The potential of CYP46A1 as a novel therapeutic target for neurological disorders: An updated review of mechanisms.

Cholesterol is a key component of the cell membrane that impacts the permeability, fluidity, and functions of membrane-bound proteins. It also participates in synaptogenesis, synaptic function, axonal growth, dendrite outgrowth, and microtubule stability. Cholesterol biosynthesis and metabolism are in balance in the brain. Its metabolism in the brain is mediated mainly by CYP46A1 or cholesterol 24-hydroxylase. It is responsible for eliminating about 80% of the cholesterol excess from the human brain. CYP46A1 converts cholesterol to 24S-hydroxycholesterol (24HC) that readily crosses the blood-brain barrier and reaches the liver for the final elimination process. Studies show that cholesterol and 24HC levels change during neurological diseases and conditions. So, it was hypothesized that inhibition or activation of CYP46A1 would be an effective therapeutic strategy. Accordingly, preclinical studies, using genetic and pharmacological interventions, assessed the role of CYP46A1 in main neurodegenerative disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, multiple sclerosis, spinocerebellar ataxias, and amyotrophic lateral sclerosis. In addition, its role in seizures and brain injury was evaluated. The recent development of soticlestat, as a selective and potent CYP46A1 inhibitor, with significant anti-seizure effects in preclinical and clinical studies, suggests the importance of this target for future drug developments. Previous studies have shown that both activation and inhibition of CYP46A1 are of therapeutic value. This article, using recent studies, highlights the role of CYP46A1 in various brain diseases and insults.

Enhancement of nerve regeneration with nimodipine treatment after sciatic nerve injury.

Peripheral nerve injuries (PNI/s) are common orthopedic conditions, characterized by motor and sensory deficits in the damaged region. There is growing evidence that the L-type calcium channel antagonist nimodipine has neuroprotective and neuroregenerative effects in animal models of neurological disorders. The efficacy of nimodipine on improving motor function and sensation following a sciatic nerve crush model was investigated in male Wistar rats as a model of PNI. At different time periods following damage, we evaluated motor function, sensory recovery, electrophysiology, histomorphometry, and gene expression. Moreover, we used histological and mass ratio analysis of the gastrocnemius muscle to assess atrophy. Our findings suggest that the nimodipine improves motor and sensory function more quickly in the damaged region 2, 4, and 6 weeks after 1 week of treatment. Nimodipine treatment also increased the number of myelinated fibers while decreasing their thickness, as shown by histomorphometry. Additionally, nimodipine treatment increases the mRNA levels of neurotrophic factors (BDNF and NGF), which are known to contribute to the regeneration of injured neurons. The impact of nimodipine in PNI recovery may be due to its stimulation of the CREB signaling pathway and suppression of pro-inflammatory factor production.

Neuroprotective effects of celastrol on sciatic nerve transection model in male Wistar rats.

Objectives: Celastrol is an herbal compound with neuroprotective properties. Our research aimed to assess the neuroprotective properties of celastrol on sciatic nerve transection in rats. Materials and Methods: The rats' left sciatic nerve was cut and sutured directly. The animals were then given 1 or 2 mg/kg celastrol intraperitoneally for two weeks. The sensory and locomotor behaviors of the animals were then evaluated for 16 weeks. Immunohistochemistry, ELISA, and real-time PCR were also utilized to evaluate macrophage polarization, cytokine secretion, and neurotrophin expression in injured nerves. Results: Results showed that both doses of celastrol significantly accelerated nerve regeneration and improved sensorimotor functional recovery when compared with controls. Nevertheless, administration of 2 mg/kg of celastrol significantly outperforms treatment with a dose of 1 mg/kg. Celastrol treatment-induced M2 polarization in macrophages decreased proinflammatory cytokines at the injury site. It also increased the expression of BDNF mRNA. Conclusion: These findings suggest that a two-week treatment with celastrol had neuroprotective effects in a rat sciatic nerve transection model, most likely by inducing macrophage M2 polarization and anti-inflammatory effects.