Therapeutic efficacy of novel memantine nitrate MN‐08 in animal models of Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is a leading cause of dementia in elderly individuals and therapeutic options for AD are very limited. Over‐activation of N‐methyl‐D‐aspartate (NMDA) receptors, amyloid β (Aβ) aggregation, a decrease in cerebral blood flow (CBF), and downstream pathological events play important roles in the disease progression of AD. In the present study, MN‐08, a novel memantine nitrate, was found to inhibit Aβ accumulation, prevent neuronal and dendritic spine loss, and consequently attenuate cognitive deficits in 2‐month‐old APP/PS1 transgenic mice (for a 6‐month preventative course) and in the 8‐month‐old triple‐transgenic (3×Tg‐AD) mice (for a 4‐month therapeutic course). In vitro, MN‐08 could bind to and antagonize NMDA receptors, inhibit the calcium influx, and reverse the dysregulations of ERK and PI3K/Akt/GSK3β pathway, subsequently preventing glutamate‐induced neuronal loss. In addition, MN‐08 had favorable pharmacokinetics, blood‐brain barrier penetration, and safety profiles in rats and beagle dogs. These findings suggest that the novel memantine nitrate MN‐08 may be a useful therapeutic agent for AD.

NPLC0393 from Gynostemma pentaphyllum ameliorates Alzheimer's disease‐like pathology in mice by targeting protein phosphatase magnesium‐dependent 1A phosphatase

“…Currently, several anti‐AD drugs were approved by the FDA, including four cholinesterase inhibitors (e.g., tacrine, donepezil, galantamine, and rivastigmine), a N ‐methyl‐ d ‐aspartate receptor partial antagonist (e.g., memantine), and a monoclonal antibody targeting Aβ oligomers (aducanumab). A preclinical study in 3×Tg‐AD mice showed that administration of memantine, donepezil, or rivastigmine could reverse cognitive deficits via different mechanisms (Ray et al, 2020; Wu et al, 2021). In the present study, NPLC0393 ameliorated learning and memory impairment, protected against synaptic impairment, and repressed inflammatory response and tauopathy in 3×Tg‐AD mice by targeting PPM1A.…”

Advances in the application of manganese dioxide and its composites for theranostics

“…MRI can monitor behavior during Mn(II) take up and capture the high-intensity signal retrospectively, which provides a basis for detecting neuronal diseases. Mn(II) has unique physiological properties that make it an appealing nerve contrast agent, including the ability to monitor cell transport kinetics and neuronal projection anatomy in the brain, 109 progress of Alzheimer's disease, [110][111][112] emotion management, 113 Parkinson's disease, 114 etc. Remarkably, MnO 2 can be reduced to Mn(II) in vivo, which plays a crucial role in imaging neurodegenerative diseases.…”

Adverse event profile of memantine and donepezil combination therapy: a real-world pharmacovigilance analysis based on FDA adverse event reporting system (FAERS) data from 2004 to 2023

“…However, excessive glutamate release at the synapse causes intracellular Ca2+ overload, increased free radical production, and Aβ formation, leading to neuronal excitotoxicity and subsequent neuronal dysfunction and apoptosis ( Simões et al, 2018 ; Calvo-Rodriguez et al, 2020 ; Goel et al, 2022 ). This key pathophysiological mechanism is thought to underlie the widespread necrosis and functional impairment in the brains of dementia patients ( Wu et al, 2021 ; Zhang et al, 2022 ). In contrast, memantine is a noncompetitive NMDA receptor antagonist that prevents NMDA overactivation and glutamate-mediated neurotoxicity, thereby protecting neuronal cells ( Chayrov et al, 2022 ; Turcu et al, 2022 ).…”