Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada; Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB, T2N 4N1, Canada.
Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada; Departments of Medical Genetics and Biochemistry & Molecular Biology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada.
Neuropharmacology. 2023 Nov 1;238:109653. doi: 10.1016/j.neuropharm.2023.109653. Epub 2023 Jul 6.
Prolonged severe hypoxia follows brief seizures and represents a mechanism underlying several negative postictal manifestations without interventions. Approximately 50% of the postictal hypoxia phenomenon can be accounted for by arteriole vasoconstriction. What accounts for the rest of the drop in unbound oxygen is unclear. Here, we determined the effect of pharmacological modulation of mitochondrial function on tissue oxygenation in the hippocampus of rats after repeatedly evoked seizures. Rats were treated with mitochondrial uncoupler 2,4 dinitrophenol (DNP) or antioxidants. Oxygen profiles were recorded using a chronically implanted oxygen-sensing probe, before, during, and after seizure induction. Mitochondrial function and redox tone were measured using in vitro mitochondrial assays and immunohistochemistry. Postictal cognitive impairment was assessed using the novel object recognition task. Mild mitochondrial uncoupling by DNP raised hippocampal oxygen tension and ameliorated postictal hypoxia. Chronic DNP also lowered mitochondrial oxygen-derived reactive species and oxidative stress in the hippocampus during postictal hypoxia. Uncoupling the mitochondria exerts therapeutic benefits on postictal cognitive dysfunction. Finally, antioxidants do not affect postictal hypoxia, but protect the brain from associated cognitive deficits. We provided evidence for a metabolic component of the prolonged oxygen deprivation that follow seizures and its pathological sequelae. Furthermore, we identified a molecular underpinning of this metabolic component, which involves excessive oxygen conversion into reactive species. Mild mitochondrial uncoupling may be a potential therapeutic strategy to treat the postictal state where seizure control is absent or poor.
短暂癫痫发作后会出现长时间的严重缺氧，这是多种无干预性癫痫后负面表现的发生机制。大约 50%的癫痫后缺氧现象可以归因于小动脉收缩。其余氧分压下降的原因尚不清楚。在此，我们确定了反复诱发癫痫后，药物调节线粒体功能对大鼠海马组织氧合的影响。用线粒体解偶联剂 2,4-二硝基苯酚（DNP）或抗氧化剂处理大鼠。使用慢性植入的氧敏探头在癫痫诱导前后记录氧谱。使用体外线粒体测定和免疫组织化学测定测量线粒体功能和氧化还原状态。使用新物体识别任务评估癫痫后认知障碍。轻度线粒体解偶联剂 DNP 可提高海马氧张力，改善癫痫后缺氧。慢性 DNP 还降低了癫痫后缺氧期间海马中线粒体来源的活性氧和氧化应激。解偶联线粒体对癫痫后认知功能障碍具有治疗益处。最后，抗氧化剂不会影响癫痫后缺氧，但可防止大脑发生与缺氧相关的认知缺陷。我们为癫痫发作后长时间缺氧及其病理后果的代谢成分提供了证据。此外，我们确定了这种代谢成分的分子基础，其中涉及氧的过度转化为活性物质。轻度线粒体解偶联可能是一种潜在的治疗策略，可以治疗癫痫发作控制缺失或不佳的情况下的癫痫后状态。
