l-Borneol ameliorates cerebral ischaemia by downregulating the mitochondrial calcium uniporter-induced apoptosis cascade in pMCAO rats.

OBJECTIVES Stroke is one of the leading causes of disability and death worldwide, and ischaemic stroke is the most common subtype. Moreover, we found that L-borneol has an obvious therapeutic effect on cerebral ischaemia. This study aimed to investigate the potential mechanism of L-borneol in permanent middle cerebral artery occlusion (pMCAO) rats via the mitochondrial calcium uniporter (MCU)-related apoptosis cascade. METHODS A pMCAO model was used to simulate cerebral ischaemia, and neurological function was evaluated. Cerebral infarction was observed by TTC staining. HE staining was also used to reflect the pathophysiological changes in the rat hippocampus and cortex. Furthermore, MCU-related signals and apoptosis signalling pathways were detected at both the gene and protein levels. RESULTS The neurological function scores of the high-dose L-borneol (H-B) group, medium-dose L-borneol (M-B) group and low-dose L-borneol (L-B) group were significantly lower than that of the model group at 24 h (P < 0.05, P < 0.01). High and medium doses of L-borneol could reverse the cerebral infarction area, similar to Nimotop. After HE staining, the cells in the H-B group and M-B group were neatly and densely arranged, with largely normal morphological structures. High-dose L-borneol could significantly reduce the gene and protein levels of Apaf-1, Bad and Caspase-3 and increase the expression of Bcl-2 (P < 0.05, P < 0.01). In addition, the MCU expression of the H-B group was significantly decreased compared with that of the model group at both the gene and protein levels (P < 0.05, P < 0.01). The expression of IDH2 was similar to that of MCU but not MEP (P < 0.05, P < 0.01). CONCLUSION L-borneol can achieve brain protection by downregulating the excessive expression of MCU-related signalling pathway and further inhibiting the apoptosis of neurons during pMCAO.

[1]  Jianxia Wen,et al.  Metabolomics coupled with integrative pharmacology reveals the therapeutic effect of l-borneolum against cerebral ischaemia in rats. , 2020, The Journal of pharmacy and pharmacology.

[2]  R. Rahbarghazi,et al.  Down-regulation of Bcl2 and Survivin, and up-regulation of Bax involved in copper (II) phenylthiosemicarbazone complex-induced apoptosis in leukemia stem-like KG1a cells , 2020 .

[3]  Chun Xing Li,et al.  Influence of Chronic Ethanol Consumption on Apoptosis and Autophagy Following Transient Focal Cerebral Ischemia in Male Mice , 2020, Scientific Reports.

[4]  Yuxue Yang,et al.  Role of Xingnaojing Injection in treating acute cerebral hemorrhage , 2020, Medicine.

[5]  Guijuan Zhang,et al.  Aloe-Emodin Induces Breast Tumor Cell Apoptosis through Upregulation of miR-15a/miR-16-1 That Suppresses BCL2 , 2020, Evidence-based complementary and alternative medicine : eCAM.

[6]  N. Jiang,et al.  Dishevelled-1 regulated apoptosis through NF-κB in cerebral ischemia/reperfusion injury in rats , 2020, Neuroscience Letters.

[7]  Michael S. Phipps,et al.  Management of acute ischemic stroke , 2020, BMJ.

[8]  M. Luby,et al.  Blood-brain barrier integrity of stroke patients presenting in an extended time window , 2020, BMC Neurology.

[9]  Jian Xu,et al.  HIF-1α attenuates neuronal apoptosis by upregulating EPO expression following cerebral ischemia-reperfusion injury in a rat MCAO model , 2020, International journal of molecular medicine.

[10]  Wenyi Liu,et al.  MiR-211 protects cerebral ischemia/reperfusion injury by inhibiting cell apoptosis , 2020, Bioengineered.

[11]  Lijun Zheng,et al.  Ozone alleviates ischemia/reperfusion injury by inhibiting mitochondrion‐mediated apoptosis pathway in SH‐SY5Y cells , 2019, Cell biology international.

[12]  N. Araki,et al.  Effects of Edaravone on Nitric Oxide, Hydroxyl Radicals and Neuronal Nitric Oxide Synthase During Cerebral Ischemia and Reperfusion in Mice. , 2019, Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association.

[13]  Yongtai Zhang,et al.  Increased microneedle-mediated transdermal delivery of tetramethylpyrazine to the brain, combined with borneol and iontophoresis, for MCAO prevention. , 2019, International journal of pharmaceutics.

[14]  Qiongxiu Zhou,et al.  Mitochondria as a therapeutic target for ischemic stroke. , 2019, Free radical biology & medicine.

[15]  H. Tabassum,et al.  Ischemic stroke and mitochondria: mechanisms and targets , 2019, Protoplasma.

[16]  Zhiping Hu,et al.  Potential Neuroprotective Treatment of Stroke: Targeting Excitotoxicity, Oxidative Stress, and Inflammation , 2019, Front. Neurosci..

[17]  C. Borlongan,et al.  Neuroprotective effects of human bone marrow mesenchymal stem cells against cerebral ischemia are mediated in part by an anti-apoptotic mechanism , 2019, Neural regeneration research.

[18]  Ling Zhu,et al.  Voluntary exercise promotes neurotrophic factor and suppresses apoptosis in hippocampal ischemia. , 2019, Journal of integrative neuroscience.

[19]  R. C. Chang,et al.  Borneol for Regulating the Permeability of the Blood-Brain Barrier in Experimental Ischemic Stroke: Preclinical Evidence and Possible Mechanism , 2019, Oxidative medicine and cellular longevity.

[20]  A. Gadicherla,et al.  Slow Ca2+ Efflux by Ca2+/H+ Exchange in Cardiac Mitochondria Is Modulated by Ca2+ Re-uptake via MCU, Extra-Mitochondrial pH, and H+ Pumping by FOF1-ATPase , 2019, Front. Physiol..

[21]  Xin Ma,et al.  Metabolomics Study on the Effects of Salvianolic Acid B and Borneol for Treating Cerebral Ischemia in Rats by Ultra-Performance Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry. , 2019, Rejuvenation research.

[22]  Jian Wang,et al.  The protective roles of L-borneolum, D-borneolum and synthetic borneol in cerebral ischaemia via modulation of the neurovascular unit. , 2018, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[23]  G. Robertson,et al.  Tamoxifen-induced knockdown of the mitochondrial calcium uniporter in Thy1-expressing neurons protects mice from hypoxic/ischemic brain injury , 2018, Cell Death & Disease.

[24]  Shang-Der Chen,et al.  Diverse roles of mitochondria in ischemic stroke , 2018, Redox biology.

[25]  Q. Tong,et al.  Additive Neuroprotective Effect of Borneol with Mesenchymal Stem Cells on Ischemic Stroke in Mice , 2018, Front. Physiol..

[26]  Jie Liu,et al.  Borneol Attenuates Ultrasound-Targeted Microbubble Destruction-Induced Blood–Brain Barrier Opening in Focal Cerebral Ischemia , 2017, Front. Neurol..

[27]  Jian Wang,et al.  Meta-Analysis for Clinical Evaluation of Xingnaojing Injection for the Treatment of Cerebral Infarction , 2017, Front. Pharmacol..

[28]  M. Ruan,et al.  The Synergic Effect of Tetramethylpyrazine Phosphate and Borneol for Protecting Against Ischemia Injury in Cortex and Hippocampus Regions by Modulating Apoptosis and Autophagy , 2017, Journal of Molecular Neuroscience.

[29]  Lei Chang,et al.  (+)-Borneol is neuroprotective against permanent cerebral ischemia in rats by suppressing production of proinflammatory cytokines , 2017, Journal of biomedical research.

[30]  P. Bernardi,et al.  Commentary: The m-AAA Protease Associated with Neurodegeneration Limits MCU Activity in Mitochondria , 2016, Front. Physiol..

[31]  M. Ruan,et al.  Synergic Effect of Borneol and Ligustrazine on the Neuroprotection in Global Cerebral Ischemia/Reperfusion Injury: A Region-Specificity Study , 2016, Evidence-based complementary and alternative medicine : eCAM.

[32]  Y. Li,et al.  The role of the mitochondrial calcium uniporter in cerebral ischemia/reperfusion injury in rats involves regulation of mitochondrial energy metabolism. , 2013, Molecular medicine reports.