OXIDATIVE STRESS IN THE BRAIN FOLLOWING INTRAVENTRICULAR ADMINISTRATION OF ETHYLCHOLINE AZIRIDINIUM (AF64A)

AF64A is a toxic analog of choline that disrupts high affinity choline transport and produces a persistent presynaptic cholinergic hypofunct ion. The observed neuroprotectant effects of Vitamin E in the AF64A mo del suggested that oxidative stress contributed to the cholinotoxicity of AF64A. The studies presented here examined whether intraventricula r injection of AF64A produces oxidative stress in the brain of male Wi star rats. Indices of oxidative stress including thiobarbituric acid r eactive species (TEARS), free radical generation using hydrogen peroxi de-induced, luminol-dependent chemiluminescence (CL) and superoxide sc avenging/generating activity were measured in cerebral cortex, hippoca mpus and the rest of the brain, without cerebellum, 1, 3 or 5 days aft er bilateral intraventricular injection of 3 nmol of AF64A or artifici al CSF (sham surgery). The sham operation itself induced oxidative str ess throughout the brain (increased TEARS, CL and superoxide generatio n). In addition to the oxidative stress of the sham surgery AF64A incr eased basal TEARS on day 1 and Fe/ascorbate-induced TEARS on days 3 an d 5 throughout the brain. AF64A produced compensatory 'antioxidative' changes as well with increased superoxide scavenging activity observed on day 3 and decreased basal TEARS on day 5. AF64A also induced speci fic changes in the hippocampus including a decrease of CL and an incre ase of superoxide scavenging activity on day 5. The increased superoxi de scavenging activity persisted up to 126 days. The results of the pr esent study provide the first direct evidence that AF64A induces oxida tive stress following intraventricular injection.