Transforming growth factor-β1 mediates the beneficial effects of arketamine on demyelination and remyelination in the brains of cuprizone-treated mice

Eur J Pharmacol. 2024 Dec 15:985:177096. doi: 10.1016/j.ejphar.2024.177096. Epub 2024 Nov 3.

Abstract

The novel antidepressant arketamine, the (R)-enantiomer of ketamine, has been shown to ameliorate demyelination and facilitate remyelination in the brains of cuprizone (CPZ)-treated mice. However, the mechanisms behind its effects remain unclear. Given the role of transforming growth factor β1 (TGF-β1) in arketamine's antidepressant-like effects, we examined whether TGF-β1 also plays a role in arketamine's effects on demyelination and remyelination in CPZ-treated mice. Additionally, we investigated the effects of intranasal TGF-β1 on demyelination and remyelination in these mice. Repeated intermittent administration of arketamine (10 mg/kg/day, twice weekly for the last 2-weeks) attenuated demyelination in the corpus callosum (CC) of CPZ (6 weeks)-treated mice. Furthermore, pretreatment with RepSox (10 mg/kg/day), an inhibitor of the TGF-β receptor 1, significantly blocked the beneficial effects of arketamine on the demyelination in the CC of CPZ-treated mice. Additionally, repeated intermittent administration of TGF-β1 (3.0 μg/kg/day, twice weekly for 2 weeks) significantly ameliorated demyelination and facilitated remyelination in the CC of CPZ-treated mice. These data suggest that arketamine can mitigate demyelination and facilitates remyelination in the brains of CPZ-treated mice through a TGF-β1-dependent mechanism.

Keywords: Arketamine; Cuprizone; Demyelination; Remyelination; TGF-β1.

MeSH terms

  • Animals
  • Brain* / drug effects
  • Brain* / metabolism
  • Brain* / pathology
  • Corpus Callosum / drug effects
  • Corpus Callosum / metabolism
  • Corpus Callosum / pathology
  • Cuprizone* / toxicity
  • Demyelinating Diseases* / chemically induced
  • Demyelinating Diseases* / drug therapy
  • Demyelinating Diseases* / pathology
  • Ketamine* / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL*
  • Myelin Sheath / drug effects
  • Myelin Sheath / metabolism
  • Myelin Sheath / pathology
  • Remyelination* / drug effects
  • Transforming Growth Factor beta1* / metabolism

Substances

  • Cuprizone
  • Transforming Growth Factor beta1
  • Ketamine