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Aims: Alzheimer's disease (AD) is a devastating dementia characterized by extracellular amyloid‐β (Aβ) protein aggregates and intracellular tau protein deposition. Clinically available drugs mainly target acetylcholinesterase (AChE) and indirectly sustain cholinergic neuronal tonus. Butyrylcholinesterase (BChE) also controls acetylcholine (ACh) turnover and is involved in the formation of Aß aggregates and senile plaques. UW‐MD‐95 is a novel carbamate‐based compound acting as a potent pseudo‐irreversible BChE inhibitor, with high selectivity versus AChE, and showing promising protective potentials in AD. Methods: We characterized the neuroprotective activity of UW‐MD‐95 in mice treated intracerebroventricularly with oligomerized Aβ25‐35 peptide using behavioral, biochemical, and immunohistochemical approaches. Results: When injected acutely 30 min before the behavioral tests (spontaneous alternation in the Y‐maze, object recognition, or passive avoidance), UW‐MD‐95 (0.3‐3 mg/kg) showed anti‐amnesic effects in Aβ25‐35‐treated mice. When injected once a day over 7 days, it prevented Aβ25‐35‐induced memory deficits. This effect was lost in BChE knockout mice. Moreover, the compound prevented Aβ25‐35‐induced oxidative stress (assessed by lipid peroxidation or cytochrome c release), neuroinflammation (IL‐6 and TNFα levels or GFAP and IBA1 immunoreactivity) in the hippocampus and cortex, and apoptosis (Bax level). Moreover, UW‐MD‐95 significantly reduced the increase in soluble Aβ1‐42 level in the hippocampus induced by Aβ25‐35. Conclusion: UW‐MD‐95 appeared as a potent neuroprotective compound in the Aβ25‐35 model of AD, with potentially an impact on Aβ1‐42 accumulation that could suggest a novel mechanism of neuroprotection. [ABSTRACT FROM AUTHOR]

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 wfs1abKO 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 wfs1abKO larvae without affecting wfs1abWT 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 Aβ25‐35‐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. [ABSTRACT FROM AUTHOR]