Expression of nerve growth factor carried by pseudotyped lentivirus improves neuron survival and cognitive functional recovery of post-ischemia in rats.

AIMS: Nerve growth factor (NGF) has been reported to prevent neuronal damage and contributes to the functional recovery in animal brain injury models and human ischemic disease as well. We aimed to investigate a potential therapeutic effect of NGF gene treatment in ischemic stroke and to estimate the functional recovery both at the cellular and cognitive levels in an ischemia rat model. METHODS: After microinjection of pseudolentivirus-delivered ß-NGF into an established ischemic stroke model in rats (tMCAO), we estimated neuronal cell apoptosis with TUNEL labeling and neurogenesis by cell proliferation marker Ki67 staining in both ischemic core and penumbra of striatum. Furthermore, we used behavioral functional tests, Morris water maze performance, to evaluate cognitive functional recovery in vivo and propose a potential underlying mechanism. RESULTS: We found that pseudolentivirus-mediated delivery of ß-NGF gene into the brain induced high expression in striatum of the infarct core area after ischemia in rats. The ß-NGF overexpression in the striatal infarction core after ischemia not only improved neuronal survival by reducing cell apoptosis and increasing cell proliferation, but also rescued cognitive functional impairment through upregulation of GAP-43 protein expression in tMCAO rat model of ischemia. CONCLUSION: This study demonstrates a potential ß-NGF gene therapy by utilization of pseudolentivirus in ischemia and indicates future applications of NGF gene treatment in ischemic patients.

Potassium channel dysfunction in neurons and astrocytes in Huntington's disease.

Huntington's disease (HD) is a late-onset fatal neurodegenerative disease, characterized by progressive movement disorders, psychiatric symptoms, and cognitive impairment. The cytosine-adenine-guanine (CAG) triplet expansion encoding glutamine present in the protein huntingtin (Htt), produces widespread neuronal and glial pathology. Mutant huntingtin (mHtt) nuclear aggregates are the primary cause of cortical and striatal neuron degeneration, neuronal inflammation, apoptosis and eventual cell loss. The precise mechanisms underlying the pathogenesis of neurodegeneration in HD remain poorly understood and HD patients have no current cure. Potassium channels are widely expressed in most cell types. In neurons, they play a crucial role in setting the resting membrane potential, mediating the rapid repolarization phase of the action potential and controlling sub-threshold oscillations of membrane potentials. In glial cells, their major contributions are maintaining the resting membrane potential and buffering extracellular K+ . Thus, potassium channels have an essential function in both physiological and pathological brain conditions. This review summarizes recent progress on potassium channels involved in the pathology of HD by using different HD mouse models. Exploring the dysfunction of potassium channels in the brain illustrates new approaches for targeting this channel for the treatment of HD.

Roles of NG2-glia in ischemic stroke.

Recent studies have shown that a widely distributed class of glial cells, termed NG2-glia, engages in rapid signaling with surrounding neurons through direct synaptic contacts in the developing and mature central nervous system (CNS). This unique glial cell group has a typical function of proliferating and differentiating into oligodendrocytes during early development of the brain, which is crucial to axon myelin formation. Therefore, NG2-glia are also called oligodendrocyte precursor cells (OPCs). In vitro and in vivo studies reveal that NG2-glia expressing receptors and ion channels demonstrate functional significance for rapid signaling with neuronal synapses and modulation of neuronal activities in both physiological and pathological conditions. Although it is well known that NG2-glia play an important role in demyelinating diseases such as multiple sclerosis, little is known about how NG2-glia or OPCs impact neurons and brain function following ischemic injury. This review summarizes recent progress on the roles of NG2-glia in ischemic stroke and illustrates new approaches for targeting NG2-glia in the brain to treat this disease.

Ca(2+) signaling evoked by activation of Na(+) channels and Na(+)/Ca(2+) exchangers is required for GABA-induced NG2 cell migration.

NG2 cells originate from various brain regions and migrate to their destinations during early development. These cells express voltage-gated Na(+) channels but fail to produce typical action potentials. The physiological role of Na(+) channels in these cells is unclear. We found that GABA induces membrane depolarization and Ca(2+) elevation in NG2 cells, a process requiring activation of GABA(A) receptors, Na(+) channels, and Na(+)/Ca(2+) exchangers (NCXs), but not Ca(2+) channels. We have identified a persistent Na(+) current in these cells that may underlie the GABA-induced pathway of prolonged Na(+) elevation, which in turn triggers Ca(2+) influx via NCXs. This unique Ca(2+) signaling pathway is further shown to be involved in the migration of NG2 cells. Thus, GABAergic signaling mediated by sequential activation of GABA(A) receptors, noninactivating Na(+) channels, and NCXs may play an important role in the development and function of NG2 glial cells in the brain.