Neuroprotective effects of 2‐aminoethoxydiphenyl borate (2‐APB) in β‐amyloid‐induced memory dysfunction is mediated through inhibition of transient receptor potential melastatin 2 (TRPM2) channels

Abstract

β‐amyloid (Aβ) peptide is a hallmark of Alzheimer’s disease (AD) and associated with a progressive decline of cognition, a characteristic feature of AD. Aggregation of Aβ initiates the dysregulation of calcium ion homeostasis. Recently, it has been shown that transient receptor potential melastatin 2 (TRPM2), a Ca2+‐permeable non‐selective cation channel plays a crucial role in the Aβ‐induced neuronal cell death. However, the therapeutic potential of 2‐aminoethoxydiphenyl borate (2‐APB), a TRPM2 inhibitor has not been investigated in the Aβ‐induced cognitive deficits in rats yet. In the present study, I.C.V. administration of Aβ (Aβ25‐35, 10 μg) markedly induced cognitive impairment which shown in cognitive behavioral parameters. Moreover, mRNA and protein expression of TRPM2 were upregulated in the hippocampus of Aβ‐treated animals. AchE activity was also increased in the cortex of Aβ‐treated animals. Three‐week treatment with 2‐APB led to the down‐regulation of TRPM2 mRNA and protein expression in the hippocampus and also improved the cognitive functions. Moreover, the 2‐APB treatment also increased the calcium and memory associated proteins namely p‐CaMKII, p‐GSK3β, p‐CREB and PSD‐95 in the hippocampus and reduced the mRNA level of calcium buffering protein and calcineurin A (PPP3CA) in the hippocampus. Furthermore, 2‐APB significantly reduced the AchE activity in the cortex. Thus, our findings suggest that 2‐APB depicted potential neuroprotective effect against Aβ‐induced cognitive impairment.Support or Funding InformationNational Institute of Pharmaceutical Education and Research and National Agri‐Food Biotechnology Institute