School of Medicine, Shandong University, Jinan, Shandong 250013, China.
Department of Endocrinology, Jinan Central Hospital, Affiliated to Shandong University, Jinan, Shandong 250013, China.
Epilepsy Behav. 2019 Sep;98(Pt A):173-187. doi: 10.1016/j.yebeh.2019.07.032. Epub 2019 Aug 1.
Epilepsy is a serious neurological disorder posing a severe burden to our society. Cognitive deficits are very common comorbidities of epilepsy. It is known that enhanced cognition has been demonstrated as an indicator for successful treatment of epilepsy. Physical exercise shows a positive consequence on cognition in healthy individuals and improves health and life conditions in people with epilepsy. However, there is no direct evidence to determine the role and the potential mechanism of physical exercise on the cognitive impairment and the relationship of susceptibility to seizures. The goal of the current investigation was to explore whether sustained physical exercise improves the cognitive dysfunction and simultaneously decreases the susceptibility to seizures in rats with epilepsy. Rats were treated with pentylenetetrazole (PTZ) (35 mg/kg, i.p. [intraperitoneally]) for 36 days to induce chronic epilepsy. During the induction period, rats were exposed to voluntary wheel running or forced swimming 30 min prior to each PTZ injection from the 16th day. The cognition of rats was evaluated by object recognition test and passive avoidance test. The susceptibility to seizures was evaluated by seizure frequency and duration. The levels of synaptic-related proteins including PSD95 (postsynaptic density 95), Synapsin, GluA1, and BDNF (brain-derived neurotrophic factor) were measured to evaluate the hippocampal synaptic plasticity. Furthermore, the GAD67 (glutamic acid decarboxylase) levels and GABA (γ-aminobutyric acid)ergic function in PTZ-treated rats were also determined. Finally, antagonist of GABAR (GABA receptors) bicuculline was used to explore the reversal effects of physical activity on seizures and cognition. The results showed that rats subjected to voluntary wheel running or forced swimming showed a significant reduction of seizure frequency and duration in PTZ-treated group relative to rats without running or swimming. In addition, both running and swimming improved cognitive function as measured by enhanced performance in object recognition test and passive avoidance test. Furthermore, the reduced levels of synaptic-related proteins and GABAergic function were reversed by exercise compared with rats without exercise. Moreover, antagonism of hippocampal CA3 (cornu ammonis 3) GABAergic neurons blocks the reversal effects of physical activity on seizures and cognition in PTZ-treated rats. These data showed that chronic physical exercise reduced the frequency of seizures and improved the cognitive function in a rat model of chronic epilepsy through normalization of CA3 synaptic plasticity and GABAergic function. Our findings suggest that chronic physical exercise has beneficial effects on controlling seizure through enhancement of cognition and highlights the possibility to translate into reduced seizure recurrence in people with epilepsy.
癫痫是一种严重的神经障碍，给我们的社会带来了严重的负担。认知缺陷是癫痫的常见合并症。众所周知，认知能力的提高已被证明是癫痫治疗成功的一个指标。体育锻炼对健康个体的认知有积极的影响，并改善癫痫患者的健康和生活条件。然而，目前还没有直接的证据来确定体育锻炼对认知障碍的作用和潜在机制，以及对癫痫易感性的关系。本研究的目的是探讨慢性运动是否能改善癫痫大鼠的认知功能障碍，同时降低癫痫发作的易感性。用戊四氮（PTZ）（35mg/kg，腹腔注射）处理大鼠 36 天，诱导慢性癫痫。在诱导期内，从第 16 天开始，在每次 PTZ 注射前，大鼠分别进行 30 分钟的自愿轮跑或强迫游泳。通过物体识别试验和被动回避试验评估大鼠的认知能力。通过癫痫发作频率和持续时间评估癫痫发作的易感性。测量突触相关蛋白的水平，包括 PSD95（突触后密度 95）、Synapsin、GluA1 和脑源性神经营养因子（BDNF），以评估海马突触可塑性。此外，还测定了 PTZ 处理大鼠的 GAD67（谷氨酸脱羧酶）水平和 GABA（γ-氨基丁酸）能功能。最后，使用 GABA 受体拮抗剂荷包牡丹碱（bicuculline）来探讨运动对癫痫和认知的逆转作用。结果表明，与未跑步或游泳的大鼠相比，进行自愿轮跑或强迫游泳的大鼠在 PTZ 处理组中的癫痫发作频率和持续时间显著降低。此外，跑步和游泳都能提高认知功能，表现在物体识别试验和被动回避试验中的表现增强。此外，与未运动的大鼠相比，运动可逆转突触相关蛋白和 GABA 能功能的降低。此外，阻断海马 CA3（角状突 3）GABA 能神经元可阻断慢性运动对 PTZ 处理大鼠癫痫发作和认知的逆转作用。这些数据表明，慢性运动通过正常化 CA3 突触可塑性和 GABA 能功能，降低癫痫发作频率，改善慢性癫痫大鼠的认知功能。我们的发现表明，慢性运动通过增强认知能力对控制癫痫发作有有益的影响，并强调了在癫痫患者中减少癫痫发作复发的可能性。
