24-hydroxycholesterol, a major polar metabolite of brain cholesterol, has neurotoxic effects. However, little is known about the effects of this polar metabolite on the CNS. In the present study, the effects of 24-hydroxycholesterol on behavior changes were investigated. Rats were divided into three groups: (i) a control group; (ii) a sham group: 0.5 ml PBS was infused into the cerebral ventricle;(iii) a model group: 0.5 ml 24-hydroxycholesterol (10 mu M) was infused into the cerebral ventricle. 24-hydroxycholesterol can obviously impair rats' acquisition and probe trial in the Morris Water Maze task. Compared with rats in the sham group, rats in the model group had longer escape latency time and traveled more distance, and performed worse in the probe trial task manifested by spending less time in the annulus and training quadrant, which probably was attributed to the neuronal degeneration in hippocampal CA1 area induced by 24-hydroxycholesterol as examined by histological assay and apoptotic assay. Our results revealed that the polar metabolites, such as 24-hydroxycholesterol, exert neurotoxic effects and exacerbate the neuron injury with their abnormal accumulation. These findings suggest that measures taken promptly to eliminate or inhibit the accumulation of polar metabolites should be a potential strategy to prevent neurological dysfunctions and promote the recovery of functional deficits after neurotoxic insult. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.