Neuronal Sodium Channels in Neurodegeneration and Neuroprotection
Abstract
Severe disruptions in ionic dynamics of the depolarizing neuron have long been recognized as possible mediators of excitotoxicity. In neurodegeneration leading to neuronal cell death, injury-induced imbalances in intracellular calcium (Ca++i) have received considerable attention, leading many, including our own laboratory, to propose the "calcium mechanism" of neuronal injury and neurodegeneration. However, of possibly equal consequence to the responsiveness of an injured neuron is the state of the Na+-Ca++ exchanger, and the influence of altered sodium dynamics to promote calcium overload, presynaptic membrane depolarization, and excitation. The pathophysiological importance of neuronal sodium channels to membrane stabilization has been recognized and studied in epilepsy, and more recently in peripheral neuropathy and other neurodegenerative conditions. The results of these studies have led to the cloning, sequencing and physiological characterization of at least four neuronal sodium channels. However, despite these discoveries and the exciting prospect of protecting neurons against excitotoxic insults with the development of novel sodium channel blocking drugs, the role of sodium channels in cell death mechanisms and neuroprotection has received relatively limited attention. It is becoming increasingly apparent that blockade of neuronal sodium channels may prevent, or at least attenuate, neurodegeneration and offer an exciting therapeutic approach for the treatment CNS injury. Therefore, the primary objective of this research proposal is to characterize the molecular expression and determine the functional significance of the respective neuronal sodium channel genes relative to the development and recovery mechanisms of the injury process. A second objective is to study the effects of sodium channel blockade on the molecular and cellular consequences of neuronal injury, and its influence to improve recovery and repair mechanisms.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2003
- Accession Number
- ADA419516
Entities
People
- Frank C. Tortella
Organizations
- Henry M. Jackson Foundation for the Advancement of Military Medicine