’s disease (AD). Given that synaptic activity can regulate Aβ generation, we postulated that 5HT2A‐Rs may regulate Aβ as well,” the study wrote.

    “Chronic administration of Pimavanserin by subcutaneous osmotic pump to aged APP/PS1 mice significantly reduced CSF Aβ levels and Aβ pathology and improved cognitive function in these mice.”

    Pimavanserin is otherwise known as Nuplazid. Although it was aimed to target Parkinson’s psychosis, it may also very well be the key to preventing beta-amyloid plaque production in various types of dementia.

    FAQ (Frequently Asked Questions)

    What is 5 ht6 receptor antagonist for Alzheimer's disease?​

    5-HT6 receptor antagonists are drugs being investigated as a potential treatment for Alzheimer's disease (AD) to improve cognitive function. They work by blocking the activity of the serotonin 5-HT6 receptor, which is thought to be involved in memory and learning processes.

    Here's a breakdown:

    • Shows promise in enhancing cognition in AD patients.
    • Several antagonists have undergone clinical trials, with some showing positive results.
    • Still under development, and no approved drugs are available yet.

    Why no Haldol for Lewy body dementia?

    Haldol (haloperidol) is a medication not typically used for Lewy body dementia (LBD) due to the risk of worsening symptoms. LBD can involve hallucinations, and Haldol, an antipsychotic, can worsen these in some cases.

    What is the drug of choice for Lewy body dementia?

    There is no single "cure" for LBD, but several medications can help manage symptoms. These include:

    • Acetylcholinesterase inhibitors: Similar to those used in Alzheimer's, they may improve cognitive function.
    • Dopamine agonists: Can help with movement problems and rigidity.
    • Antidepressants: May be used to treat depression and anxiety common in LBD.

    How do you treat hallucinations in Lewy body dementia? ​

    NMDA antagonists were once a promising avenue for Alzheimer's treatment, but research has shown limited effectiveness. They work by blocking a specific receptor involved in nerve cell communication. While some early studies showed promise, larger trials did not show significant benefits.

    What are 5 HT1 agonists used as?

    5-HT1A agonists are drugs that activate the serotonin 5-HT1A receptor. They have various uses depending on the specific medication:

    • Anxiety disorders: Some 5-HT1A agonists are prescribed to treat anxiety.
    • Depression: Can be used as an adjunct medication for depression in some cases.
    • Migraines: Some medications targeting the 5-HT1A receptor are used to prevent migraines.