Neuroscience
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Approximately 50% of patients who survived after aneurysmal subarachnoid hemorrhage (SAH) have cognitive or neurobehavioral dysfunction. The mechanisms are not known. NR2B, one of the subunits of N-methyl-d-aspartate (NMDA) receptors, has been proved to be an important factor for synapse function and behavior cognition. ⋯ The immunohistochemical staining demonstrated expression of NR2B was present mainly in the neurons in all of the three different regions, such as the cortex, hippocampus, and cerebellum. After Ro 25-6981 intraperitoneal administration, learning deficits induced by SAH was markedly aggravated and clinical behavior scale was also significantly decreased. Our results suggest that NR2B expression is down-regulated in the brain after experimental SAH and NR2B antagonism resulted in augmentation of the development of cognitive dysfunction after SAH.
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Neuronal electrical activity has been known to affect the viability of neurons in the central nervous system. Here we show that long-lasting membrane depolarization induced by elevated extracellular K(+) recruits nitric oxide (NO)/soluble guanylyl cyclase/protein kinase G signaling pathway, induces 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP)-mediated protein S-guanylation, and confers dopaminergic neuroprotection. Treatment of primary mesencephalic cell cultures with 1-methyl-4-phenylpyridinium (MPP(+)) for 72 h decreased the number of dopaminergic neurons, whereas the cell loss was markedly inhibited by elevated extracellular concentration of K(+) (+40 mM). ⋯ Zinc protoporphyrin IX also inhibited the neuroprotective effect of elevated extracellular K(+). On the other hand, KT5823 or Rp-8-Br-PET-cGMPS did not inhibit the induction of HO-1 protein expression by 8-nitro-cGMP, although these protein kinase G inhibitors abrogated the neuroprotective effect of 8-nitro-cGMP. These results suggest that protein S-guanylation (leading to HO-1 induction) as well as canonical protein kinase G signaling pathway plays an important role in NO-mediated, activity-dependent dopaminergic neuroprotection.
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Inhibition of poly(ADP-ribose) polymerase (PARP) has been proposed to have a neuroprotective effect on hippocampal neurons in animal models of epilepsy. However, the mechanisms of PARP-mediated epileptic neuron apoptosis in vitro are still not thoroughly understood. Therefore, we investigated the effect of PARP inhibition and the underlying mechanisms in the hippocampal neuronal culture model of acquired epilepsy which is generally accepted as the neuronal culture model of spontaneous seizure discharge in vitro. ⋯ Western blot and confocal laser scanning microscopy (CLSM) analysis showed that DPQ increased the phosphorylation of Akt and attenuated mitochondria-nucleus translocation of the apoptosis-inducing factor (AIF). Furthermore, wortmannin, an inhibitor of PI-3K, inhibited the translocation of AIF to the nucleus. The results of the present study demonstrated that the inhibition of PARP might have therapeutic value in seizure-induced hippocampal neuron damage in vitro via suppressing Akt-mediated AIF translocation.
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Progesterone has been shown to exert pleiotropic actions in the brain of both male and females. In particular, after traumatic brain injury (TBI), progesterone has important neuroprotective effects. In addition to intracellular progesterone receptors, membrane receptors of the hormone such as membrane progesterone receptor (mPR) may also be involved in neuroprotection. ⋯ The wide neuroanatomical distribution of mPRα suggests that this receptor may play a role beyond neuroendocrine and reproductive functions. However, in the absence of injury its role might be restricted to neurons. The induction of mPRα after TBI in microglia, astrocytes and oligodendrocytes, points to a potential role in mediating the modulatory effects of progesterone in inflammation, ion and water homeostasis and myelin repair in the injured brain.