The Effects Of Gp120 And Methamphetamine On Outward Rectified Potassium Channels In HIV Associated Dementia

Part one: Both TEA and 4-AP sensitive potassium channels were involved in gp120-induced hippocampal cell apoptosisThe HIV envelop glyprotein gp120 has been intensively studied over the years and is associated with the development of HIV-associated demential (HAD) in HIV infectors. However, its molecular targets are still not fully uncovered. Therefore, identifying the molecular or pharmacological targets requires an understanding of the events preceding the neuronal damage in the CNS. It was recently reported that the K~+ channels could be a functional substrate for the disease, for the prolonged K~+ outflow resulted in cell apoptosis. Thus in the present study, the whole-cell patch clamp technique was performed and the data showed that gp120 significantly increased the amplitude of K~+ currents in a dose-dependent manner. Further investigation suggested that both TEA and 4-AP sensitive K~+ channels were involved in the elevation of the current, which was in line with the toxicological results in MTT and TUNEL assay that both TEA and 4-AP markedly retarded the hippocampal cell damage induced by gp120. These results, taken together, suggest that gp120 increases both TEA and 4-AP sensitive K~+ currents, leading to K~+ outflow and ultimate neuronal apoptosis.Part two: Involvement of 4-AP sensitive potassium current in methamphetamine-induced hippocampal neuronal apoptosisMethamphetamine (Meth) is an illicit psychostimulant that is widely abused in the world. It is reported that Meth abuse leads to neuronal damage, such as loss of gray matter in the cortices and the shrinkage of hippocampi. However, the mechanism is still largely unknown. K~+ homeostasis is believed to be closely related with cell volume, and persistent K~+ efflux results in apoptotic volume decrease. In the present study, we explored whether K~+ channels were involved in Meth-induced apoptosis in primary rat hippocampal neuronal cultures. Using the whole-cell patch clamp techniques, we observed that bath application of Meth differentially increased the amplitude of 4-amonopyridine (4-AP)-sensitive K~+ current, but not the K~+ current sensitive to tetraethylammonium (TEA), which is in line with the toxicological results that the Meth-induced neuronal apoptosis was significantly blocked by 4-AP, but not TEA. Further investigation revealed that Meth enhanced 4-AP-sensitive K~+ current might by inhibition of ERK phosphorylation. These results, taken together, suggest that Meth increases 4-AP- sensitive K~+ currents by inhibition of ERK phosphorylation, leading to apoptotic volume decrease and ultimate neuronal apoptosis.Part three: The combined effects of Methamphetamine and gp120 on rat hippocampal cellsThe drug abuse is a vital risk factor responsible for the neural degenerative disease and the way for the propagation of HIV. Drug abuse may act in concert with HIV to wreak havoc on the central nervous system, and accerlarate the development of HAD. Methamphetamine (Meth) is most widely used and is proved to be toxic to neurons, leading to the shrink of hippocampus and activation of glia. Based on the results on the part one and two, we hypothesized that gp120 may act in concert with Meth and result in neurotoxicity exceeds gp120 or Meth treated alone. Therefore, in the present study, the MTT and TUNEL assays were perfomed , however, no additive or synergistic effects were observed between gp120 +Meth treated group and gp120 or Meth treated group and it still needs further explore.