Progress in Neuro-Psychopharmacology and Biological Psychiatry
Antioxidant properties of propofol and erythropoietin after closed head injury in rats
Introduction
Head trauma and subsequently traumatic brain injury (TBI) occur sufficiently serious to require hospitalization. Posttraumatic period has early ischemic injury induced by release of reactive oxygen species (ROS) and accumulation of activated neutrophils (Juurlink and Paterson, 1998). Oxygen radicals that accumulated during trauma can damage proteins, carbohydrates, lipids and nucleic acids in cellular components. To cope with this potential damage, organisms have enzymatic SOD, glutathione peroxidase, and catalase and nonenzymatic (glutathione, ascorbic acid, carotenes, tocopherols, ubiquinol) antioxidant systems in intracellular and extracellular compartments.
During ischemia, adenosine triphosphate is degraded to adenosine monophosphate (Winn et al., 1979). At the end of purine catabolism, hypoxanthine formed from inosine is metabolized to xanthine and xanthine to uric acid by XO enzyme in the presence of oxygen. XO is one of the major potential sources of ROS in the organism. Nonenzymatic lipid peroxidation is an example of a free radical-associated process through which oxidative stress promotes cellular damage. Serum MDA is the end product of the major reactions leading to significant oxidation of such polyunsaturated fatty acids in cellular membranes and thus serves as a reliable marker of oxidative stress (Irmak et al., 2003). It has been noticed that NO plays an important role in modulating tissue injury and blood flow in normal and several pathological conditions (Sahin et al., 2002). There remains uncertainty about the role of NO in the TBI and also as to when, and indeed whether, NO production is increased or decreased. Endothelium-derived NO, which causes vasodilation, probably exerts a protective action on ischemic damage (Weight et al., 1998). However, administration of exogenous NO donors have been shown to be unequivocally beneficial against ischemia–reperfusion insults (Ohmori et al., 1998).
Propofol (2,6-diisopropylphenol) has widely been used clinically as an intravenous general anesthetic and as a sedative for critically ill patients. The structure of propofol differs from other hypnotic sedatives, but resembles the native nonenzymatic antioxidant vitamin E, in containing a phenolic hydroxyl group. The hydroxyl group (–OH) scavenges ROS and inhibits lipid peroxidation. The antioxidant characteristics of propofol may provide protection against ischemia of the central nervous system (CNS) (Ito et al., 1999, Boland et al., 2000). Although its antioxidant effects, propofol has not been investigated against TBI to date. Erythropoietin (EPO) is a cytokine glycoprotein hormone secreted from kidney that stimulates erythropoiesis under hypoxic conditions. Under ischemic conditions, glial cells have been shown to produce EPO in the brain (Masuda et al., 1994). EPO has been found to have modulatory action on the antioxidant defence system in the 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced neurotoxicity in vivo (Genc et al., 2002). Also, EPO has been shown to play a unique role in protecting the oxidative damage of membranes by hydroxyl radical in red blood cells (Chattonadhyay et al., 2000). Like propofol, the protective role of EPO against TBI has not been investigated to date.
The aim of the present experimental study was to investigate whether treatment with propofol and/or erythropoietin modifies the levels of the endogenous indices of oxidant stress and antioxidant enzyme activity in rats subjected to closed head injury (CHI). For this purpose, we examined various oxidative stress markers such as MDA, NO and XO as well as antioxidant enzyme SOD in rats with head injury pretreated with either propofol and/or EPO.
Section snippets
Animals
Female Wistar Albino rats (60 days) were used in the experiments. The animals were housed in quiet rooms with 12:12-h light–dark cycle and the experiments were performed in accordance with “Guide for the Care and Use of Laboratory Animals” (1985) and approved by ethical committee. Rats were randomly assigned to one of five groups: untreated rats served as sham operation group (n = 4), rats subjected to head trauma served as control group (n = 6), rats treated with intraperitoneal (i.p.) propofol in
Results and discussion
Results were summarized in Fig. 1, Fig. 2, Fig. 3, Fig. 4. Some changes in the activities of SOD and XO enzymes were observed in certain study groups; however, there was not statistically significance among groups (Fig. 1, Fig. 2). The mean values of serum MDA levels in the control TBI group were significantly higher than sham operation group (p < 0.012) (Fig. 3). Mean MDA levels in propofol, EPO and propofol + EPO groups were found to be decreased compared to control TBI group (p < 0.039, p < 0.030
Conclusion
Oxidative stress may have a pathophysiological role in closed head injury. This study demonstrates that prophylactic single or mix administration of propofol and EPO protect brain from traumatic injury. Further investigations with different doses and different time intervals of both propofol and EPO are needed to provide definitive data about the protective effects of these two agents against closed head injury in rats and possible clinical therapeutical approach for brain injuries.
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