Neuroscience
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Exposure to blast overpressure (BOP) is associated with behavioral, cognitive, and neuroimaging abnormalities. We investigated the dynamic responses of cortical vasculature and its relation to microglia/macrophage activation in mice using intravital two-photon microscopy following mild blast exposure. We found that blast caused vascular dysfunction evidenced by microdomains of aberrant vascular permeability. ⋯ Repetitive, but not single, BOPs also caused TNFα elevation two weeks post-blast. In addition, following a single BOP we found that aberrantly phosphorylated tau rapidly accumulated in perivascular domains, but cleared within four hours, suggesting it was removed from the perivascular area, degraded, and/or dephosphorylated. Taken together these findings argue that mild blast exposure causes an evolving CNS insult that is initiated by discrete disturbances of vascular function, thereby setting the stage for more protracted and more widespread neuroinflammatory responses.
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The most promising therapeutic approach to finding the cure for devastating demyelinating conditions is the identification of clinically safe pharmacological agents that can promote differentiation of endogenous oligodendrocyte precursor cells (OPCs). Here we show that the breast cancer medication tamoxifen (TMX), with well-documented clinical safety and confirmed beneficial effects in various models of demyelinating conditions, stimulates differentiation of rat glial progenitors to mature oligodendrocytes in vitro. Clinically applicable doses of TMX significantly increased both the number of CNPase-positive oligodendrocytes and protein levels of myelin basic protein, measured with Western blots. ⋯ In contrast to TMXC and 4-hydroxy-TMX, endoxifen also induced astrogliogenesis, but independent of the ER activation. In sum, we showed that the TMX prodrug and its two main metabolites (4-hydroxy-TMX and endoxifen) promote ER-dependent oligodendrogenesis in vitro, not reported before. Given that differentiating effects of TMX were achieved with clinically safe doses, TMX is likely one of the most promising FDA-approved drugs for the possible treatment of demyelinating diseases.
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Monoamine neurotransmitter, serotonin (5-HT) has its own specific receptors in both pre- and post-synapse. In the present study the role of carnosine on aging-induced changes of [(3)H]-5-HT receptor binding in different brain regions in a rat model was studied. The results showed that during aging (18 and 24 months) the [(3)H]-5-HT receptor binding was reduced in hippocampus, hypothalamus and pons-medulla with a decrease in their both Bmax and KD but in cerebral cortex the [(3)H]-5-HT binding was increased with the increase of its only Bmax. ⋯ The decrease in pons-medullary [(3)H]-5-HT binding including its Bmax of 18-month-aged rats was promoted with carnosine without any significant change in its cerebral cortex. The [(3)H]-5-HT receptor binding with the same dosages of carnosine in 4-month-young rats (a) increased in the cerebral cortex and hippocampus with the increase in their only Bmax whereas (b) decreased in hypothalamus and pons-medulla with a decrease in their both Bmax and KD. These results suggest that carnosine treatment may (a) play a preventive role in aging-induced brain region-specific changes in serotonergic activity (b) not be worthy in 4-month-young rats in relation to the brain regional serotonergic activity.
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Minocycline, a second-generation tetracycline, is well known for its antibiotic, anti-inflammatory, and antinociceptive effects. Modulation of synaptic transmission is one of the analgesic mechanisms of minocycline. Although it has been reported that minocycline may suppress excitatory glutamatergic synaptic transmission, it remains unclear whether it could affect inhibitory synaptic transmission, which also plays a key role in modulating pain signaling. ⋯ However, the facilitatory effect of minocycline on sIPSCs was eliminated in a Ca(2+)-free Krebs solution or by co-administration with calcium channel blockers. In summary, our data demonstrate that baseline inhibitory synaptic transmission in SG neurons is markedly enhanced by minocycline. This may function to decrease the excitability of SG neurons, thus leading to a modulation of nociceptive transmission.
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The tumor necrosis factor like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor-inducible 14 (Fn14), mediate inflammation and neuronal apoptosis in cerebral edema, ischemic stroke and multiple sclerosis. The downstream effectors and pathways linked to TWEAK-Fn14 signaling are strongly implicated in the pathology of Parkinson's disease (PD), thus indicating a putative role for TWEAK/Fn14 signaling in PD neurodegeneration. Using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, we aimed to determine whether genetic ablation or pharmacologic mitigation of the TWEAK protein and its Fn14 receptor affected substantia nigra and striatum Parkinsonian pathology. ⋯ Mitigating the effects of endogenous TWEAK protein using neutralizing antibody did affect MPTP-mediated neurotoxicity in the substantia nigra using the sub-acute model of MPTP (30mg/kg i.p. over five consecutive days). Neither TWEAK nor Fn14 genetic ablation led to attenuation of MPTP-toxicity in the acute model. These findings suggest that TWEAK signaling might be an aspect of MPTP-mediated neuropathology and be involved in the overall neurodegenerative pathology of PD.