Otsuka Shotaro, Setoyama Kentaro, Takada Seiya, Nakanishi Kazuki, Terashi Takuto, Norimatsu Kosuke, Tani Akira, Sakakima Harutoshi, Maruyama Ikuro, Tancharoen Salunya, Tanaka Eiichiro, Kikuchi Kiyoshi
Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Science, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.
Division of Laboratory Animal Science, Research Support Center, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan.
Mol Neurobiol. 2021 Nov;58(11):5602-5617. doi: 10.1007/s12035-021-02506-7. Epub 2021 Aug 9.
Subarachnoid hemorrhage (SAH) is a catastrophic form of stroke responsible for significant morbidity and mortality. Oxidative stress, inflammation, and neuronal apoptosis are important in the pathogenesis of early brain injury (EBI) following SAH. Preconditioning exercise confers neuroprotective effects, mitigating EBI; however, the basis for such protection is unknown. We investigated the effects of preconditioning exercise on brain damage and sensorimotor function after SAH. Male rats were assigned to either a sham-operated (Sham) group, exercise (Ex) group, or no-exercise (No-Ex) group. After a 3-week exercise program, they underwent SAH by endovascular perforation. Consciousness level, neurological score, and sensorimotor function were studied. The expression of nuclear factor erythroid 2 p45-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), 4-hydroxynonenal (4HNE), nitrotyrosine (NT), ionized calcium-binding adaptor molecule 1 (Iba1), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 1β (IL-1β), 14-3-3γ, p-β-catenin Ser37, Bax, and caspase-3 were evaluated by immunohistochemistry or western blotting. The terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick end labeling (TUNEL) assay was also performed. After SAH, the Ex group had significantly reduced neurological deficits, sensorimotor dysfunction, and consciousness disorder compared with the No-Ex group. Nrf2, HO-1, and 14-3-3γ were significantly higher in the Ex group, while 4HNE, NT, Iba1, TNF-α, IL-6, IL-1β, Bax, caspase-3, and TUNEL-positive cells were significantly lower. Our findings suggest that preconditioning exercise ameliorates EBI after SAH. The expression of 4HNE and NT was reduced by Nrf2/HO-1 pathway activation; additionally, both oxidative stress and inflammation were reduced. Furthermore, preconditioning exercise reduced apoptosis, likely via the 14-3-3γ/p-β-catenin Ser37/Bax/caspase-3 pathway.
蛛网膜下腔出血（SAH）是一种灾难性的中风形式，会导致严重的发病率和死亡率。氧化应激、炎症和神经元凋亡在SAH后的早期脑损伤（EBI）发病机制中起着重要作用。预处理运动具有神经保护作用，可减轻EBI；然而，这种保护的基础尚不清楚。我们研究了预处理运动对SAH后脑损伤和感觉运动功能的影响。将雄性大鼠分为假手术（Sham）组、运动（Ex）组或不运动（No-Ex）组。经过3周的运动计划后，通过血管内穿孔使其发生SAH。研究了意识水平、神经评分和感觉运动功能。通过免疫组织化学或蛋白质印迹法评估核因子红细胞2 p45相关因子2（Nrf2）、血红素加氧酶1（HO-1）、4-羟基壬烯醛（4HNE）、硝基酪氨酸（NT）、离子钙结合衔接分子1（Iba1）、肿瘤坏死因子α（TNF-α）、白细胞介素6（IL-6）、白细胞介素1β（IL-1β）、14-3-3γ、磷酸化β-连环蛋白Ser37、Bax和半胱天冬酶-3的表达。还进行了末端脱氧核苷酸转移酶介导的生物素化dUTP缺口末端标记（TUNEL）测定。SAH后，与No-Ex组相比，Ex组的神经功能缺损、感觉运动功能障碍和意识障碍明显减轻。Ex组中Nrf2、HO-1和14-3-3γ明显升高，而4HNE、NT、Iba1、TNF-α、IL-6、IL-1β、Bax、半胱天冬酶-3和TUNEL阳性细胞明显降低。我们的研究结果表明，预处理运动可改善SAH后的EBI。Nrf2/HO-1途径激活可降低4HNE和NT的表达；此外，氧化应激和炎症均减轻。此外，预处理运动可能通过14-3-3γ/磷酸化β-连环蛋白Ser37/Bax/半胱天冬酶-3途径减少细胞凋亡。
