2. Academic Validation
  3. A synthetic pregnenolone analog promotes microtubule dynamics and neural development

A synthetic pregnenolone analog promotes microtubule dynamics and neural development

  • Cell Biosci. 2022 Dec 1;12(1):190. doi: 10.1186/s13578-022-00923-2.
Viktoryia Kolas # 1 2,  Jose Sandino A Bandonil # 1,  Niaz Wali 3 4 5,  Kuo-Chiang Hsia 1,  Jiun-Jie Shie 6,  Bon-Chu Chung 7 8 9
Affiliations

Affiliations

  • 1 Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
  • 2 Institute of Molecular and Cellular Biology, National Tsing-Hua University, Hsinchu, Taiwan.
  • 3 Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
  • 4 Institute of Biochemical Sciences, National Taiwan University, Taipei, 10617, Taiwan.
  • 5 Chemical Biology and Molecular Biophysics, Taiwan International Graduate Program, (TIGP-CBMB) Academia Sinica, Taipei, 11529, Taiwan.
  • 6 Institute of Chemistry, Academia Sinica, Taipei, Taiwan. shiejj@gate.sinica.edu.tw.
  • 7 Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan. mbchung@sinica.edu.tw.
  • 8 Institute of Molecular and Cellular Biology, National Tsing-Hua University, Hsinchu, Taiwan. mbchung@sinica.edu.tw.
  • 9 Graduate Institute of Biomedical Sciences, Neuroscience and Brain Disease Center, China Medical University, Taichung, 404, Taiwan. mbchung@sinica.edu.tw.
  • # Contributed equally.
PMID: 36456994 DOI: 10.1186/s13578-022-00923-2
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.

Keywords

Cerebellum; Drug; Microtubules; Neurite; P5; Zebrafish.

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