Abstract
Although the molecular basis of ischaemic damage of the brain is as yet unknown, it has been postulated that the uncontrolled production of reactive oxygenated species derived from molecular oxygen (including hydroxyl radicals, Superoxide radicals and singlet oxygen) may play a major role in the production of such injury. The ability of various barbiturates to modify the nature and extent of membrane damage produced by various oxygen radicals generated under well-defined conditionsin vitro has been directly examined using the human erythrocyte as model membrane system. Our results indicate that barbiturates are unlikely to exert their protective effects by directly scavenging singlet oxygen, Superoxide or hydroxyl radicals. The highly lipophilic barbiturate thiopentone is capable of decreasing the susceptibility of membranes to oxidative degradation by a direct membrane action, a property shared by amphipathic membrane stabilizers such as propranolol. The barbiturates were found to stabilize the haeme moiety of haemoglobin preventing its conversion to methaemoglobin in the presence of hydrogen peroxide. It is postulated that a major aspect of barbiturate action in decreasing ischaemic injury to the brain may involve the stabilization of haeme-coordinated iron complexes, thereby preventing the participation of these ubiquitous substances in initiating and potentiating free radical-mediated processes which have been implicated in the production of such injury.
Résumé
Bien que la théorie fondamentale du dommage cérébral ischémique ne soit pas encore élucidée, on a postulé que l’excès de production de dérivés réactifs de l’oxygène moléculaire (tels les radicaux hydroxyl, superoxyde et l’oxygène univalent) pouvait jouer un rôle important dans la genèse de la lésion hypoxique. Cette capacité pour certains barbituriques de modifier la nature et l’étendue du dommage causé à la membrane par certains radicaux générés in vitro dans des conditions expérimentales spécifiques a été étudiée directement sur un modèle de membrane de l’érythrocyte humain. Nos résultats montrent que les barbituriques n’exercent probablement pas leur effet protecteur par épuration de l’oxygène univalent et des radicaux hydroxyl et superoxyde. Le thiopentone qui est une substance fortement lipophile a la propriété de diminuer la susceptibilité de la membrane à la dégradation oxydative par action membranaire directe, comme les stabilisateurs amphipatiques tels le propranolol. Les barbituriques stabilisent la fraction hème de l’hémoglobine en empêchant sa conversion en methémoglobine en présence de peroxyde d’hydrogène. Il est postulé qu’un facteur important de l’activité barbiturique dans la diminution de la lésion ischémique consiste à stabiliser les complexes ferreux contrôlés par la production d’hème, empêchant ces substances toujours présentes d’initier et de potentialiser les processus médiés par l’intervention des radicaux libres qu’on croit responsables de la production de la lésion.
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Godin, D.V., Mitchell, M.J. & Saunders, B.A. Studies on the interaction of barbiturates with reactive oxygen rabicals: Implications regarding barbiturate protection against cerebral ischaemia. Can. Anaesth. Soc. J. 29, 203–211 (1982). https://doi.org/10.1007/BF03007117
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DOI: https://doi.org/10.1007/BF03007117