Molecular neurobiology
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Molecular neurobiology · May 2018
Adolescent Binge Alcohol Exposure Affects the Brain Function Through Mitochondrial Impairment.
In the young population, binge drinking is a pattern of problematic alcohol consumption, characterized by a short period of heavy drinking followed by abstinence which is frequently repeated over time. This drinking pattern is associated with mental problems, use of other drugs, and an increased risk of excessive alcohol intake during adulthood. However, little is known about the effects of binge drinking on brain function in adolescents and its neurobiological impact during the adulthood. ⋯ Additionally, BEP alters the regulation of mitochondrial dynamics and modifies the expression of mitochondrial permeability transition pore (mPTP) components, such as cyclophilin D (Cyp-D) and the voltage-dependent anion channel (VDAC). These mitochondrial structural changes result in the impairment of mitochondrial bioenergetics, decreasing ATP production progressively until adulthood. These results strongly suggest that teenage alcohol binge drinking impairs the function of the adult hippocampus including memory and synaptic plasticity as a consequence of the mitochondrial damage induced by alcohol and that the recovery of hippocampal function could implicate the activation of alternative pathways that fail to reestablish mitochondrial function.
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Molecular neurobiology · May 2018
Toll-Like Receptor 4 (TLR4) and Triggering Receptor Expressed on Myeloid Cells-2 (TREM-2) Activation Balance Astrocyte Polarization into a Proinflammatory Phenotype.
Astrocytes react to brain injury with a generic response known as reactive gliosis, which involves activation of multiple intracellular pathways including several that may be beneficial for neuronal survival. However, by unknown mechanisms, reactive astrocytes can polarize into a proinflammatory phenotype that induces neurodegeneration. In order to study reactive gliosis and astroglial polarization into a proinflammatory phenotype, we used cortical devascularization-induced brain ischemia in Wistar rats and primary astroglial cell cultures exposed to oxygen-glucose deprivation (OGD). ⋯ While TREM-2+ macrophages were abundant at 3 days post-lesion (DPL) in the ischemic core, TREM-2+ astrocytes persisted in the penumbra until 14DPL. This study demonstrates that TLR4 expression increases astroglial sensitivity to ligands facilitating astrocyte conversion towards a proinflammatory phenotype, and that astroglial TREM-2 modulates this response reducing the downstream NF-κB activation. Therefore, the availability of TLR4 and TREM-2 ligands in the ischemic environment may control proinflammatory astroglial conversion to the neurodegenerative phenotype.
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Previous studies have shown that protein kinase M zeta (PKMζ), a brain-specific isoform of protein kinase C, is involved in the central processing of nociception in several pain models by using a synthetic zeta inhibitory peptide. In the present study, we investigated whether PKMζ contributes to the pathogenesis of postsurgical pain using both conditional and conventional PKMζ knockout mice. Our results showed that the expression of PKMζ in anterior cingulate cortex, but not spinal cord, of the conditional PKMζ knockout mice was inhibited following tamoxifen injection. ⋯ Moreover, the expression of PKMζ was inhibited in both anterior cingulate cortex and spinal cord of the conventional PKMζ knockout mice. And there were no significant differences in the development of postsurgical pain among wild-type, heterozygous, and homozygous conventional PKMζ knockout mice. These data suggest that PKMζ is not required for the development of postsurgical pain after plantar incision.
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Molecular neurobiology · Mar 2018
Time-of-Day Dependent Neuronal Injury After Ischemic Stroke: Implication of Circadian Clock Transcriptional Factor Bmal1 and Survival Kinase AKT.
Occurrence of stroke cases displays a time-of-day variation in human. However, the mechanism linking circadian rhythm to the internal response mechanisms against pathophysiological events after ischemic stroke remained largely unknown. To this end, temporal changes in the susceptibility to ischemia/reperfusion (I/R) injury were investigated in mice in which the ischemic stroke induced at four different Zeitgeber time points with 6-h intervals (ZT0, ZT6, ZT12, and ZT18). ⋯ Moreover, ribosomal protein S6, mTOR, and Bad were also significantly increased, while the levels of PRAS40, negative regulator of AKT and mTOR, and phosphorylated p53 were decreased at this time point compared to ZT0 (06:00). Furthermore, detailed proteomic analysis revealed significantly decreased CSKP, HBB-1/2, and HBA levels, while increased GNAZ, NEGR1, IMPCT, and PDE1B at midnight as compared with early morning. Our results indicate that nighttime I/R injury results in less severe neuronal damage, with increased neuronal survival, increased levels of survival kinases and circadian clock proteins, and also alters the circadian-related proteins.
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Molecular neurobiology · Mar 2018
Matrix Metalloproteinase-8 Inhibition Prevents Disruption of Blood-Spinal Cord Barrier and Attenuates Inflammation in Rat Model of Spinal Cord Injury.
After spinal cord injury (SCI), tight junction (TJ) protein degradation increases permeability and disrupts the blood-spinal cord barrier (BSCB). The BSCB is primarily formed of endothelial cell, which forms a specialized tight seal due to the presence of TJs. BSCB disruption after SCI allows neutrophil infiltration. ⋯ Thus, our result suggests that MMP-8 plays an imperative role in inflammation and degradation of TJ proteins. Increased MMP-8 expression was associated with the early inflammatory phase of SCI. Inhibiting MMP-8 significantly attenuated SCI-induced inflammation, BSCB breakdown, and cell injury.