Prevention of memory impairment and hippocampal injury with blarcamesine in an Alzheimer's disease model

Abstract

Alzheimer's disease (AD) is the most common dementia, with rising global prevalence, still incomplete pathogenetic understanding and very limited effective therapies. Recent advances in biomarker identification of Aβ peptides and phospho-tau protein, and in anti-Aβ immunotherapy are suggesting that more early intervention will be more effective. Alternative therapeutic strategies to anti-Aß immunotherapy have received comparably less attention, yet one specific approach toward upstream neuroprotection by improvement of intracellular calcium homeostasis, activation of endogenous neuroprotection and restoration of autophagy through sigma-1 receptor activation recently demonstrated positive clinical data with oral blarcamesine in a phase IIb/III trial in 508 patients with early AD. AD-preventive approaches beyond lifestyle interventions become attractive candidates when meeting criteria of: (i) record of effective early intervention in mild disease, (ii) record of human safety, (iii) ease of administration, (iv) scalability to population level, (v) relative cost-effectiveness considering longer-term preventive use at population level. Here, we assessed blarcamesine's efficacy at preventing memory impairment and brain oxidative injury in the mouse preclinical model induced by intracerebroventricular injection of aggregated Aβ25-35 peptide, that permitted a clean preventive approach before administration of the pathology-inducing amyloidogenic Aβ fragment. We observed significant preventions of Aβ25-35-induced memory impairments, for both spatial working and contextual long-term memories, and of Aβ25-35-induced increase in lipid peroxidation in the mouse hippocampi. These new insights, together with blarcamesine's clinical record in early AD render blarcamesine an attractive candidate for AD pharmacological prevention.