Search

The number of people with dementia worldwide is estimated at 50 million by 2018 and continues to rise mainly due to increasing aging and population growth. Clinical impact of current interventions remains modest and all efforts aimed at the identification of new therapeutic approaches are therefore critical. Previously, we showed that JM-20, a dihydropyridine-benzodiazepine hybrid molecule, protected memory processes against scopolamine-induced cholinergic dysfunction. In order to gain further insight into the therapeutic potential of JM-20 on cognitive decline and Alzheimer's disease (AD) pathology, here we evaluated its neuroprotective effects after chronic aluminum chloride (AlCl3) administration to rats and assessed possible alterations in several types of episodic memory and associated pathological mechanisms. Oral administration of aluminum to rodents recapitulates several neuropathological alterations and cognitive impairment, being considered a convenient tool for testing the efficacy of new therapies for dementia. We used behavioral tasks to test spatial, emotional- associative and novel object recognition memory, as well as molecular, enzymatic and histological assays to evaluate selected biochemical parameters. Our study revealed that JM-20 prevented memory decline alongside the inhibition of AlCl3 -induced oxidative stress, increased AChE activity, TNF-α and pro-apoptotic proteins (like Bax, caspase-3, and 8) levels. JM-20 also protected against neuronal damage in the hippocampus and prefrontal cortex. Our findings expanded our understanding of the ability of JM-20 to preserve memory in rats under neurotoxic conditions and confirm its potential capacity to counteract cognitive impairment and etiological factors of AD by breaking the progression of key steps associated with neurodegeneration.

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.

Objective: Scopolamine (SCO) administration to rats induces molecular features of AD and other dementias, including impaired cognition, increased oxidative stress, and imbalanced cholinergic transmission. Although mitochondrial dysfunction is involved in different types of dementias, its role in cognitive impairment induced by SCO has not been well elucidated. The aim of this work was to evaluate the in vivo effect of SCO on different brain mitochondrial parameters in rats to explore its neurotoxic mechanisms of action.Methods: Saline (Control) or SCO (1 mg/kg) was administered intraperitoneally 30 min prior to neurobehavioral and biochemical evaluations. Novel object recognition and Y-maze paradigms were used to evaluate the impact on memory, while redox profiles in different brain regions and the acetylcholinesterase (AChE) activity of the whole brain were assessed to elucidate the amnesic mechanism of SCO. Finally, the effects of SCO on brain mitochondria were evaluated both ex vivo and in vitro, the latter to determine whether SCO could directly interfere with mitochondrial function.Results: SCO administration induced memory deficit, increased oxidative stress, and increased AChE activities in the hippocampus and prefrontal cortex. Isolated brain mitochondria from rats administered with SCO were more vulnerable to mitochondrial swelling, membrane potential dissipation, H2O2 generation and calcium efflux, all likely resulting from oxidative damage. The in vitro mitochondrial assays suggest that SCO did not affect the organelle function directly.Conclusion: In conclusion, the present results indicate that SCO induced cognitive dysfunction and oxidative stress may involve brain mitochondrial impairment, an important target for new neuroprotective compounds against AD and other dementias.

Objective: JM-20, a novel hybrid synthetic molecule, has been reported to have antioxidant, mitoprotective, anti-excitotoxic, anti-apoptotic and anti-inflammatory properties. However, the neuroprotective effect of JM-20 against memory impairment in preclinical AD-like models has not been analyzed. The aim of this study was to evaluate the potential neuroprotection of JM-20 that preserves essential memory process from cholinergic dysfunction and other molecular damages. Methods: The effects of JM-20 on scopolamine (1 mg/kg)-induced cognitive disorders were studied. Male Wistar rats (220-230 g) were treated with JM-20 and/or scopolamine, and behavioral tasks were performed. The AChE activity, superoxide dismutase activity, catalase activity, MDA and T-SH level on brain tissue were determined by spectrophotometric methods. Mitochondrial functionality parameters were measured after behavioral tests. Histological analyses on hippocampus and prefrontal cortex were processed with hematoxylin and eosin, and neuronal and axonal damage were determined. Results: The behavioral, biochemical and histopathological studies revealed that oral pre-treatment with JM-20 (8 mg/kg) significantly attenuated the scopolamine-induced memory deficits, mitochondrial malfunction, oxidative stress, and prevented AChE hyperactivity probably due to specific inhibition of AChE enzyme. It was also observed marked histological protection on hippocampal and prefrontal-cortex regions. Conclusions: The multimodal action of this molecule could mediate the memory protection here observed and suggest that it may modulate different pathological aspects of memory de?cits associated with AD in humans.