Convolamine, a tropane alkaloid extracted from Convolvulus plauricalis, is a potent sigma-1 receptor-positive modulator with cognitive and neuroprotective properties

Abstract

Background and aim: By using an in vivo phenotypic screening assay in zebrafish, we identified Convolamine, a tropane alkaloid from Convulvus plauricalis, as a positive modulator of the sigma-1 receptor (S1R). The wfs1ab^KO zebrafish larva, a model of Wolfram syndrome, exhibits an increased visual-motor response due to a mutation in Wolframin, a protein involved in endoplasmic reticulum-mitochondria communication. We previously reported that ligand activating S1R, restored the cellular and behavioral deficits in patient fibroblasts and zebrafish and mouse models.

Experimental procedures: We screened a library of 108 repurposing and natural compounds on zebrafish motor response.

Key results: One hit, the tropane alkaloid Convolamine, restored normal mobility in wfs1ab^KO larvae without affecting wfs1ab^WT controls. They did not bind to the S1R agonist/antagonist binding site nor dissociated S1R from BiP, an S1R activity assay in vitro, but behaved as a positive modulator by shifting the IC₅₀ value of the reference agonist PRE-084 to lower values. Convolamine restored learning in Wfs1^∆Exon8 , Dizocilpine-treated, and Aβ_25-35 -treated mice. These effects were observed at low ~1 mg/kg doses, not shared by Convolvine, the desmethyl metabolite, and blocked by an S1R antagonist.

Conclusion and implications: Convolamine therefore acts as an S1R positive modulator and this pharmacological action is relevant to the traditional use of Shankhpushpi in memory and cognitive protection.

Keywords: Convolamine; anti-amnesia; natural compounds; neuroprotection; phenotypic screening; shankhpushpi; sigma-1 receptor; zebrafish.