The long-term objective of this project is to elucidate the mechanism of acute neurotoxicity of aluminum. Aluminum is a potent neurotoxin. The impairment of cognitive function in aging has been linked to accumulation of aluminum in tissues. Aluminum has been implicated in three diseases of the central nervous system: dialysis encephalopathy, Alzheimer's disease, and the amyotrophic lateral sclerosis-parkinsonism dementia complex of Guam. A prominent feature of aluminum neurotoxicity is epileptic seizures, but the mechanism responsible for seizures remains unclear. At present, very little is known about the acute neurotoxicity of aluminum. The seizures can be explained by the hypothesis that aluminum inhibits the inactivation mechanism of the voltage-gated sodium channel, thereby inducing abnormal neuronal discharges. To test this hypothesis, the effects of aluminum on the sodium and potassium channels of neurons and axons will be studied using the voltage clamp and patch clamp techniques. The prolongation of the sodium conductance induced by aluminum will be characterized. The nature of interaction between aluminum and the sodium channel will be defined by the reaction rate constants deduced from dose-response relation. Aluminum-modified currents will be analyzed to derive the kinetic parameters of activation and inactivation. The general location of aluminum binding site will be determined. Single channel properties of the aluminum-modified channels will be characterized using the patch clamp technique. The blocking effect of aluminum on the sodium and potassium channels will be examined, and the mechanisms of block will be determined. Aluminum is neurotoxic when it is accumulated in the central nervous system. Understanding its &cute effects on neurons in isolated preparations is a prerequisite for a better understanding of the etiological role of the element in aluminum-induced neurotoxic diseases. This project should contribute significantly to the research of aluminum neurotoxicity.
