Risperidone Treatment after Transient Ischemia Induces Hypothermia and Provides Neuroprotection in the Gerbil Hippocampus by Decreasing Oxidative Stress

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.

CD200 Change Is Involved in Neuronal Death in Gerbil Hippocampal CA1 Field Following Transient Forebrain Ischemia and Postischemic Treatment with Risperidone Displays Neuroprotection without CD200 Change

“…Finally, we investigated CD200 immunoreactivity in the ischemic CA1 field after postischemic treatment with 10 mg/kg RIS, because we recently demonstrated that therapeutic treatment with 10 mg/kg RIS after 5-min tFI in gerbils displayed excellent neuroprotective effects in a gerbil model of tFI and a rat model of MCAO-induced transient focal cerebral ischemia [ 36 , 37 ]. We found that posttreatment with RIS strongly protected pyramidal neurons in the ischemic CA1 field: this finding is consistent with the previous finding.…”

“…To investigate whether CD200 affected the neuroprotection of the CA1 pyramidal neurons from tFI injury, 10 mg/kg RIS was treated after tFI according to a published method [36]. It was reported that treatment with RIS, an atypical antipsychotic drug, after tFI induced hypothermia and provided neuroprotection in the gerbil hippocampal CA1 field by decreasing oxidative stress (Yang et al, 2019).…”

“…To investigate whether CD200 affected the neuroprotection of the CA1 pyramidal neurons from tFI injury, 10 mg/kg RIS was treated after tFI according to a published method [36]. It was reported that treatment with RIS, an atypical antipsychotic drug, after tFI induced hypothermia and provided neuroprotection in the gerbil hippocampal CA1 field by decreasing oxidative stress (Yang et al, 2019). In short, the gerbils (subtotal n = 40) were assigned to 4 groups: (1) sham/vehicle group (n = 5), which was given sham surgery for tFI and intraperitoneally injected with vehicle (0.3% Tween 80 in saline);…”

Therapeutic Effects of Risperidone against Spinal Cord Injury in a Rat Model of Asphyxial Cardiac Arrest: A Focus on Body Temperature, Paraplegia, Motor Neuron Damage, and Neuroinflammation

“…As shown in Figure 1, vehicle or RIS (10 mg/kg) (Sigma-Aldrich, St. Louis, MO, USA) was injected into the peritoneal cavity immediately after ACA/CPR operation. The dose of RIS was selected based on a previous study [21]. RIS was dissolved in 0.3% Tween 80 (in 0.85% saline; NaCl w/v; Junsei Chemical Co., Ltd., Tokyo, Japan).…”

“…Studies in 2003 and 2004 reported that RIS induced hypothermia in patients with brain disorders, such as schizophrenia [19,20]. In a recent experimental study, RIS induced hypothermia in gerbils and effectively protected cells or neurons from ischemiareperfusion injury in the hippocampus by attenuating glial activation and maintaining antioxidants [21].…”