Pu Hongjian, Jiang Xiaoyan, Wei Zhishuo, Hong Dandan, Hassan Sulaiman, Zhang Wenting, Liu Jialin, Meng Hengxing, Shi Yejie, Chen Ling, Chen Jun
Cell Transplant. 2017 Apr 13;26(4):555-569. doi: 10.3727/096368916X693842. Epub 2016 Nov 24.
Traumatic brain injury (TBI) is one of the most disabling clinical conditions that could lead to neurocognitive disorders in survivors. Our group and others previously reported that prophylactic enrichment of dietary omega-3 polyunsaturated fatty acids (n-3 PUFAs) markedly ameliorate cognitive deficits after TBI. However, it remains unclear whether a clinically relevant therapeutic regimen with n-3 PUFAs administered after TBI would still offer significant improvement of long-term cognitive recovery. In the present study, we employed the decline of spatial cognitive function as a main outcome after TBI to investigate the therapeutic efficacy of post-TBI n-3 PUFA treatment and the underlying mechanisms. Mice were subjected to sham operation or controlled cortical impact, followed by random assignment to receive the following four treatments: (1) vehicle control; (2) daily intraperitoneal injections of n-3 PUFAs for 2 weeks, beginning 2 h after TBI; (3) fish oil dietary supplementation throughout the study, beginning 1 day after TBI; or (4) combination of treatments (2) and (3). Spatial cognitive deficits and chronic brain tissue loss, as well as endogenous brain repair processes such as neurogenesis, angiogenesis, and oligodendrogenesis, were evaluated up to 35 days after TBI. The results revealed prominent spatial cognitive deficits and massive tissue loss caused by TBI. Among all mice receiving post-TBI n-3 PUFA treatments, the combined treatment of fish oil dietary supplement and n-3 PUFA injections demonstrated a reproducible beneficial effect in attenuating cognitive deficits although without reducing gross tissue loss. Mechanistically, the combined treatment promoted post-TBI restorative processes in the brain, including generation of immature neurons, microvessels, and oligodendrocytes, each of which was significantly correlated with the improved cognitive recovery. These results indicated that repetitive and prolonged n-3 PUFA treatments after TBI are capable of enhancing brain remodeling and could be developed as a potential therapy to treat TBI victims in the clinic.
创伤性脑损伤（TBI）是最具致残性的临床病症之一，可导致幸存者出现神经认知障碍。我们团队及其他研究团队此前报告称，预防性补充膳食中的ω-3多不饱和脂肪酸（n-3 PUFAs）可显著改善创伤性脑损伤后的认知缺陷。然而，TBI后给予n-3 PUFAs的临床相关治疗方案是否仍能显著改善长期认知恢复尚不清楚。在本研究中，我们将TBI后空间认知功能的下降作为主要观察指标，以研究TBI后n-3 PUFA治疗的疗效及其潜在机制。对小鼠进行假手术或控制性皮质撞击，随后随机分为四组接受以下四种治疗：（1）溶剂对照；（2）TBI后2小时开始，每日腹腔注射n-3 PUFAs，持续2周；（3）TBI后1天开始，在整个研究过程中给予鱼油膳食补充剂；或（4）联合治疗（2）和（3）。在TBI后长达35天的时间里，评估空间认知缺陷、慢性脑组织损失以及内源性脑修复过程，如神经发生、血管生成和少突胶质细胞生成。结果显示，TBI导致明显的空间认知缺陷和大量组织损失。在所有接受TBI后n-3 PUFA治疗的小鼠中，鱼油膳食补充剂和n-3 PUFA注射的联合治疗在减轻认知缺陷方面显示出可重复的有益效果，尽管并未减少总体组织损失。从机制上讲，联合治疗促进了TBI后脑的修复过程，包括未成熟神经元、微血管和少突胶质细胞的生成，每一项都与认知恢复的改善显著相关。这些结果表明，TBI后重复和长期的n-3 PUFA治疗能够增强脑重塑，有望开发成为治疗TBI患者的潜在临床疗法。
