China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China.
Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Biomolecules. 2022 Jun 19;12(6):851. doi: 10.3390/biom12060851.
Stroke is a leading threat to human life. Metabolic dysfunction of glucose may play a key role in stroke pathophysiology. Pharmacological hypothermia (PH) is a potential neuroprotective strategy for stroke, in which the temperature is decreased safely. The present study determined whether neuroprotective PH with chlorpromazine and promethazine (C + P), plus dihydrocapsaicin (DHC) improved glucose metabolism in acute ischemic stroke. A total of 208 adult male Sprague Dawley rats were randomly divided into the following groups: sham, stroke, and stroke with various treatments including C + P, DHC, C + P + DHC, phloretin (glucose transporter (GLUT)-1 inhibitor), cytochalasin B (GLUT-3 inhibitor), TZD (thiazolidinedione, phosphoenolpyruvate carboxykinase (PCK) inhibitor), and apocynin (nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor). Stroke was induced by middle cerebral artery occlusion (MCAO) for 2 h followed by 6 or 24 h of reperfusion. Rectal temperature was monitored before, during, and after PH. Infarct volume and neurological deficits were measured to assess the neuroprotective effects. Reactive oxygen species (ROS), NOX activity, lactate, apoptotic cell death, glucose, and ATP levels were measured. Protein expression of GLUT-1, GLUT-3, phosphofructokinase (PFK), lactate dehydrogenase (LDH), PCK1, PCK2, and NOX subunit gp91 was measured with Western blotting. PH with a combination of C + P and DHC induced faster, longer, and deeper hypothermia, as compared to each alone. PH significantly improved every measured outcome as compared to stroke and monotherapy. PH reduced brain infarction, neurological deficits, protein levels of glycolytic enzymes (GLUT-1, GLUT-3, PFK and LDH), gluconeogenic enzymes (PCK1 and PCK2), NOX activity and its subunit gp91, ROS, apoptotic cell death, glucose, and lactate, while raising ATP levels. In conclusion, stroke impaired glucose metabolism by enhancing hyperglycolysis and gluconeogenesis, which led to ischemic injury, all of which were reversed by PH induced by a combination of C + P and DHC.
中风是对人类生命的主要威胁。葡萄糖代谢功能障碍可能在中风病理生理学中起关键作用。药物降温（PH）是中风的一种潜在神经保护策略，其中安全地降低体温。本研究旨在确定氯丙嗪和异丙嗪（C + P）加二氢辣椒素（DHC）的神经保护 PH 是否改善急性缺血性中风中的葡萄糖代谢。总共 208 只成年雄性 Sprague Dawley 大鼠被随机分为以下组：假手术组、中风组和包括 C + P、DHC、C + P + DHC、根皮苷（葡萄糖转运蛋白（GLUT）-1 抑制剂）、细胞松弛素 B（GLUT-3 抑制剂）、TZD（噻唑烷二酮，磷酸烯醇丙酮酸羧激酶（PCK）抑制剂）和 apocynin（烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOX）抑制剂）在内的各种治疗组。中风通过大脑中动脉闭塞（MCAO）诱导 2 小时，然后再进行 6 或 24 小时的再灌注。在 PH 之前、期间和之后监测直肠温度。测量梗死体积和神经功能缺损以评估神经保护作用。测量活性氧（ROS）、NOX 活性、乳酸、凋亡细胞死亡、葡萄糖和 ATP 水平。用 Western blot 法测量 GLUT-1、GLUT-3、磷酸果糖激酶（PFK）、乳酸脱氢酶（LDH）、PCK1、PCK2 和 NOX 亚基 gp91 的蛋白表达。与中风和单一疗法相比，C + P 和 DHC 联合的 PH 诱导更快、更长和更深的降温。与中风和单一疗法相比，PH 显著改善了所有测量结果。PH 降低了脑梗死、神经功能缺损、糖酵解酶（GLUT-1、GLUT-3、PFK 和 LDH）、糖异生酶（PCK1 和 PCK2）、NOX 活性及其亚基 gp91、ROS、凋亡细胞死亡、葡萄糖和乳酸的蛋白水平，同时提高了 ATP 水平。总之，中风通过增强高糖酵解和糖异生来损害葡萄糖代谢，从而导致缺血性损伤，所有这些都被 C + P 和 DHC 联合诱导的 PH 逆转。
