Phytomedicine 2021 Sep 01;90:153646. doi: 10.1016/j.phymed.2021.153646.

Stigmasterol can be new steroidal drug for neurological disorders: Evidence of the GABAergic mechanism via receptor modulation.

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BACKGROUND: Gamma-aminobutyric acid A (GABAA) receptors have been implicated in anxiety and epileptic disorders. HYPOTHESIS/PURPOSE: This study aimed to investigate the effects of stigmasterol, a plant sterol (phytosterol) isolated from Artemisia indica Linn on neurological disorders. METHODS: Stigmasterol was evaluated on various recombinant GABAA receptor subtypes expressed in Xenopus laevis oocytes and its anxiolytic and anticonvulsant potential was assessed using the elevated plus maze (EPM), light-dark box (LDB) test, and pentylenetetrazole- (PTZ-) induced seizure paradigms. Furthermore, computational modeling of α2β2γ2L, α4β3δ, and α4β3 subtypes was performed to gain insights into the GABAergic mechanism of stigmasterol. For the first time, a model of GABAδ subtype was generated. Stigmasterol was targeted to all the binding sites (neurotransmitters, positive and negative modulator binding sites) of GABAA α2β2γ2L, α4β3, and α4β3δ complexes by in silico docking. RESULTS: Stigmasterol enhanced GABA-induced currents at ternary α2β2γ2L, α4β3δ, and binary α4β3 GABAAR subtypes. The potentiation of GABA-induced currents at extrasynaptic α4β3δ was significantly higher compared to the binary α4β3 subtype, indicating that the δ subunit is important for efficacy. Stigmasterol was found to be a potent positive modulator of the extrasynaptic α4β3δ subtype, which was also confirmed by computational analysis. The computational analysis reveals that stigmasterol preferentially binds at the transmembrane region shared by positive modulators or a binding site constituted by the M2-M3 region of α4 and M1-M2 of β3 at α4β3δ complex. In in vivo studies, Stigmasterol (0.5-3.0 mg/kg, i.p.) exerted significant anxiolytic and anticonvulsant effects in an identical manner of allopregnanolone, indicating the involvement of a GABAergic mechanism. CONCLUSION: To our knowledge, this is the first study reporting the positive modulation of GABAA receptors, anxiolytic and anticonvulsant potential of stigmasterol. Thus, stigmasterol is considered to be a candidate steroidal drug for the treatment of neurological disorders due to its positive modulation of GABA receptors.

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Species referenced: Xenopus laevis
Genes referenced: gabarap