Date of Award
Doctor of Philosophy in Pharmaceutical Sciences
Pharmacy and Toxicology
The mechanisms whereby pargyline, succinic acid and absorbic acid protect against hyperbaric oxygen convulsions, pulmonary damage and mortality following hyperbaric oxygen exposure were investigated in relation to the effects of these agents on hyperbaric oxygen-induced alterations in brain gamma-aminobutyric acid and ammonia metabolism.
Exposure to hyperbaric oxygen (60 pounds per square inch, gauge pressure) produced convulsions, post-exposure lethality and elevation in lung weight, lung water content and lung hemoglobin content. Pargyline, succinic acid and ascorbic acid provided partial production against all of the above aspects of toxicity.
Comparison of the doses of pargyline, succinic acid and ascorbic acid that provided maximal protection against hyperbaric oxygen convulsions showed that all three agents were approximately equal, in the doses used, with respect to their effectiveness in decreasing the incidence of hyperbaric oxygen convulsions and increasing the latency to their onset. Pargylune and succinic acid were approximately equal, in the doses used, in their ability to reduce post-exposure lethality and hyperbaric oxygen-induced increased in lung weight, water content and hemoglobin content. Ascorbic acid was less effective in its ability to reduce the above changes induced by hyperbaric oxygen exposure.
Hyperbaric oxygen decreased brain gamma-aminobutyric acid levels. This decrease was due to inhibition of glutamic acid decarboxylase without any effect on gamma-aminobutyric acid transaminase activity. Both pargyline and succinic acide increased brain gamma-aminobutyric acid levels in room air-exposed mice and prevented the decrease in brain gamma-aminobutyric acid produced by hyperbaric oxygen exposure. Pargyline increased gamma-aminobutyric acid levels by inhibiting gamma-aminobutyric acid transaminase activity in room air- and hyperbaric oxygen-exposed mice. Succinic acid increased the activity of both glutamic acid decarboxylase and gamma-aminobutyric acid transaminase, glutamic acid decarboxylase to a greater degree than gamma-aminobutyric acid transaminase. Glutamic acid decarboxylase activity was still slightly increased in mice exposed to hyperbaric oxygen. These alterations in enzyme activity were responsible for the ability of pargyline and succinic acid to increase brain gamma-aminobutyric acid levels in room air-exposed mice and to prevent the hyperbaric oxygen-induced decrease in brain gamma-aminobutyric acid in animals exposed to hyperbaric oxygen. There was a significant correlation between hyperbaric oxygen seizure susceptibility and brain gamma-aminobutyric acid levels in pargyline - or succunic acid – treated mice.
In pargyline- or succinic acid-treated mice there was a dose-response relationship between amount of drug administered and degree of elevation in brain gamma-aminobutyric acid.
Ascorbic acid had no effect on brain gamma-aminobutyric acid levels nor did it prevent the hyperbaric oxygen-induced decrease in brain gamma-aminobutyric acid. Ascorbic acid treatment had no effect on glutamic acid decarboxylase or gamma-aminobutyric acid transaminase activities nor did it prevent the hyperbaric oxygen-induced decrease in glutamic acid decarboxylase activity.
Hyperbaric oxygen exposure increased brain ammonia levels and decreased brain glutamine levels. All three agents reduced these hyperbaric oxygen-induced alterations. There was a correlation between brain ammonia levels and hyperbaric oxygen seizure susceptibility in mice treated with pargyline, succinic acid or ascorbic acid. The same was true for glutamine levels and hyperbaric oxygen seizure susceptibility.
These results demonstrate that decreased gamma-aminobutyric acid levels and increased ammonia levels in the brain are involved in the etiology of hyperbaric oxygen toxicity. The effectiveness of the three agents tested as protective agents against hyperbaric oxygen toxicity appears related to their ability to alter the hyperbaric oxygen-induced changes in brain ammonia and gamma-aminobutyric acid metabolism.
The relationship between hyperbaric oxygen-induced alteration in gamma-aminobutyric acid and ammonia metabolism and the effects of pargyline, succinic acid and ascorbic acid thereon are discussed with respect to mitochondrial function and consequent adenosine triphosphate production.
Schatz, Robert Alfred, "PARGYLINE, SUCCINIC ACID AND L-ASCORBIC ACID AS PROTECTIVE AGENTS AGAINST HYPERBARIC OXYGEN TOXICITY: POSSIBLE INVOLVEMENT OF ALTERED GAMMA-AMINOBUTYRIC ACID AND AMMONIA METABOLISM" (1972). Open Access Dissertations. Paper 164.