Neurophysiology Unit, Department of Neurological Sciences, Christian Medical College, Vellore, India.
Neurophysiology Unit, Department of Neurological Sciences, Christian Medical College, Vellore, India.
World Neurosurg. 2019 May;125:e743-e753. doi: 10.1016/j.wneu.2019.01.164. Epub 2019 Feb 5.
Traumatic brain injury (TBI) results in both focal and diffuse brain pathological features that become severely exacerbated after the initial injury. Owing to this disease complexity, no effective therapeutic measure has yet been devised aimed directly at these pathological processes. We developed a clinically relevant model of TBI and tested the bidirectional neuroprotective role of adenosine 2A receptors (A2ARs) at different times.
Wistar rats were divided into 4 treatment groups (sham, TBI, A2AR agonist [CGS-21680], and A2AR antagonist [SCH-58261]) and 4 post-TBI intervals (15 minutes and 1, 12, and 24 hours). A2AR agonist and antagonist effects were tested by the neurological functional score (NFS) and levels of cyclic adenosine monophosphate, interleukin-1β, oxidative stress antioxidant markers, and caspase-3.
The A2AR agonist-treated group showed significant NFS improvement at 15 minutes and 1 hour after TBI compared with the TBI group. However, no improvement was observed at 12 and 24 hours. The A2AR antagonists resulted in no NFS improvement at 15 minutes and 1 hour, and significant improvement observed at 12 and 24 hours. Significant neuroprotective effect with an A2AR agonist were observed with cyclic adenosine monophosphate, interleukin-1β, oxidative stress markers, catalase, and caspase-3 levels at 15 minutes and 1 hour after TBI. The A2AR antagonist showed no effect at these intervals but showed a protective effect at 12 and 24 hours after TBI.
The A2AR agonist showed a beneficial neuroprotective effect at the early stages after TBI, and the A2AR antagonist showed a benefit at the later stages after TBI. These findings suggest that A2AR agonists and antagonists should be used in accordance with the point at which the TBI occurred.
创伤性脑损伤（TBI）导致局灶性和弥漫性脑病理特征，这些特征在初始损伤后会严重恶化。由于这种疾病的复杂性，目前还没有针对这些病理过程的有效治疗方法。我们开发了一种具有临床相关性的 TBI 模型，并在不同时间测试了腺苷 A2A 受体（A2ARs）的双向神经保护作用。
Wistar 大鼠分为 4 个治疗组（假手术、TBI、A2AR 激动剂[CGS-21680]和 A2AR 拮抗剂[SCH-58261]）和 4 个 TBI 后时间间隔（15 分钟和 1、12 和 24 小时）。通过神经功能评分（NFS）和环磷酸腺苷、白细胞介素-1β、氧化应激抗氧化标志物和半胱天冬酶-3 水平测试 A2AR 激动剂和拮抗剂的作用。
与 TBI 组相比，A2AR 激动剂治疗组在 TBI 后 15 分钟和 1 小时时 NFS 显著改善。然而，在 12 和 24 小时时没有观察到改善。A2AR 拮抗剂在 15 分钟和 1 小时时没有改善 NFS，但在 12 和 24 小时时观察到显著改善。在 TBI 后 15 分钟和 1 小时时，A2AR 激动剂观察到环磷酸腺苷、白细胞介素-1β、氧化应激标志物、过氧化氢酶和半胱天冬酶-3 水平的显著神经保护作用。A2AR 拮抗剂在这些时间点没有作用，但在 TBI 后 12 和 24 小时显示出保护作用。
A2AR 激动剂在 TBI 后早期阶段显示出有益的神经保护作用，而 A2AR 拮抗剂在 TBI 后晚期阶段显示出益处。这些发现表明，A2AR 激动剂和拮抗剂应根据 TBI 发生的时间点使用。
