Neuroscience
-
Evidence is emerging that reactive oxygen species (ROS)-induced oxidative stress has a crucial role in the pathogenesis of neurodegenerative diseases. To find the effective therapies for neurodegenerative diseases, evaluation of the relevant molecular mechanisms is necessary. In the current study, we investigated the effects of hydrogen peroxide (H2O2)-induced oxidative stress on SK-N-MC cell death with focus on HIF-1α, Foxo3a and Notch1 signaling factors. ⋯ In contrast, Notch inhibition resulted in HIF-1α/Foxo3a signaling pathway up-regulation, suggesting the bidirectional crosstalk between HIF-1α and Notch1. These results collectively suggest that ROS are involved in activation of both the defensive and pro-apoptotic pathways encompassing HIF-1α and p53, respectively. Regarding the HIF-1α-mediated neuroprotection role, elucidation of the molecular mechanism would certainly be essential for effective drug design against neurodegenerative diseases.
-
High accumulation of D-2-hydroxyglutaric acid (D-2-HG) is the biochemical hallmark of patients affected by the inherited neurometabolic disorder D-2-hydroxyglutaric aciduria (D-2-HGA). Clinically, patients present neurological symptoms and basal ganglia injury whose pathophysiology is poorly understood. We investigated the ex vivo effects of intrastriatal administration of D-2-HG on important parameters of redox status in the striatum of weaning rats. ⋯ Vacuolization, lymphocytic infiltrates and macrophages indicating brain damage were also observed in the striatum of rats injected with D-2-HG. The present data provide in vivo solid evidence that D-2-HG disrupts redox homeostasis and causes histological alterations in the rat striatum probably mediated by NMDA overstimulation and RNS production. It is therefore presumed that disturbance of redox status may contribute at least in part to the basal ganglia alterations characteristic of patients affected by D-2-HGA.
-
The cholinergic system is implicated in visuospatial attention and inhibition, however the exact role is still unclear. Two key mechanisms in visuospatial attention are bias and disengagement. Bias refers to neuronal signals that enhance the sensitivity of the sensory cortex, disengagement is the decoupling of attention. ⋯ Nicotine enhanced inhibition more in non-smokers relative to smokers. Integrating the results, nicotine-abstinent smokers do not seem to resemble ADHD patients, and do not seem to smoke in order to self-medicate a pre-existing deficit pertaining to mechanisms of visuospatial attention and inhibition. Nicotine may affect inhibition more in non-smokers relative to smokers, consistent with a drug-tolerance account.
-
Inflammation mediated by glial activation appears to play a critical role in the pathogenesis of Parkinson disease (PD). Glia maturation factor (GMF), a proinflammatory protein predominantly localized in the central nervous system was isolated, sequenced and cloned in our laboratory. We have previously demonstrated immunomodulatory and proinflammatory functions of GMF, but its involvement in 1-methyl-4-phenylpyridinium (MPP(+)), active metabolite of classical parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), inducing loss of dopaminergic (DA) neurons has not been studied. ⋯ Subsequently, GMF deficiency ameliorates antioxidant balance, as evidenced by the decreased level of lipid peroxidation, less ROS production along with increased level of glutathione; and attenuated the DA neuronal loss via the downregulation of NF-κB-mediated inflammatory responses. In conclusion, our overall data indicate that GMF modulates oxidative stress and release of deleterious agents by MPP(+) leading to loss of DA neurons. Our study provides new insights into the potential role of GMF and identifies targets for therapeutic interventions in neurodegenerative diseases.
-
The process of glutamate release, activity, and reuptake involves the astrocyte, the presynaptic and postsynaptic neurons. Glutamate is released into the synapse and may occupy and activate receptors on both neurons and astrocytes. Glutamate is rapidly removed from the synapse by a family of plasma membrane excitatory amino acid transporters (EAATs), also localized to neurons and astrocytes. ⋯ Expression of EAAT1 protein on neurons may be due to the hypoxia associated with the postmortem interval, and requires further confirmation. The localization of EAATs on the astrocytic plasma membrane and adjacent to excitatory synapses is consistent with the function of facilitating glutamate reuptake and limiting glutamate spillover. Establishment that EAAT1 and EAAT2 can be measured at the EM level in human postmortem tissues will permit testing of hypotheses related to these molecules in diseases lacking analogous animal models.