Cyclooxygenase (COX) and lipoxygenase (LOX) are responsible for the metabolism of arachidonic acid into inflammatory metabolites, prostaglandins and leukotrienes, respectively. The upregulation of these enzymes in the central nervous system has been demonstrated to be responsible for the increased neuronal vulnerability to degeneration. Kainic acid, a glutamate receptor agonist and responsible for neuronal excitotoxicity and oxidative damage via different mechanisms, is capable of stimulating mRNA of both COX-2 and 5-LOX in the brain. The present study was designed to study the effects of COX inhibitors (indomethacin, nimesulide, rofecoxib) and a 5-LOX inhibitor (acetyl-11-keto-beta-boswellic acid; AKBA) and the combination of these inhibitors (dual inhibition) on kainic acid induced excitotoxicity and oxidative and nitrosative damage in mice. The results from the present study indicated that AKBA, indomethacin, and nimesulide per se did not produce any change in the behavioural parameters after kainic acid administration; however, rofecoxib per seproduced a significant increase in the latency of clonic (seizure-like) movement and a decrease in mortality rate as compared with kainic acid treated animals. In combination studies AKBA, rofecoxib, and nimesulide produced a more pronounced effect than either of these drugs alone. Further, the effect of AKBA combined with rofecoxib was significantly more marked when compared with AKBA combined with nimesulide. Besides this, identical results were found for the effect of these agents and their combination against oxidative damage induced by kainic acid. These findings indicate the potential role of COX-2 inhibitors and also their combination with the 5-LOX inhibitor in kainic acid induced excitotoxicity and oxidative damage by virtue of their antioxidant effect and suggest the need for the development of dual inhibitors for the treatment of neuronal excitotoxicity.
Copyright (c) 2007 S. Karger AG, Basel.