Neuroscience
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Beta-secretase (BACE1) and gamma-secretase activating protein (GSAP) are pivotal enzymes in the cleavage of amyloid precursor protein (APP). Beta-amyloid (Aß) formation is considered one of the main reasons for Alzheimer's disease (AD) pathology. In our preliminary study, a series of microRNAs (miRs) with possible interaction with BACE1 and/or GSAP was selected using computational analysis. ⋯ Also, western blotting and immunocytochemistry confirmed the regulatory role of miR-4422-5p mimic on BACE1 and GSAP genes. miR-4422-5p mimic significantly decreased BACE1 and GSAP protein expression in SH-SY5Y and A549 cells, respectively. Moreover, miR-4422-5p-inhibitor reversed the expression processes in both cell lines. Our data suggest that miR-4422-5p may be an important regulator of both BACE1 and GSAP genes and can represent a novel potential biomarker or therapeutic target in AD.
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Benzodiazepines are the primary treatment option for organophosphate (OP)-induced status epilepticus (SE), but these antiseizure drugs (ASDs) lose efficacy as treatment is delayed. In the event of a mass civilian or military exposure, significant treatment delays are likely. New ASDs that combat benzodiazepine-resistant, OP-induced SE are critically needed, particularly if they can be efficacious after a long treatment delay. ⋯ At 60 mg/kg, retigabine without MDZ strongly reduced seizure activity and neuronal degeneration against soman-induce SE. This study demonstrates the antiseizure and neuroprotective efficacy of retigabine against OP-induced SE. Our data suggest retigabine could be a useful adjunct to standard-of-care and has potential for use in the absence of MDZ.
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Dual orexinergic antagonists (DORAs) have been recently developed as a pharmacotherapy alternative to established hypnotics. Hypnotics are largely evaluated in preclinical rodent models in the dark/active period yet should be ideally evaluated in the light/inactive period, analogous to when sleep disruption occurs in humans. We describe here the hypnotic efficacy of DORA-22 in rodent models of sleep disturbance produced by cage changes in the light/inactive period. ⋯ EEG measures indicated that all DORA-22 doses largely promoted sleep in the first hour. The lowest dose (1 mg/kg) did not decrease sleep onset latency at the six-hour timepoint, suggesting no residual hypersomnolence. We described here DORA-22 hypnotic efficacy during the normal sleep period of nocturnal rats, and demonstrate that well-chosen (low) hypnotic doses of DORA-22 may be hypnotically effective yet have minimal lingering effects.
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Clinical studies clearly indicate that early-life stress (ELS) may cause physical and mental health problems later in life. Therefore, the identification of universal biomarkers of ELS-related diseases is very important. The 70-kDa heat shock proteins (HSP70s), specifically HSPA5 and HSPA1B, have been recently shown to be potentially associated with occurrence of anxiety, mood disorders, and schizophrenia; thus, we hypothesized that HSP70s are potential candidate biomarkers of ELS-induced psychopathologies. ⋯ Concurrently, MS adult rats exhibited aberrations in LTP in the mPFC and hippocampus and a less anxious behavioral phenotype. These results indicate that MS may produce enduring overexpression of HSPA1B and HSPA5 in the brain and blood. Therefore, both HSP70 family members may be potential candidate peripheral and brain biomarkers of ELS-induced changes in brain functioning.
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Long-term living at high altitude causes significant impairment of cognitive function. Central neurotransmitters are potential mediators of cognitive performance. ⋯ Consistent with this result, peripheral plasma DOPA, dopamine, serotonin, 5-HIAA and glutamate were associated with brain neurotransmitter levels after chronic HH exposure in rats. These results provide experimental data indicating that neurotransmitter levels and cognitive performance are modified in chronic high-altitude exposure, with a possible causal effect.