Abstract
Compelling evidence from preclinical and clinical studies has shown that mild hypothermia is neuroprotective against ischemic stroke. We investigated the neuroprotective effect of post-risperidone (RIS) treatment against transient ischemic injury and its mechanisms in the gerbil brain. Transient ischemia (TI) was induced in the telencephalon by bilateral common carotid artery occlusion (BCCAO) for 5 min under normothermic condition (37 ± 0.2 °C). Treatment of RIS induced hypothermia until 12 h after TI in the TI-induced animals under uncontrolled body temperature (UBT) compared to that under controlled body temperature (CBT) (about 37 °C). Neuroprotective effect was statistically significant when we used 5 and 10 mg/kg doses (p < 0.05, respectively). In the RIS-treated TI group, many CA1 pyramidal neurons of the hippocampus survived under UBT compared to those under CBT. In this group under UBT, post-treatment with RIS to TI-induced animals markedly attenuated the activation of glial cells, an increase of oxidative stress markers [dihydroethidium, 8-hydroxy-2′ -deoxyguanosine (8-OHdG), and 4-Hydroxynonenal (4-HNE)], and a decrease of superoxide dismutase 2 (SOD2) in their CA1 pyramidal neurons. Furthermore, RIS-induced hypothermia was significantly interrupted by NBOH-2C-CN hydrochloride (a selective 5-HT2A receptor agonist), but not bromocriptine mesylate (a D2 receptor agonist). Our findings indicate that RIS-induced hypothermia can effectively protect neuronal cell death from TI injury through attenuation of glial activation and maintenance of antioxidants, showing that 5-HT2A receptor is involved in RIS-induced hypothermia. Therefore, RIS could be introduced to reduce body temperature rapidly and might be applied to patients for hypothermic therapy following ischemic stroke.
Highlights
Neuroprotective compounds provide protection in models of ischemic stroke; none have shown efficacy in clinical trials [1]
Under uncontrolled body temperature (UBT) condition, an abrupt elevation of body temperature was seen in the Transient ischemia (TI) + vehicle group after TI, and the maximum temperature (39 ± 0.5 ◦C) was at 1 h after TI; thereafter, body temperature was gradually decreased (Figure 1A)
We reported that treatment with RIS dose-dependently protected against TI-induced delayed neuronal death (DND) of CA1 pyramidal neurons in the gerbil hippocampus [13]
Summary
Neuroprotective compounds provide protection in models of ischemic stroke; none have shown efficacy in clinical trials [1]. It has been attempted to find drugs, including atypical antipsychotic agents with hypothermic effects [6,7], to treat ischemic stroke. This study determined whether neuroprotective effect of RIS is hypothermia as a post-conditioning stimulus for inducing ischemic tolerance and elucidated RIS-induced hypothermic mechanisms. For this purpose, we intended (1) to compare effects of RIS on transient ischemic damage between ischemic animals without regulating body temperature and with maintaining body temperature; (2) to study effects of RIS against ischemia-induced oxidative stress; and (3) to investigate roles of central 5-HT2A and D2 receptors in body temperature regulation in RIS-treated animals
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