Neuroscience
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Oxidative stress contributes significantly to brain aging. Animals lacking glutamate transporter type 3 (EAAT3) have a decreased level of glutathione, the major intracellular anti-oxidant, in neurons, and present with early onset of brain aging including brain atrophy and cognitive impairment at 11 months of age. Here, 12-month-old male EAAT3 knockout mice received intraperitoneal injection of N-acetylcysteine (NAC) at 150 mg/kg once every day for 4 weeks. ⋯ The knockout mice also had decreased levels of glutathione and increased levels of 4-hydroxy-2-nonenal and proteins containing nitrotyrosine, indicators of oxidative stress, in the cerebral cortex and hippocampus. NAC but not saline injection attenuated these behavioral and biochemical changes in the EAAT3 knockout mice. These results suggest that improvement of anti-oxidative capacity in neurons reverses the existing cognitive impairment in aging brains, implying a potential role of glutathione replacement in cognitive improvement of aging population.
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Spinal muscular atrophy (SMA), a fatal genetic motor disorder of infants, is caused by diminished full-length survival of motor neuron (SMN) protein levels. Normally involved in small nuclear ribonucleoprotein (snRNP) assembly and pre-mRNA splicing, recent studies suggest that SMN plays a critical role in regulating apoptosis. Interestingly, the anti-apoptotic Bcl-x isoform, Bcl-xL, is reduced in SMA. ⋯ We also found that exogenous SMN expression increased full-length SMN transcripts, possibly by promoting exon 7 inclusion. Finally, co-expression of SMN and Bcl-xL produced an additive anti-apoptotic effect following PI3-kinase inhibition in SH-SY5Y cells. Our findings implicate Bcl-xL as another potential target in SMA therapeutics, and indicate that therapeutic increases in SMN may arise from modest increases in total SMN.
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We have recently reported on the efficacy of an NK1 tachykinin receptor antagonist in improving outcome following stroke, including reduced blood-brain barrier (BBB) disruption, reduced cerebral edema and improved functional outcome. The clinically approved stroke treatment, tissue plasminogen activator (tPA), has been associated with an increased risk of hemorrhage and death, if given at later time points. Accordingly, adjunctive therapies have been investigated to reduce the adverse effects of tPA and improve outcome. ⋯ BBB permeability was assessed by Evans Blue extravasation. Combination therapy of an NK1 tachykinin receptor antagonist with tPA significantly reduced BBB permeability, functional deficits and the incidence of intracerebral hemorrhage and death. As such, combined tPA-NK1 tachykinin receptor antagonist treatment may represent a novel therapeutic intervention for the treatment of reperfusion injury in acute ischemic stroke.
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The Ts65Dn (TS) mouse model of Down syndrome (DS) displays a number of behavioral, neuromorphological and neurochemical phenotypes of the syndrome. Altered GABAergic transmission appears to contribute to the mechanisms responsible for the cognitive impairments in TS mice. Increased functional expression of the trisomic gene encoding an inwardly rectifying potassium channel, subfamily J, member 6 (KCNJ6) has been reported in DS and TS mice, along with the consequent impairment in GAB Aergic function. ⋯ Also, ETH and GAB did not induce anxiety in the open field or plus maze tests, did not alter performance in the Morris water maze, and did not affect cued - or context - fear conditioning. Our results thus suggest that KCNJ6 may not be a promising drug target candidate in DS. As a corollary, they also show that long-term use of ETH and GAB is devoid of adverse behavioral and cognitive effects.
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Randomized Controlled Trial
Influence of the amount of use on hand motor cortex representation: effects of immobilization and motor training.
Converging evidence from animal and human studies has revealed that increased or decreased use of an extremity can lead to changes in cortical representation of the involved muscles. However, opposite experimental manipulations such as immobilization and motor training have sometimes been associated with similar cortical changes. Therefore, the behavioral relevance of these changes remains unclear. ⋯ No change was found for other TMS variables (motor thresholds or map location/volume/area) in either condition. In conclusion, our results indicate that a 4-day decrease, but not increase, in the amount of use of nondominant hand muscles is sufficient to induce a change in corticospinal excitability. The lack of a training effect might be explained by the use of an unspecific task (that is nevertheless representative of "real-life" training situations) and/or by insufficient duration/intensity to induce long-lasting changes.