Reduction of cellular energy requirements

Screening for agents that may protect against CNS ischemia

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✓ Protection of the brain and spinal cord against ischemia is a goal of vast clinical importance. One approach to this objective is to reduce the tissue's functional activity in order to preserve energy for the metabolic processes that are essential to viability. Experiments to explore ways of reducing function-related energy demands were performed on isolated rabbit retina, a well-characterized model of organized adult mammalian central nervous system (CNS) tissue. The retina was maintained in a nearly physiological state in a miniature “heart-lung” apparatus. Energy metabolism (oxygen consumption and glycolysis) and electrophysiological function (determined by electroretinogram) of the in vitro retina were monitored, and their responses to a series of agents that may reduce energy requirements were determined.

Large reversible reductions in O2 consumption, glycolysis, and electrophysiological function were seen in response to mild hypothermia ( −3° to −6°C), phenytoin (Dilantin, 100 to 200 mg/kg), chlordiazepoxide (Librium, 200 µM), lithium (1 to 4 mM), Mg++ (6 to 20 mM), strophanthidin (0.15 to 0.25 µM), CO2 (25% to 30%), 2-amino-5-phosphonovaleric acid (APV, 500 µM), amiloride (1 mM), and dantrolene (1 mM). One retina was exposed simultaneously to a combination of six of these agents, which reduced its oxidative and glycolytic metabolism to less than 50% of the control level. The retina recovered metabolic and electrophysiological function after a 2½-hour exposure period. Other agents tested (diphenhydramine, midazolam, nifedipine, nimodipine, and quercetin) had effects on energy metabolism and electrophysiological function that were poorly reversible. Surprisingly little effect was seen in response to general anesthetic agents (thiopental and Althesin) and other CNS depressants (chlorpromazine, ethanol, lidocaine, paraldehyde, valproic acid, and baclofen). The presumed mechanisms through which these agents reduce cellular energy requirements, as well as their potential roles in the treatment of CNS ischemia, are discussed.

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Contributor Notes

Address reprint requests to: Adelbert Ames, M.D., Neurosurgical Service, Massachusetts General Hospital, Boston, Massachusetts 02114.

© AANS, except where prohibited by US copyright law.

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