Journal of neurochemistry
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Journal of neurochemistry · Feb 2010
Cyclic GMP phosphodiesterase inhibition alters the glial inflammatory response, reduces oxidative stress and cell death and increases angiogenesis following focal brain injury.
Recent evidence obtained in cultured glial cells indicates that cGMP-mediated pathways regulate cytoskeleton dynamics, glial fibrillary acidic protein expression and motility in astrocytes, as well as inflammatory gene expression in microglia, suggesting a role in the regulation of the glial reactive phenotype. The aim of this work was to examine if cGMP regulates the glial inflammatory response in vivo following CNS damage caused by a focal cryolesion onto the cortex in rats. Results show that treatment with the cGMP phosphodiesterase inhibitor zaprinast (10 mg/kg i.p.) 2 h before and 24 and 48 h after the lesion results 3 days post-lesion in notably enhanced astrogliosis manifested by increased glial fibrillary acidic protein immunoreactivity and protein levels around the lesion. ⋯ This altered inflammatory response is accompanied by a decrease in protein oxidative stress, apoptotic cell death and neuronal degeneration. In addition, zaprinast enhanced angiogenesis in the lesioned cortex probably as a result of vascular endothelial growth factor expression in reactive astrocytes. These results suggest that regulation of the glial inflammatory response may contribute to the reported neuroprotective effects of cGMP-phosphodiesterase inhibitors in brain injury.
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Journal of neurochemistry · Feb 2010
The fibroblast growth factor receptor substrate 3 adapter is a developmentally regulated microtubule-associated protein expressed in migrating and differentiated neurons.
Fibroblast growth factor (FGF) mediated signaling is essential to many aspects of neural development. Activated FGF receptors signal primarily through the FGF receptor substrate (Frs) adapters, which include Frs2/Frs2alpha and Frs3/Frs2beta. While some studies suggest that Frs3 can compensate for the loss of Frs2 in transfected cells, the lack of an effective Frs3 specific antibody has prevented efforts to determine the role(s) of the endogenous protein. ⋯ Subcellular fractionation studies demonstrate that endogenous Frs3 is both soluble and plasma membrane associated while Frs3 expressed in 293T cells associates exclusively with lipid rafts. Lastly, we demonstrate that neuronal Frs3 binds microtubules comparable to the microtubule-associated protein, MAP2, while Frs2 does not. Collectively, these data suggest that neuronal Frs3 functions as a novel microtubule binding protein and they provide the first biochemical evidence that neuronal Frs3 is functionally distinct from Frs2/Frs2alpha.
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Journal of neurochemistry · Feb 2010
Inhibition of myosin light chain kinase reduces brain edema formation after traumatic brain injury.
The role of the endothelial contractile apparatus in the process of brain edema formation after brain trauma is not characterized. Phosphorylation of myosin light chains by myosin light chain kinases (MLCK) activates endothelial contractile elements and results in a rearrangement of the cytoskeleton. This may enhance post-traumatic blood-brain barrier dysfunction. ⋯ Prevention of brain edema formation did not translate into improved neurological outcome or reduced brain lesion. In conclusion, the results confirm that the endothelial contractile apparatus is activated by CCI and opens the endothelial barrier leading to vasogenic brain edema formation. Lack of neurological and histological improvement suggests that specific targeting of vasogenic brain edema at the endothelial level is not sufficient to limit secondary brain damage and has, therefore, to be combined with other potential neuroprotective strategies.