Abstract:
The biochemical and molecular events associated with lead (Pb2+)-induced neuronal dysfunction is complex and multifactorial. The present study evaluated the in vitro and in vivo interaction of lead with the synaptosomal ouabain-sensitive electrogenic sodium pump as a possible component mechanism of its observed severe toxicity on brain function. In addition, the possible involvement of oxidative stress and oxidation of essential thiols of the synaptosomal pump as likely component events in lead-induced toxicity of the pump was also assessed in vitro and in vivo. The results show that Pb2+ ion inhibited the activity of the synaptosomal electrogenic sodium pump in a concentration-dependent manner and also caused an increase in lipid peroxidation level in vitro. Furthermore, Pb2+ ion evoked a concentration-dependent inhibition on the activity of the electrogenic pump irrespective of the absence of the substrates [adenosine triphosphate (ATP) and the cations (Na+ and K+)] at the binding sites. Furthermore, irrespective of the exposed substrate binding sites, pre-incubation of the enzyme with exogenous thiol, dithiolthreitol (DTT) prevented Pb2+-mediated inhibition of the activities of the synaptosomal Na+/K+-ATPase, whereas, post incubation of the enzyme with DTT, did not recover the inhibition of the enzyme previously exerted by Pb2+. However, vitamin E prevented lipid peroxidation but not inhibition of the pump’s activity. Interestingly, under in vivo situation, Pb2+-mediated inhibition of the synaptosomal enzyme was reversed by dithiothreitol. In addition, Pb2+ ion caused a depletion of the GSH level and also the free radical scavenging ability of the synaptosome with attendant increase in lipid peroxidation in the synaptosomal fraction. Consequently, within the limit of the present data, it appears that the severity of lead-mediated neuronal dysfunction may be related to its inhibition of the synaptosomal transmembrane pump. Considering the fact that lead-induced decreased activity of the synaptosomal enzyme could be reversed by the dithiol DTT, it is rational to suggest that Pb2+-mediated toxicity on the
vi
pump under in vivo situation may not be related to its direct binding on the protein. Consequently, Pb2+ ion assault on the synaptosomal sodium pump may not be the prime molecular event that characterize the severity of lead toxicity. Apparently, thiols may be potential candidate in the management of such neuronal dysfunctions induced by lead
