68. Neuroprotective Actions of Olanzapine in Rat: Mechanism

Psychotic patients treated with olanzapine (OLZ) do not exhibit extrapyramidal side-effects (EPS) similar to patients treated with haloperidol (HAL). Also, OLZ treated patients show significantly improved cognitive performance and negative symptoms, including patients previously treated with HAL. Haloperidol has been suggested to cause/exacerbate the neuropathological changes that are relevant to some of the sideeffects associated with its treatment. In animals, chronic HAL treatment has been found to cause neuropathology that is relevant to the behavioral effects, and this neuropathology is suggested to be a result of HAL associated free radical-mediated cellular damage. A possible mechanism of neuroprotection by OLZ against HAL induced neuropathology were studied in rats. Three groups of rats (CON, HAL, OLZ) were treated for 45 days and 90 days. After 45 days of treatment, one third (N 5 15) of the rats in each of the HAL and OLZ groups were switched to OLZ and HAL, respectively, in order to determine the protective/restorative actions of OLZ against HAL effects. The cellular effects were investigated by staining for DNA breaks that are often caused by free radical action and/or during replication/ translation. The cells were also stained with neuronal and glial markers to identify the cell types. After 45 days of treatment, a higher number of cells were labeled in cerebral cortex in OLZ group than HAL group, but fewer number of cells were labeled in caudate/putamen. The labeled cells were of both neuronal and glial types. There were no labeled cells in control group. The number of cells labeled decreased after 90 days of treatment proportionately in both drug groups but did not reach to the levels in controls. Preor the post-treatment with OLZ reduced the number of cells labeled compared to HAL treatment alone. The level of brain lipid peroxides, index of free radical damage, was higher in HAL group than OLZ group and was reduced by pre or post OLZ treatment, indicating that OLZ prevents the cellular neuropathology.