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

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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: CNS; Excitotoxic centarl nervous system response; Glia; Glial Membrane Transduction; Glutathione; Glycolysis; Homeostatis; Intrinsic Optical Signals; Micro Pulse; Na-K/ATPase; Ouabain; Ringer solution; gluatamate; retinal spreading depression

Document Type: Research Article


Affiliations: Experimental Surgery Laboratory-LIM 26 Medical Faculty, University of Sao Paulo, Av Dr Arnaldo 455 Sao Paulo, SP, Brazil.

Publication date: March 1, 2012

More about this publication?
  • CNS & Neurological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in neurological and central nervous system (CNS) disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in neurological and CNS disorders. As the discovery, identification, characterization and validation of novel human drug targets for neurological and CNS drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.

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