International Experimental CNS Injury & Repair (IECNSIR), University Hospital, Uppsala University, Uppsala, Sweden; School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
Int Rev Neurobiol. 2017;137:65-98. doi: 10.1016/bs.irn.2017.09.001. Epub 2017 Nov 3.
The possibility that histamine influences the spinal cord pathophysiology following trauma through specific receptor-mediated upregulation of neuronal nitric oxide synthase (nNOS) was examined in a rat model. A focal spinal cord injury (SCI) was inflicted by a longitudinal incision into the right dorsal horn of the T10-11 segments. The animals were allowed to survive 5h. The SCI significantly induced breakdown of the blood-spinal cord barrier to protein tracers, reduced the spinal cord blood flow at 5h, and increased the edema formation and massive upregulation of nNOS expression. Pretreatment with histamine H1 receptor antagonist mepyramine (1mg, 5mg, and 10mg/kg, i.p., 30min before injury) failed to attenuate nNOS expression and spinal cord pathology following SCI. On the other hand, blockade of histamine H2 receptors with cimetidine or ranitidine (1mg, 5mg, or 10mg/kg) significantly reduced these early pathophysiological events and attenuated nNOS expression in a dose-dependent manner. Interestingly, TiO-naowire delivery of cimetidine or ranitidine (5mg doses) exerted superior neuroprotective effects on SCI-induced nNOS expression and cord pathology. It appears that effects of ranitidine were far superior than cimetidine at identical doses in SCI. On the other hand, pretreatment with histamine H3 receptor agonist α-methylhistamine (1mg, 2mg, or 5mg/kg, i.p.) that inhibits histamine synthesis and release in the central nervous system thwarted the spinal cord pathophysiology and nNOS expression when used in lower doses. Interestingly, histamine H3 receptor antagonist thioperamide (1mg, 2mg, or 5mg/kg, i.p.) exacerbated nNOS expression and cord pathology after SCI. These novel observations suggest that blockade of histamine H2 receptors or stimulation of histamine H3 receptors attenuates nNOS expression and induces neuroprotection in SCI. Taken together, our results are the first to demonstrate that histamine-induced pathophysiology of SCI is mediated via nNOS expression involving specific histamine receptors.
本研究旨在探讨组胺是否通过特定受体介导的神经元型一氧化氮合酶（nNOS）上调来影响创伤后脊髓的病理生理学。研究人员建立了大鼠脊髓损伤模型，通过在 T10-11 节段的背角做一个纵向切口造成局灶性脊髓损伤。动物存活 5 小时后，对其进行检测。研究结果显示，脊髓损伤显著导致蛋白示踪剂的血脊髓屏障破裂，5 小时时脊髓血流量减少，同时水肿形成和 nNOS 表达大量上调。损伤前 30 分钟预先给予组胺 H1 受体拮抗剂甲吡二胺（1mg、5mg 和 10mg/kg，腹腔注射），未能减轻脊髓损伤后的 nNOS 表达和脊髓病理。另一方面，组胺 H2 受体阻滞剂西咪替丁或雷尼替丁（1mg、5mg 或 10mg/kg）以剂量依赖性方式显著减轻这些早期的病理生理事件，并减轻 nNOS 的表达。有趣的是，西咪替丁或雷尼替丁（5mg 剂量）的 TiO-naowire 递药在脊髓损伤诱导的 nNOS 表达和脊髓病理方面表现出优越的神经保护作用。在相同剂量下，雷尼替丁的效果似乎远优于西咪替丁。另一方面，预先给予组胺 H3 受体激动剂α-甲基组胺（1mg、2mg 或 5mg/kg，腹腔注射），该激动剂可以抑制中枢神经系统中的组胺合成和释放，在较低剂量下可阻止脊髓的病理生理和 nNOS 表达。有趣的是，组胺 H3 受体拮抗剂噻哌酰胺（1mg、2mg 或 5mg/kg，腹腔注射）在脊髓损伤后加剧了 nNOS 表达和脊髓病理。这些新的观察结果表明，组胺 H2 受体阻断或组胺 H3 受体刺激可减轻 nNOS 表达并诱导脊髓损伤中的神经保护作用。综上所述，我们的研究结果首次表明，组胺诱导的脊髓损伤的病理生理学是通过涉及特定组胺受体的 nNOS 表达来介导的。
