The Kinetics of Non-Synaptically Triggered Acute Excitotoxic Responses in the Central Nervous System Observed Using Intrinsic Optical Signals

Vera Maura Fernandes de Lima, Wolfgang Hanke

doi:10.2174/187152712800269704

Abstract

Background and purpose: Excitotoxic central nervous system (CNS) response is believed to be important in the pathophysiology of irreversible sequelae of anoxia and brain trauma. Furthermore, the sodium pump has been associated with functional CNS syndromes such as migraine and epilepsy. Thus, a detailed description of the kinetics of excitotoxic responses elicited by glutamatergic pathway activation and sodium pump blockade can be useful in pre-clinical research. This should be aimed at minimizing the brain damage due to anoxia or trauma or the prophylaxis of functional syndromes.

Experimental Approach: The kinetics of the intrinsic optical signals of excitotoxic responses were examined in detail following N-methyl-D-aspartic acid or ouabain extrinsic pulses in in vitro retinas and compared to optical profiles of retinal spreading depression waves in intact retinae in chicken eye-cups. Additional experiments recorded field potentials simultaneously with the intrinsic optical signals. The protective effects of extracellular magnesium and glutathione were also examined.

Results: The initial phase (10 min) of the excitotoxic responses were very similar, however the final outcome was different: usually, irreversible damage was restricted to patches of tissue following N-methyl-D-aspartic acid pulses. By contrast, extrinsic ouabain experiments resulted in whole tissue death even with concentrations as low as 10 nM, except in three experiments in which glutathione at physiological concentrations was added to the perfusion 60 min before the pulse.

Conclusion: the glial sodium pump must be a receptor of endogenous cardiac glycosides and its blockade can trigger excitotoxicity with a non-synaptic mechanism. The demonstration of glutathione protective effect suggests the importance of the transducer role of this membrane ATPase in the CNS.

Keywords: Excitotoxic central nervous system response, retinal spreading depression, glutamate, ouabain, Na-K/ATPase, glia, intrinsic optical signals, glutathione, glial membrane transduction