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.2019 Sep 18;20(18):4621.
doi: 10.3390/ijms20184621.

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

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

Go Eun Yang et al. Int J Mol Sci..

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.

Keywords: 5-HT2A antagonist; antipsychotic drug; delayed neuronal death; ischemia/reperfusion; post-treatment; thermoregulation.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Effects of risperidone (RIS) against transient ischemia (TI) injury under uncontrolled body temperature (UBT) condition. (A) Changes in body temperature under UBT condition for 12 h after TI. Body temperature is significantly low in the TI + 10 mg/kg RIS group compared to the TI + vehicle group. White arrows indicate times of RIS treatment. The bars indicate the means ± SEM,n = 7/group, two-way analysis of variance (ANOVA) with a post-hoc Bonferroni’s multiple comparison test (*p < 0.05 vs. sham + vehicle group; #p < 0.05 vs. TI + vehicle group). (B) Effects of RIS on NeuN+ and F-J B+ cells in the CA1 under UBT condition after TI. In the sham + vehicle group, CA1 pyramidal neurons are well stained with NeuN; however, no F-J B+ CA1 pyramidal cells are found. In the TI + vehicle group, a few NeuN+ cells (arrows) are shown in the stratum pyramidale (SP) 5 days after TI; however, the distribution of NeuN+ cells in the TI + RIS group is similar to that in the sham + vehicle group. In the TI + vehicle group, many F-J B+ cells (asterisks) are detected in the SP 5 days after TI, and many F-J B+ CA1 pyramidal cells (asterisks) are detected; however, in the TI + RIS group, RIS produces a dose-dependent increase in the number of NeuN+ CA1 pyramidal neurons, and a dose-dependent decrease in the number of F-J B+ CA1 pyramidal cells 5 days after TI. CA1, cornu ammonis 1; CA3, cornu ammonis 3; DG, dentate gyrus; SO, stratum oriens; SR, stratum radiatum. Scale bar = 50 μm. Note histograms of quantitative analyses of NeuN+ and F-J B+ cells in all the groups, as shown (C) and (D). The bars indicate the means ± SEM,n = 7/group, two-way analysis of variance (ANOVA) with a post-hoc Bonferroni’s multiple comparison test (*p < 0.05 vs. sham + vehicle group; #p < 0.05 vs. TI + vehicle group).
Figure 2
Figure 2
Effects of RIS on GFAP+ astrocytes (A) and Iba-1+ microglia (B) in the CA1 after TI under UBT condition. GFAP+ astrocytes (arrows in (A)) and Iba-1+ microglia (arrows in (B)) are markedly increased in the TI + vehicle group 5 days after TI; however, their immunoreactivity in the TI + RIS group is significantly lower than that in the TI + vehicle group. SO, stratum oriens; SP, stratum pyramidale; SR, stratum radiatum. Scale bar  =  50 μm. Quantitative analyses of GFAP+ (C) and Iba-1+ cells (D). The bars indicate the means ± SEM,n = 7/group, two-way analysis of variance (ANOVA) with a post-hoc Bonferroni’s multiple comparison test (*p < 0.05 vs. sham + vehicle group; #p < 0.05 vs. TI + vehicle group).
Figure 3
Figure 3
Effects of RIS against TI injury under controlled body temperature (CBT) condition. (A) Changes in body temperature under CBT condition for 12 h after TI. Body temperature is slightly low in the TI + 10 mg/kg RIS group compared to the TI + 5 mg/kg RIS group. White arrows indicate times of RIS treatment. The bars indicate the means ± SEM,n = 7/group, two-way analysis of variance (ANOVA) with a post-hoc Bonferroni’s multiple comparison test (*p < 0.05 vs. sham + vehicle group; #p < 0.05 vs. TI + vehicle group). (B) Effect of RIS (10 mg/kg) on NeuN+, F-J B+, GFAP+, and Iba-1+ cells in the CA1 under CBT after TI 5 days after TI. In the TI + RIS group, a few NeuN+ neurons (arrows) and many F-J B+ cells (asterisks) are shown in the stratum pyramidale (SP) at 5 days after TI. GFAP+ astrocytes (arrows) and Iba-1+ microglia (asterisks) are markedly increased in the TI + RIS group under CBT 5 days after TI. SO, stratum oriens; SP, stratum pyramidale; SR, stratum radiatum. Scale bar  =  50 μm. Quantitative analyses of NeuN+ and F-J B+ cells (C), and GFAP+ and Iba-1+ cells (D). The bars indicate the means ± SEM,n = 7/group, two-way analysis of variance (ANOVA) with a post-hoc Bonferroni’s multiple comparison test (*p < 0.05 vs. sham + vehicle group).
Figure 4
Figure 4
Effects of RIS on superoxide anion production after TI under UBT and CBT conditions. (A) Changes of DHE immunofluorescence in the CA1 after TI under UBT and CBT conditions. DHE immunofluorescence is significantly increased in CA1 pyramidal neurons of the stratum pyramidale (SP, asterisks) in the TI + vehicle group under UBT and TI + RIS group under CBT at 1 day after TI; however, DHE immunofluorescence is not significantly increased in the SP of the TI + RIS group under UBT condition. SO, stratum oriens; SR, stratum radiatum. Scale bar = 50 μm. (B) Note analyses of DHE immunofluorescence in the SP. A ratio of the ROD is calibrated as %, with the sham + vehicle group designated as 100%. The bars indicate the means ± SEM,n = 7/group, two-way analysis of variance (ANOVA) with a post-hoc Bonferroni’s multiple comparison test (*p < 0.05 vs. sham + TI + vehicle group under UBT condition; #p < 0.05 vs. TI + vehicle group under UBT condition; †p < 0.05 vs. TI + RIS group under UBT condition.).
Figure 5
Figure 5
Effects of RIS on 8-OhdG and 4-HNE immunoreactivities after TI under UBT and CBT conditions. Representative images of immunohistochemistry for 8-OhdG (A) and 4-HNE (B) in the hippocampal CA1 after TI under UBT and CBT conditions. Under UBT condition, 8-OhdG and 4-HNE immunoreactivities in the TI + vehicle group are significantly increased in CA1 pyramidal neurons of the stratum pyramidale (SP, asterisks) in the TI + vehicle group under UBT and TI + RIS group under CBT at 1 day after TI; however, the immunoreactivities are significantly low (arrows) in the TI + RIS group under UBT. Scale bar = 50 μm. Note analyses of 8-OhdG (C) and 4-HNE (D) immunoreactivity in the SP. A ratio of the ROD is calibrated as %, with the sham + vehicle group designated as 100%. The bars indicate the means ± SEM,n = 7/group, two-way analysis of variance (ANOVA) with a post-hoc Bonferroni’s multiple comparison test (*p < 0.05 vs. sham + vehicle group under UBT condition; #p < 0.05 vs. TI + vehicle group under UBT condition; †p < 0.05 vs. TI + RIS group under UBT condition).
Figure 6
Figure 6
Effects of RIS on levels and immunoreactivity of SOD2 protein after TI under UBT and CBT conditions. (A) Western blot analysis of SOD2 protein in the hippocampus after TI under UBT and CBT conditions. Note that SOD2 levels are maintained in the TI + RIS group under UBT after TI. (B) Quantitative analysis of SOD2 protein in the hippocampus. Protein expression is normalized to β-actin. The bars indicate the means ± SEM,n = 7/group, two-way analysis of variance (ANOVA) with a post-hoc Bonferroni’s multiple comparison test (*p < 0.05 vs. sham + vehicle group under UBT condition; †p < 0.05 vs. TI + RIS group under UBT condition). (C) Representative images of immunohistochemistry for SOD2 in the hippocampal CA1 after TI under UBT and CBT conditions. SOD2 immunoreactivity is significantly decreased in CA1 pyramidal neurons of the stratum pyramidale (SP, asterisks) in the TI + vehicle group under UBT and TI + RIS group under CBT at 1 day after TI; however, the immunoreactivity is maintained (arrows) in the TI + RIS group under UBT. SO, stratum oriens; SR, stratum radiatum. Scale bar = 50 μm. (D) Quantitative analysis of SOD2 immunoreactivity in CA1 pyramidal neurons. A ratio of ROD is calibrated as %, with the sham + vehicle group designated as 100%. The bars indicate the means ± SEM,n = 7/group, two-way analysis of variance (ANOVA) with a post-hoc Bonferroni’s multiple comparison test (*p < 0.05 vs. sham + vehicle group under UBT condition; †p < 0.05 vs. TI + RIS group under UBT condition).
Figure 7
Figure 7
Effects of endogenous 5-HT2A- and, D2-receptors on RIS-induced hypothermia. Hypothermia was defined as a reduction of at least 2 °C below baseline (normothermia). NBOH-2C-CN hydrochloride does not alter body temperature, but bromocriptine mesylate significant decreased body temperature at 80 min after the administration, and (±)-DOI hydrochloride slightly increases body temperature at 60 min after the administration. Namely, RIS-induced hypothermia is interrupted following the administration of NBOH-2C-CN hydrochloride and (±)-DOI hydrochloride. The bars indicate the means ± SEM,n = 7/group, two-way analysis of variance (ANOVA) with a post-hoc Bonferroni’s multiple comparison test (*p < 0.05 vs. sham group; #p < 0.05 vs. RIS group).
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