Neuroinflammation: nootropics and compounds | sci-wiki

CMS-121

CMS-121 is an experimental drug created by chemically redesigning fisetin, a plant flavonoid; the result is a synthetic quinoline rather than a flavonoid itself, and it is not the same substance as fisetin. In animals it blocks fatty acid synthase, an enzyme that builds fats, and this reduces oxidative damage to the fats in cell membranes; treated mice held onto memory better in models of Alzheimer's disease, Huntington's disease and accelerated ageing, and also showed improved blood sugar and body weight. Human evidence is limited to a single Phase 1 study in 99 healthy volunteers that asked only whether the drug was tolerated and how the body handled it, not whether it helps anyone; that report remains an unpublished preprint. Almost all of the animal work comes from the one laboratory that invented the compound, no human being has ever been tested for a benefit, and CMS-121 is not approved anywhere for any use.

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Nootropic

Etifoxine

Etifoxine (brand name Stresam; also called etafenoxine) is a benzoxazine anxiolytic (an anti-anxiety drug from a chemical family unrelated to the benzodiazepines like Valium). It has been prescribed for the anxious, tense, physical side of stress mainly in France and a handful of other countries since the late 1970s, and it is not approved by the US FDA. What makes it interesting is a dual mechanism: it calms the brain both by directly tuning up GABA-A receptors and by nudging the body to make more of its own calming neurosteroids. In head-to-head trials it eased anxiety comparably to some benzodiazepines while causing less sedation, less memory and psychomotor impairment, and little rebound or dependence when stopped. It has also been explored beyond anxiety for helping injured peripheral nerves heal and for damping neuroinflammation (inflammation inside nervous tissue). The important caveat is safety: rare but serious liver injury and severe skin reactions have been reported.

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Nootropic

FGL

FGL is a synthetic 15-residue peptide copying the loop that the neural cell adhesion molecule (NCAM) uses to switch on FGFR1 growth-factor signalling. In rodents it has sharpened learning and memory, strengthened synaptic transmission, and protected hippocampal neurons against amyloid-beta, ischemia and injury. Its dimeric form cleared a single-dose phase 1 study in 24 healthy men and the announced Alzheimer's trial never followed, so every efficacy claim on this page is still an animal claim. Two findings sit against the promise: it lowered the seizure threshold in a kindling model, and it reduced neuron counts in uninjured brains.

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Hormone

Progesterone

Progesterone (P4; pregn-4-ene-3,20-dione) is an endogenous pregnane steroid hormone best known for its reproductive roles and is the prototypical neuroactive precursor within the neurosteroid system. Although the parent hormone signals principally through classical nuclear progesterone receptors and through membrane-associated receptors such as PGRMC1 and the mPR/PAQR family, most of its rapid effects on neuronal excitability arise only after sequential metabolism to 5-alpha-dihydroprogesterone and then to allopregnanolone, one of the most potent endogenous positive allosteric modulators of the GABA-A receptor (the brain's principal inhibitory chloride channel). Progesterone and its metabolites are synthesized within the nervous system itself, where they regulate myelination, neuronal survival, neuroinflammation, and inhibitory tone. It has been studied extensively as a neuroprotective agent, with strong preclinical support but negative large-scale human trials in acute traumatic brain injury.

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Anticonvulsant

Ganaxolone

Ganaxolone (research code CCD-1042; brand name Ztalmy) is a synthetic neuroactive steroid, specifically the 3-beta-methyl analog of the endogenous neurosteroid allopregnanolone (a metabolite of progesterone). It is a positive allosteric modulator (a molecule that amplifies a receptor's response to its natural activator) of the GABA-A receptor, the brain's principal inhibitory chloride channel, and it enhances both synaptic (phasic) and extrasynaptic (tonic) inhibition, with particularly strong activity at delta-subunit-containing receptors. In March 2022 it became the first medicine approved by the United States Food and Drug Administration for seizures associated with CDKL5 deficiency disorder (a rare genetic developmental and epileptic encephalopathy caused by mutations in the cyclin-dependent kinase-like 5 gene), and the first synthetic neurosteroid approved as an anticonvulsant. The defining 3-beta-methyl group makes ganaxolone orally bioavailable, metabolically stable, and non-hormonal, distinguishing it from its parent neurosteroid, which requires intravenous administration.

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Neuroprotection

Ibudilast

Ibudilast (MN-166, Ketas) is a brain-penetrant, multi-target neuroimmune modulator that stands apart from the pure PDE4 crowd. It inhibits several phosphodiesterases (PDE3/4/10/11) while also blocking macrophage migration inhibitory factor (MIF) and toll-like receptor 4 (TLR4), quieting overactive glia and shifting cytokines toward repair. Marketed for decades in Japan for asthma and post-stroke dizziness, it has advanced internationally as MN-166 through progressive MS, ALS and addiction trials.

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Nootropic

VU0486846

VU0486846 is an experimental M1 muscarinic acetylcholine receptor positive allosteric modulator (an "M1 PAM"; it makes the M1 receptor respond more strongly to the brain's own acetylcholine rather than switching it on directly). It came out of the Vanderbilt neuroscience drug-discovery group and is prized as a "clean" research tool: it improves cognition in animal models without the agonist activity, seizures, and classic cholinergic side effects that plagued earlier M1 activators. It has been studied mostly in models of Alzheimer's disease, schizophrenia-related cognitive deficits, prion neurodegeneration, and Rett syndrome. It is a research compound with no human data.

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Nootropic

Fingolimod

Fingolimod is a sphingosine-1-phosphate receptor modulator used to treat relapsing forms of multiple sclerosis. Approved in 2010 and sold as Gilenya, it was the first oral disease-modifying therapy for the condition, offering an alternative to injections for many patients. It works by trapping immune cells in the lymph nodes so that fewer of them can reach and attack the brain and spinal cord.

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