Abstract:
Ischemic stroke is a leading cause of disability in New Zealand and the burden associated with this neurological disorder is increasing. A series of diverse yet inter‐related pathological processes have been identified in the underlying pathophysiology of ischemic stroke. Neuroinflammation is an important pathophysiological mechanism which contributes to the on‐going evolution of ischemic damage and cell loss in the brain. An early response following ischemic stroke is activation of microglial cells. Activated microglia induce a nonspecific innate immune response that may exacerbate acute ischemic injury through the release of reactive oxygen species, cytokines, and proteases. This response requires hours to days to fully develop, and thus presents a target for therapeutic intervention following ischemic stroke, allowing a much longer window of opportunity for treatment than those targeting acute neuroprotection. Risperidone, an anti‐psychotic agent, has been demonstrated to reduce the expression of Iba‐1‐positive activated microglia in the brains of EAE‐immunised mice, a model of multiple sclerosis. This current study investigates the immunomodulatory potential of risperidone for the treatment of stroke. We hypothesized that treatment with risperidone can reduce infarct volume via dampening microglial activation in a rodent model of stroke. However, risperidone had no significant effect on lesion volume in L‐NIO‐lesioned animals. Indeed, higher doses of risperidone increased lesion volume in sham‐lesioned animals. Furthermore, risperidone dose‐dependently increased the number of degenerating cells within the lesion area in both sham‐ and L‐NIO‐lesioned animals. These data suggest that risperidone may in fact be detrimental in the recovery of brain tissue. Activated microglia, astrocytes and macrophages were observed at 8 days after the onset of ischemia, indicating the presence of neuroinflammation. Risperidone significantly increased the expression of activated microglia following L‐NIO‐induced cerebral ischemia; this may have contributed to the observed up‐regulation in the number of degenerating cells. Activated astrocytes form glial scars which surrounded the ischemic lesion in L‐NIO‐lesioned animals. Lacking a significant increase in activated astrocyte expression was correlated with a higher number of degenerating cells. Thus astrocyte activation may be potentially beneficial to the brain following ischemia. Activated macrophages were widespread within the lesion area of the lesioned striatum, indicating that activated macrophages may participate in the progression of ischemic injury. In addition, risperidone did not alter sensorimotor function following ischemia. Overall, the results obtained from this study contrast with our hypothesis, and suggest that risperidone can aggravate the induced ischemic injury. To summarize, risperidone was not shown to modulate neuroinflammation or to alleviate ischemic damage.