Multifunctional Molecule, JM-20, Reverses Aluminum Chloride-Induced Memory Impairment and Neuronal Damage in Rats

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease that worsens with aging. Today, there is a worldwide effort to find new drugs that could delay the onset, slow the progression, or improve symptoms of AD. Oral administration of aluminum to rodents recapitulates some pathological alterations observed in AD, being considered a convenient tool for modeling and testing the efficacy of new therapeutics. Our previous studies have shown that JM-20, a dihydropyridine and benzodiazepine hybrid molecule protected memory in an environment with cholinergic dysfunction, high oxidative stress, hyperactivation of acetylcholinesterase (AChE) enzyme, and mitochondrial damage produced by scopolamine. In order to gain further insight into the effects on JM-20 on AD pathology, we evaluated the protective effects of JM-20 after chronic AlCl3 administration to rats, and assessed several types of episodic memory alterations and associated-pathological mechanisms, including mitochondrial dysfunction, AChE hyperactivity, inflammation, and apoptosis-related proteins. We used behavioral tasks to test spatial, working an emotional- associative memory, as well as molecular, enzymatic and histological assays to evaluate selected biochemical parameters. Our study showed that JM-20 prevented memory decline alongside with the inhibition of aluminum-induced alterations of oxidative parameters, and increase of AChE activity and of tumor necrosis factor alpha (TNF-α) levels. JM-20 also preserved anti-apoptotic proteins and protected against axonal and neuronal damaged in the hippocampus and prefrontal cortex. Altogether, our findings expanded our understanding of the ability of JM-20 to preserve essential types of memory in rats under neurotoxic conditions, and suggest its potential capacity to counteract etiological factors of AD by breaking the progression of key neurodegeneration-associated steps in a rat model of the disease.