Neuroscience
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The brain-derived neurotrophic factor (BDNF) is a key player in brain functions such as synaptic plasticity, stress, and behavior. Its gene structure in rodents contains 8 untranslated exons (I to VIII) whose expression is finely regulated and which spliced onto a common and unique translated exon IX. Altered Bdnf expression is associated with many pathologies such as depression, Alzheimer's disease and addiction. ⋯ Interestingly, EGR1 has been widely characterized as a regulator of brain plasticity. In conclusion, we deciphered a mechanism by which GR downregulates Bdnf expression, identifying a novel functional crosstalk between glucocorticoid pathways, immediate early growth response proteins and Bdnf. As all these factors are well-recognized germane for brain pathophysiology, these findings may have significant implications in neurosciences as well as in therapeutics.
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KY-226 is a protein tyrosine phosphatase 1B (PTP1B) inhibitor that protects neurons from cerebral ischemic injury. KY-226 restores Akt (protein kinase B) phosphorylation and extracellular signal-regulated kinase (ERK) reduction in transient middle cerebral artery occlusion (tMCAO) damage. However, the mechanisms underlying the neuroprotective effects of KY-226 are unclear. ⋯ Further, KY-226 treatment restored phosphorylation of pAkt (T308) and its downstream target forkhead box protein O1 (FoxO1) (S256) in bEnd.3 cells. Collectively, we demonstrate that KY-226 protects BBB integrity by restoration of TJ proteins, an effect partly mediated by Akt/FoxO1 pathway activation. Thus, protection of BBB integrity likely underlies KY-226-induced neuroprotection in tMCAO mice.
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Pathophysiological remodeling processes following status epilepticus (SE) play a critical role in the pathophysiology of epilepsy but have not yet been not fully investigated. In the present study, we examined changes in intrinsic properties of pyramidal neurons, basal excitatory synaptic transmission, and short-term synaptic plasticity in hippocampal slices of rats after SE. Seizures were induced in 3-week-old rats by an intraperitoneal pentylenetetrazole (PTZ) injection. ⋯ However, after 1 week, there was no difference in seizure susceptibility between control and post-SE rats. The effects of SE on functional properties of hippocampal neurons were transient in the PTZ model, and most of them had recovered 1 week after SE. However, some minor alterations, such as smaller amplitude field potentials, were observed 1 month after SE.
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Many human and animal studies have implicated inflammation as a mediator of oxidative stress and a possible contributor to hippocampal atrophy in the pathophysiology of major depressive disorder. We aimed to examine the effect of peripheral, systemic inflammation on oxidative stress and apoptosis in the hippocampi of male and female mice. We hypothesized that (1) lipopolysaccharide (LPS) would induce depressive-like behavior and hippocampal oxidative stress after 1 day in males, and (2) that a single LPS exposure would result in hippocampal apoptosis at 28 days. ⋯ Moreover, males given LPS showed increased apoptosis. Our work will provide insight into the underlying biology in males and females with MDD, and potentially underlying differences between the sexes. Also, our work will hopefully inform optimal clinical treatments that may indeed differ between the sexes.
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Hydrogen peroxide (H2O2) is one of the reactive oxygen species (ROS), endogenously produced during metabolism, which acts as a second messenger. In skeletal muscles, hypoxia- or hyperthermia-induced increase in H2O2 might affect synaptic transmission by targeting the most redox-sensitive presynaptic compartment (Giniatullin et al., 2006). However, the effects of H2O2 as a signal molecule have not previously been studied in different patterns of the synaptic activity. ⋯ We found that: (i) H2O2 at low micromole concentrations inhibited both spontaneous and evoked transmitter releases from the motor nerve terminals in a use-dependent manner, (ii) the antioxidant N-acetylcysteine (NAC) eliminated these depressant effects, (iii) the influence of H2O2 was not associated with lipid oxidation suggesting a pure signaling action, (iv) the intracellular oxidant Chloramine-T or (v) the glutathione depletion produced similar to H2O2 depressant effects. Taken together, our data revealed the effective inhibition of neurotransmitter release by ROS, which was proportional to the intensity of synaptic activity at the neuromuscular junction. The combination of various oxidants suggested an intracellular location for redox-sensitive sites responsible for modulation of the synaptic transmission in the skeletal muscle.