Valproic Acid Reduces Vasospasm through Modulation of Akt Phosphorylation and Attenuates Neuronal Apoptosis in Subarachnoid Hemorrhage Rats
Aneurysmal subarachnoid hemorrhage (SAH) is a devastating emergent event associated with high mortality and morbidity. Survivors usually experience functional neurological sequelae caused by vasospasm-related delayed ischemia. In this study, male Sprague-Dawley rats were randomly assigned to five gr...
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MDPI AG
2021-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/11/5975 |
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| author | Chieh-Hsin Wu Yi-Cheng Tsai Tai-Hsin Tsai Keng-Liang Kuo Yu-Feng Su Chih-Hui Chang Chih-Lung Lin |
| author_facet | Chieh-Hsin Wu Yi-Cheng Tsai Tai-Hsin Tsai Keng-Liang Kuo Yu-Feng Su Chih-Hui Chang Chih-Lung Lin |
| author_sort | Chieh-Hsin Wu |
| collection | DOAJ |
| description | Aneurysmal subarachnoid hemorrhage (SAH) is a devastating emergent event associated with high mortality and morbidity. Survivors usually experience functional neurological sequelae caused by vasospasm-related delayed ischemia. In this study, male Sprague-Dawley rats were randomly assigned to five groups: sham (non-SAH) group, SAH group, and three groups with SAH treated with different doses of valproic acid (VPA) (10, 20, 40 mg/kg, once-daily, for 7 days). The severity of vasospasm was determined by the ratio of cross-sectional areas to intima-media thickness of the basilar arteries (BA) on the seventh day after SAH. The BA showed decreased expression of phospho-Akt proteins. The dentate gyrus showed increased expression of cleaved caspase-3 and Bax proteins and decreased expression of Bcl-2, phospho-ERK 1/2, phospho-Akt and acetyl-histone H3 proteins. The incidence of SAH-induced vasospasm was significantly lower in the SAH group treated with VPA 40 mg/kg (<i>p</i> < 0.001). Moreover, all groups treated with VPA showed reversal of the above-mentioned protein expression in BA and the dentate gyrus. Treatment with VPA upregulated histone H3 acetylation and conferred anti-vasospastic and neuro-protective effects by enhancing Akt and/or ERK phosphorylation. This study demonstrated that VPA could alleviate delayed cerebral vasospasm induced neuro-apoptosis after SAH. |
| first_indexed | 2024-03-10T10:48:52Z |
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| language | English |
| last_indexed | 2024-03-10T10:48:52Z |
| publishDate | 2021-06-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-732cd4df5af645c9a28eb41e0d3fa1ca2023-11-21T22:22:35ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-012211597510.3390/ijms22115975Valproic Acid Reduces Vasospasm through Modulation of Akt Phosphorylation and Attenuates Neuronal Apoptosis in Subarachnoid Hemorrhage RatsChieh-Hsin Wu0Yi-Cheng Tsai1Tai-Hsin Tsai2Keng-Liang Kuo3Yu-Feng Su4Chih-Hui Chang5Chih-Lung Lin6Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80756, TaiwanGraduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, TaiwanDivision of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80756, TaiwanDivision of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80756, TaiwanDivision of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80756, TaiwanDivision of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80756, TaiwanDivision of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80756, TaiwanAneurysmal subarachnoid hemorrhage (SAH) is a devastating emergent event associated with high mortality and morbidity. Survivors usually experience functional neurological sequelae caused by vasospasm-related delayed ischemia. In this study, male Sprague-Dawley rats were randomly assigned to five groups: sham (non-SAH) group, SAH group, and three groups with SAH treated with different doses of valproic acid (VPA) (10, 20, 40 mg/kg, once-daily, for 7 days). The severity of vasospasm was determined by the ratio of cross-sectional areas to intima-media thickness of the basilar arteries (BA) on the seventh day after SAH. The BA showed decreased expression of phospho-Akt proteins. The dentate gyrus showed increased expression of cleaved caspase-3 and Bax proteins and decreased expression of Bcl-2, phospho-ERK 1/2, phospho-Akt and acetyl-histone H3 proteins. The incidence of SAH-induced vasospasm was significantly lower in the SAH group treated with VPA 40 mg/kg (<i>p</i> < 0.001). Moreover, all groups treated with VPA showed reversal of the above-mentioned protein expression in BA and the dentate gyrus. Treatment with VPA upregulated histone H3 acetylation and conferred anti-vasospastic and neuro-protective effects by enhancing Akt and/or ERK phosphorylation. This study demonstrated that VPA could alleviate delayed cerebral vasospasm induced neuro-apoptosis after SAH.https://www.mdpi.com/1422-0067/22/11/5975apoptosisAktendothelial nitric oxide synthase (eNOs)ERKsubarachnoid hemorrhage (SAH)valproic acid (VPA) |
| spellingShingle | Chieh-Hsin Wu Yi-Cheng Tsai Tai-Hsin Tsai Keng-Liang Kuo Yu-Feng Su Chih-Hui Chang Chih-Lung Lin Valproic Acid Reduces Vasospasm through Modulation of Akt Phosphorylation and Attenuates Neuronal Apoptosis in Subarachnoid Hemorrhage Rats International Journal of Molecular Sciences apoptosis Akt endothelial nitric oxide synthase (eNOs) ERK subarachnoid hemorrhage (SAH) valproic acid (VPA) |
| title | Valproic Acid Reduces Vasospasm through Modulation of Akt Phosphorylation and Attenuates Neuronal Apoptosis in Subarachnoid Hemorrhage Rats |
| title_full | Valproic Acid Reduces Vasospasm through Modulation of Akt Phosphorylation and Attenuates Neuronal Apoptosis in Subarachnoid Hemorrhage Rats |
| title_fullStr | Valproic Acid Reduces Vasospasm through Modulation of Akt Phosphorylation and Attenuates Neuronal Apoptosis in Subarachnoid Hemorrhage Rats |
| title_full_unstemmed | Valproic Acid Reduces Vasospasm through Modulation of Akt Phosphorylation and Attenuates Neuronal Apoptosis in Subarachnoid Hemorrhage Rats |
| title_short | Valproic Acid Reduces Vasospasm through Modulation of Akt Phosphorylation and Attenuates Neuronal Apoptosis in Subarachnoid Hemorrhage Rats |
| title_sort | valproic acid reduces vasospasm through modulation of akt phosphorylation and attenuates neuronal apoptosis in subarachnoid hemorrhage rats |
| topic | apoptosis Akt endothelial nitric oxide synthase (eNOs) ERK subarachnoid hemorrhage (SAH) valproic acid (VPA) |
| url | https://www.mdpi.com/1422-0067/22/11/5975 |
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