The Ethanolic Extract of Polygala paniculata L. Blocks Panx1 Channels and Reduces Ischemic Brain Infarct in a Dose- and Sex-Dependent Way.

ABSTRACT

Polygala paniculata L. is a native plant from tropical America. The therapeutic potential of the hydroalcoholic extract of P. paniculata (HEPp) has been scientifically explored due to folk medicine reports on its action against several afflictions. HEPp contains several bioactive molecules with neuroprotective activities, making it a promising candidate for stroke treatment. This study used electrophysiological, biochemical, and in vivo experiments to evaluate the molecular mechanisms underlying HEPp as a neuroprotective therapy for stroke targeting Pannexin-1 (Panx1). Panx1 is a non-selective channel that opens during ischemia and contributes to neuronal death. HEPp was not toxic to cortical neurons and pre-treatment with the extract reduced neuronal death promoted by oxygen and glucose deprivation in a dose-dependent manner. Additionally, HEPp blocked Panx1 currents in a dose-dependent manner and the effect, which was shown to be partially due to rutin. Animals submitted to photothrombosis and post-treated with HEPp had reduced infarct volume, and the effective dose was lower in males (1 mg/kg) than in females (10 mg/kg). On the other hand, in Panx1 KD mice (50% Panx1 levels), the acute treatment reduced the infarct volume only in males. Upon chronic treatment with HEPp, a reduction in Panx1 protein levels was observed. The current study provides reliable evidence of the neuroprotective properties of HEPp in both in vitro and in vivo models of stroke. The underlying mechanism involves, at least in part, the inhibition of Panx1 channel function and possibly downregulation of protein levels, suppressing the secondary events that lead to apoptosis and inflammation.