A synthetic pregnenolone analog promotes microtubule dynamics and neural development

Abstract

Background Pregnenolone (P5) is a neurosteroid that promotes microtubule polymerization. It also reduces stress and negative symptoms of schizophrenia, promotes memory, as well as recovery from spinal cord injury. P5 is the first substance in the steroid-synthetic pathway; it can be further metabolized into other steroids. Therefore, it is difficult to differentiate the roles of P5 versus its metabolites in the brain. To alleviate this problem, we synthesized and screened a series of non-metabolizable P5 derivatives for their ability to polymerize microtubules similar to P5. Results We identified compound #43 (3-beta-pregnenolone acetate), which increased microtubule polymerization. We showed that compound #43 modified microtubule dynamics in live cells, increased neurite outgrowth and changed growth cone morphology in mouse cerebellar granule neuronal culture. Furthermore, compound #43 promoted the formation of stable microtubule tracks in zebrafish developing cerebellar axons. Conclusions We have developed compound #43, a nonmetabolized P5 analog, that recapitulates P5 functions in vivo and can be a new therapeutic candidate for the treatment of neurodevelopmental diseases.

Sex‐specific susceptibility to psychotic‐like states provoked by prenatal THC exposure: Reversal by pregnenolone

“…Some of them have been recently shown to display a better pharmacokinetic profile, comparable therapeutic effects and less toxicity. 23,163,164…”

“…Irrespective of its mechanisms of action, a number of synthetic derivatives of PREG have been designed to have higher bioavailability and selectivity compared to their parent steroid PREG. Some of them have been recently shown to display a better pharmacokinetic profile, comparable therapeutic effects and less toxicity 23,163,164 …”

Pregnenolone derivatives for the treatment of Alzheimer's disease: synthesis, and in vitro inhibition of amyloid β1–42 peptide aggregation, acetylcholinesterase and carbonic anhydrase-II

“…[45][46][47][48][49] Moreover, these compounds play a neuroprotective role in addressing neuroinammatory diseases like AD and multiple sclerosis (MS), as well as in managing neuropsychiatric disorders such as schizophrenia, depression, and autism. 29,52 Our research group is involved in the structural modication of steroidal nuclei for various disease treatments. Recently, we reported structural modication of pregnenolone at C-3 and C-17 positions.…”

“…51 Moreover, these compounds play a neuroprotective role in addressing neuroinflammatory diseases like AD and multiple sclerosis (MS), as well as in managing neuropsychiatric disorders such as schizophrenia, depression, and autism. 29,52…”