A2A adenosine receptor antagonists effet on hydroxyl radical generation in DA depleted striatum with reserpine

Although the cause of DA neurons neurodegeneration is still unknown, oxidative stress is paramount in the pathogenesis of Parkinson’s disease. An accumulation of cytosolic DA has been shown to be neurotoxic through the generation of free radicals (FR). Searching for FR scavengers, we studied the effect of selective A2A adenosine receptor antagonists, shown to have neuroprotective properties, on hydroxyl radical (HR) production in rat striatum with reserpine impaired DA storage. We found an increase in extracellular glutamate and HR levels in DA-depleted striatum. CSC (1 mg/kg), ZM 241385 (3 mg/ kg) and L-DOPA (25 mg/kg) normalized glutamate release and combination of A2A antagonists and L-DOPA showed similar effect. CSC increased DA and HR levels but ZM 241385 given alone did not affect DA nor HR levels. L-DOPA enhanced DA extracellular level but did not change the production of HR. Combination of L-DOPA and CSC further elevated DA extracellular level and markedly increased HR production while combination of L-DOPA and ZM 241385 attenuated, enhanced by L-DOPA DA level and had no effect on HR production. This data suggests that disrupted balance between DA and glutamate in DA depleted nigrostriatal neurons results in generation of neurotoxic HR. Both A2A antagonists, like L-DOPA, redress the DA/glutamate balance. However, A2A antagonists in combination with L-DOPA show different pharmacological profi le in their effect on DA release and subsequent generation of HR.