JM-20 treatment prevents neuronal damage and memory impairment induced by aluminum chloride in rats.

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.

High saturated fat and low carbohydrate diet decreases lifespan independent of body weight in mice.

BACKGROUND: Obesity is a health problem that is reaching epidemic proportions worldwide. We investigated the effects of a life-long high saturated fat and low carbohydrate (HF) diet on the body mass, glucose tolerance, cognitive performance and lifespan of mice. FINDINGS: C57BL/6J mice were fed with a HF diet (60% kcal/fat) or control diets (15% kcal/fat) for 27 months. One-half of the mice on the HF diet developed obesity (diet-induced obese (DIO) mice), whereas the remaining mice were diet resistant (DR). At 8 months of age, both DIO and DR groups had increased hyperglycemic response during a glucose tolerance test, which was normalized in 16-month-old mice. At this latter time point, all groups presented similar performance in cognitive tests (Morris water maze and inhibitory avoidance). The survival curves of the HF and control diet groups started to diverge at 15 months of age and, after 27 months, the survival rate of mice in the DIO and DR groups was 40%, whereas in the control diet group it was 75%. CONCLUSIONS: AHFdiet decreased the survival of mice independent of bodyweight.

Physical exercise exacerbates memory deficits induced by intracerebroventricular STZ but improves insulin regulation of H2O2 production in mice synaptosomes.

Insulin brain resistant state is associated with cognitive deficits and Alzheimer's disease by mechanisms that may involve mitochondrial damage and oxidative stress. Conversely, physical exercise improves cognitive function and brain insulin signaling. The intracerebroventricular (i.c.v.) administration of streptozotocin (STZ) in rodents is an established model of insulin-resistant brain state. This study evaluates the effects of physical exercise on memory performance of i.c.v., STZ-treated mice(1 and 3 mg/kg) and whether insulin (50 and 100 ng/ml) modulates mitochondrial H2O2 generation in synaptosomes. S100B levels and SOD and CAT activities were assessed as markers of brain damage caused by STZ. Sedentary and exercise vehicle-treated mice demonstrated similar performance in object recognition memory task. In the water maze test, exercise vehicle-treated mice showed improvement performance in the acquisition and retrieval phases. The administration of STZ (1 mg/kg) before thirty days of voluntary physical exercise protocol impaired recognition and spatial memory only in exercised mice, whereas STZ (3 mg/kg) impaired the performance of sedentary and exercise groups. Moreover, STZ (3 mg/kg) increased hippocampal S100B levels in both groups and SOD/CAT ratio in the sedentary animals. Insulin decreased synaptosomal H2O2 production in exercised compared to sedentary mice; however, both STZ doses abolished this effect. Normal brain insulin signaling is mechanistically involved in the improvement of cognitive function induced by exercise through the regulation of mitochondrial H2O2 production. However, a prior blockade of brain insulin signaling with STZ abolished the benefits of exercise on memory performance and mitochondrial H2O2 regulation.