泊马度胺可减轻大鼠创伤性脑损伤所致的神经元丢失、神经炎症和行为障碍。

Pomalidomide mitigates neuronal loss, neuroinflammation, and behavioral impairments induced by traumatic brain injury in rat.

作者信息

Wang Jin-Ya, Huang Ya-Ni, Chiu Chong-Chi, Tweedie David, Luo Weiming, Pick Chaim G, Chou Szu-Yi, Luo Yu, Hoffer Barry J, Greig Nigel H, Wang Jia-Yi

机构信息

Graduate Institute of Medical Science, College of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan.

Department of Nursing, Hsin Sheng Junior College of Medical Care and Management, Taoyuan, Taiwan.

出版信息

J Neuroinflammation. 2016 Jun 28;13(1):168. doi: 10.1186/s12974-016-0631-6.

BACKGROUND

Traumatic brain injury (TBI) is a global health concern that typically causes emotional disturbances and cognitive dysfunction. Secondary pathologies following TBI may be associated with chronic neurodegenerative disorders and an enhanced likelihood of developing dementia-like disease in later life. There are currently no approved drugs for mitigating the acute or chronic effects of TBI.

METHODS

The effects of the drug pomalidomide (Pom), an FDA-approved immunomodulatory agent, were evaluated in a rat model of moderate to severe TBI induced by controlled cortical impact. Post-TBI intravenous administration of Pom (0.5 mg/kg at 5 or 7 h and 0.1 mg/kg at 5 h) was evaluated on functional and histological measures that included motor function, fine more coordination, somatosensory function, lesion volume, cortical neurodegeneration, neuronal apoptosis, and the induction of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6).

RESULTS

Pom 0.5 mg/kg administration at 5 h, but not at 7 h post-TBI, significantly mitigated the TBI-induced injury volume and functional impairments, neurodegeneration, neuronal apoptosis, and cytokine mRNA and protein induction. To evaluate underlying mechanisms, the actions of Pom on neuronal survival, microglial activation, and the induction of TNF-α were assessed in mixed cortical cultures following a glutamate challenge. Pom dose-dependently ameliorated glutamate-mediated cytotoxic effects on cell viability and reduced microglial cell activation, significantly attenuating the induction of TNF-α.

CONCLUSIONS

Post-injury treatment with a single Pom dose within 5 h significantly reduced functional impairments in a well-characterized animal model of TBI. Pom decreased the injury lesion volume, augmented neuronal survival, and provided anti-inflammatory properties. These findings strongly support the further evaluation and optimization of Pom for potential use in clinical TBI.

背景

创伤性脑损伤（TBI）是一个全球性的健康问题，通常会导致情绪障碍和认知功能障碍。TBI后的继发性病理变化可能与慢性神经退行性疾病有关，并且在晚年患痴呆样疾病的可能性增加。目前尚无获批用于减轻TBI急性或慢性影响的药物。

方法

在可控皮质撞击诱导的中度至重度TBI大鼠模型中评估药物泊马度胺（Pom）的作用，该药物是一种经美国食品药品监督管理局（FDA）批准的免疫调节剂。在包括运动功能、精细运动协调、躯体感觉功能、损伤体积、皮质神经退行性变、神经元凋亡以及促炎细胞因子（TNF-α、IL-1β、IL-6）诱导等功能和组织学指标上，评估TBI后静脉注射Pom（5或7小时时0.5mg/kg，5小时时0.1mg/kg）的效果。

结果

TBI后5小时而非7小时给予0.5mg/kg的Pom，可显著减轻TBI诱导的损伤体积和功能障碍、神经退行性变、神经元凋亡以及细胞因子mRNA和蛋白的诱导。为评估潜在机制，在谷氨酸刺激后的混合皮质培养物中评估了Pom对神经元存活、小胶质细胞激活和TNF-α诱导的作用。Pom剂量依赖性地改善了谷氨酸介导的对细胞活力的细胞毒性作用，并减少了小胶质细胞激活，显著减弱了TNF-α的诱导。