International Experimental Central Nervous System Injury & Repair (IECNSIR), Dept. of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Frödingsgatan 12, LGH 1103, 75185, Uppsala, Sweden.
Department of Neurology, Bethune International Peace Hospital, Zhongshan Road (West), Shijiazhuang, Hebei, China.
Neurochem Res. 2023 Jun;48(6):1864-1888. doi: 10.1007/s11064-023-03861-8. Epub 2023 Jan 31.
Neuropathic pain is associated with abnormal sensations and/or pain induced by non-painful stimuli, i.e., allodynia causing burning or cold sensation, pinching of pins and needles like feeling, numbness, aching or itching. However, no suitable therapy exists to treat these pain syndromes. Our laboratory explored novel potential therapeutic strategies using a suitable composition of neurotrophic factors and active peptide fragments-Cerebrolysin (Ever Neuro Pharma, Austria) in alleviating neuropathic pain induced spinal cord pathology in a rat model. Neuropathic pain was produced by constrictions of L-5 spinal sensory nerves for 2-10 weeks period. In one group of rats cerebrolysin (2.5 or 5 ml/kg, i.v.) was administered once daily after 2 weeks until sacrifice (4, 8 and 10 weeks). Ag, Cu and Al NPs (50 mg/kg, i.p.) were delivered once daily for 1 week. Pain assessment using mechanical (Von Frey) or thermal (Hot-Plate) nociceptive showed hyperalgesia from 2 weeks until 10 weeks progressively that was exacerbated following Ag, Cu and Al NPs intoxication in nerve lesioned groups. Leakage of Evans blue and radioiodine across the blood-spinal cord barrier (BSCB) is seen from 4 to 10 weeks in the rostral and caudal cord segments associated with edema formation and cell injury. Immunohistochemistry of albumin and GFAP exhibited a close parallelism with BSCB leakage that was aggravated by NPs following nerve lesion. Light microscopy using Nissl stain exhibited profound neuronal damages in the cord. Transmission electron microcopy (TEM) show myelin vesiculation and synaptic damages in the cord that were exacerbated following NPs intoxication. Using ELISA spinal tissue exhibited increased albumin, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP) and heat shock protein (HSP 72kD) upregulation together with cytokines TNF-α, IL-4, IL-6, IL-10 levels in nerve lesion that was exacerbated following NPs intoxication. Cerebrolysin treatment significantly reduced hyperalgesia and attenuated BSCB disruption, edema formation and cellular changes in nerve lesioned group. The levels of cytokines were also restored near normal levels with cerebrolysin treatment. Albumin, GFAP, MABP and HSP were also reduced in cerebrolysin treated group and thwarted neuronal damages, myelin vesiculation and cell injuries. These neuroprotective effects of cerebrolysin with higher doses were also effective in nerve lesioned rats with NPs intoxication. These observations suggest that cerebrolysin actively protects spinal cord pathology and hyperalgesia following nerve lesion and its exacerbation with metal NPs, not reported earlier.
神经病理性疼痛与非疼痛刺激引起的异常感觉和/或疼痛有关，即痛觉过敏导致烧灼感或冷感、刺痛感、麻木感、酸痛或瘙痒。然而，目前尚无治疗这些疼痛综合征的合适疗法。我们的实验室使用神经营养因子和活性肽片段-脑活素（奥古金，奥地利）的合适组合，探索了缓解大鼠模型中脊髓神经病理性疼痛的新的潜在治疗策略。通过对 L-5 脊髓感觉神经进行 2-10 周的压迫，产生神经病理性疼痛。在一组大鼠中，脑活素（2.5 或 5 ml/kg，iv）在 2 周后每天给药一次，直到处死（4、8 和 10 周）。Ag、Cu 和 Al NPs（50 mg/kg，ip）每周给药一次，持续 1 周。使用机械（Von Frey）或热（热板）痛觉评估疼痛显示，从 2 周到 10 周，痛觉过敏逐渐加重，在神经损伤组中，Ag、Cu 和 Al NPs 中毒后加重。从 4 周到 10 周，在头端和尾端脊髓节段可见 Evans 蓝和放射性碘穿过血脊髓屏障（BSCB）的渗漏，与水肿形成和细胞损伤有关。白蛋白和 GFAP 的免疫组织化学显示与 BSCB 渗漏密切平行，在神经损伤后，NP 加重了这种渗漏。使用尼氏染色的光镜检查显示脊髓中有明显的神经元损伤。透射电镜（TEM）显示脊髓中的髓鞘囊泡和突触损伤，在 NP 中毒后加重。使用 ELISA 检测脊髓组织显示，在神经损伤后，白蛋白、神经胶质纤维酸性蛋白（GFAP）、髓鞘碱性蛋白（MBP）和热休克蛋白（HSP 72kD）的表达上调，同时细胞因子 TNF-α、IL-4、IL-6、IL-10 水平也上调，NP 中毒后进一步加重。脑活素治疗显著减轻神经损伤大鼠的痛觉过敏，并减轻 BSCB 破坏、水肿形成和细胞变化。细胞因子水平也在脑活素治疗后接近正常水平。在脑活素治疗组中，白蛋白、GFAP、MBP 和 HSP 也减少，并阻止了神经元损伤、髓鞘囊泡和细胞损伤。神经损伤大鼠在 NP 中毒后，脑活素的这些神经保护作用（剂量更高）也是有效的。这些观察结果表明，脑活素在神经损伤后积极保护脊髓病理和痛觉过敏，并在金属 NPs 的作用下加剧，这在以前的研究中没有报道过。
