Department of Physical Medicine and Rehabilitation, Cheng Hsin General Hospital, Taipei, Taiwan, Republic of China.
Graduate Institute of Gerontology and Health Care Management, Chang Gung University of Science and Technology, Taoyuan, Taiwan, Republic of China.
Brain Pathol. 2024 Sep;34(5):e13244. doi: 10.1111/bpa.13244. Epub 2024 Feb 2.
Intracerebral hemorrhage (ICH) induces a complex sequence of apoptotic cascades and inflammatory responses, leading to neurological impairment. Transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel with high calcium permeability, has been implicated in neuronal apoptosis and inflammatory responses. This study used a mouse ICH model and neuronal cultures to examine whether TRPV1 activation exacerbates brain damage and neurological deficits by promoting neuronal apoptosis and neuroinflammation. ICH was induced by injecting collagenase in both wild-type (WT) C57BL/6 mice and TRPV1 mice. Capsaicin (CAP; a TRPV1 agonist) or capsazepine (a TRPV1 antagonist) was administered by intracerebroventricular injection 30 min before ICH induction in WT mice. The effects of genetic deletion or pharmacological inhibition of TRPV1 using CAP or capsazepine on motor deficits, histological damage, apoptotic responses, blood-brain barrier (BBB) permeability, and neuroinflammatory reactions were explored. The antiapoptotic mechanisms and calcium influx induced by TRPV1 inactivation were investigated in cultured hemin-stimulated neurons. TRPV1 expression was upregulated in the hemorrhagic brain, and TRPV1 was expressed in neurons, microglia, and astrocytes after ICH. Genetic deletion of TRPV1 significantly attenuated motor deficits and brain atrophy for up to 28 days. Deletion of TRPV1 also reduced brain damage, neurodegeneration, microglial activation, cytokine expression, and cell apoptosis at 1 day post-ICH. Similarly, the administration of CAP ameliorated brain damage, neurodegeneration, brain edema, BBB permeability, and cytokine expression at 1 day post-ICH. In primary neuronal cultures, pharmacological inactivation of TRPV1 by CAP attenuated neuronal vulnerability to hemin-induced injury, suppressed apoptosis, and preserved mitochondrial integrity in vitro. Mechanistically, CAP reduced hemin-stimulated calcium influx and prevented the phosphorylation of CaMKII in cultured neurons, which was associated with reduced activation of P38 and c-Jun NH-terminal kinase mitogen-activated protein kinase signaling. Our results suggest that TRPV1 inhibition may be a potential therapy for ICH by suppressing mitochondria-related neuronal apoptosis.
脑出血 (ICH) 诱导一系列复杂的细胞凋亡级联反应和炎症反应，导致神经功能障碍。瞬时受体电位香草酸 1 型 (TRPV1) 是一种非选择性阳离子通道，具有高钙通透性，与神经元凋亡和炎症反应有关。本研究使用小鼠 ICH 模型和神经元培养物来研究 TRPV1 的激活是否通过促进神经元凋亡和神经炎症加重脑损伤和神经功能缺损。ICH 通过在野生型 (WT) C57BL/6 小鼠和 TRPV1 小鼠双侧脑室内注射胶原酶诱导。在 WT 小鼠 ICH 诱导前 30 分钟，通过脑室内注射辣椒素 (CAP；TRPV1 激动剂) 或辣椒平 (TRPV1 拮抗剂) 进行给药。研究了使用 CAP 或辣椒平进行基因缺失或药理学抑制 TRPV1 对运动缺陷、组织学损伤、凋亡反应、血脑屏障 (BBB) 通透性和神经炎症反应的影响。研究了 TRPV1 失活诱导的抗凋亡机制和钙内流在培养的血红素刺激神经元中的作用。TRPV1 在出血性大脑中表达上调，ICH 后在神经元、小胶质细胞和星形胶质细胞中表达 TRPV1。TRPV1 基因缺失显著减轻了长达 28 天的运动缺陷和脑萎缩。TRPV1 缺失还减少了 ICH 后 1 天的脑损伤、神经退行性变、小胶质细胞激活、细胞因子表达和细胞凋亡。同样，CAP 的给药在 ICH 后 1 天改善了脑损伤、神经退行性变、脑水肿、BBB 通透性和细胞因子表达。在原代神经元培养物中，CAP 通过药理学失活 TRPV1 减轻了神经元对血红素诱导损伤的易感性，抑制了凋亡，并在体外维持了线粒体完整性。机制上，CAP 减少了血红素刺激的钙内流，并防止了培养神经元中 CaMKII 的磷酸化，这与 P38 和 c-Jun NH2 末端激酶丝裂原激活蛋白激酶信号转导的激活减少有关。我们的结果表明，TRPV1 抑制可能通过抑制与线粒体相关的神经元凋亡成为 ICH 的一种潜在治疗方法。
