文獻指出敗血症相關之全身性發炎反應可以誘發神經元過度興奮(hyperexcitability)，進而導致增加癲癇發生之感受性，並影響產生認知功能障礙。腦內的小膠質細胞(microglia)會因為全身炎症反應迅速地被活化並釋放出許多種不同的細胞素(cytokines)和信息因子，進而放大發炎反應，導致神經功能障礙之發生。由於腦中NADPH氧化酶(NADPH oxidase)透過產生活性氧類(reactive oxygen species;如超氧化物負離子)具有促進小膠質細胞活化的作用，因此我們假設阻斷NADPH 氧化酶(NOX2)活性可能具有改善敗血症所引起增加癲癇發生感受性及認知功能缺陷的作用。
為了印證此假說，我們利用調節NADPH 氧化酶NOX2重要亞單位基因缺損小鼠 p47phox (p47phox−/−)、gp91phox (gp91phox−/−) 及 NOX2-selective 抑制劑 diphenyleneiodonium (DPI)來作為達到減少NADPH氧化酶衍生活性氧化物產生的模式。首先，以腹腔內注射脂多糖 (Lipopolysaccharides，LPS)引起全身發炎反應後，利用戊四氮 (pentylenetetrazol，PTZ) 腹腔注射來誘發癲癇發作並進行三組小鼠(野生型, p47phox−/−及gp91phox−/−)之癲癇敏感性比較。在認知障礙功能研究上以八爪迷宮(Radial arm maze)進行小鼠群空間學習和記憶之比較。我們發現gp91phox−/−和 p47phox−/−基因缺損小鼠相較於野生型小鼠，在敗血症後對 PTZ 所誘發癲癇的敏感性明顯較弱。與野生型小鼠相比，gp91phox−/−和 p47phox−/−小鼠表達較低的 proconvulsive 細胞素[包括 tumor necrosis factor-α (TNFα)、interleukin-1β (IL-1β)、interleukin-6 (IL-6) 及 chemokine (C-C motif) ligand 2 (CCL2)]。在 LPS 注射後, DPI的投予明顯地降低了野生型小鼠對 PTZ 誘發癲癇的敏感性，並減少了小膠質細胞活化和腦內proconvulsive 細胞素的濃度。 此外，DPI 也會抑制LPS注射以後所誘導 gp91phox 轉錄的作用。 p47phox−/−小鼠與野生型小鼠相比，在敗血症後認知功能損害明顯地較弱。DPI投予也具有明顯降低LPS注射以後所誘導認知功能障礙的作用，減少了膠質細胞活化和腦內細胞素濃度以及突觸的喪失。
綜合此等研究發現我們認為 NADPH 氧化酶活化對敗血症後小鼠癲癇發作的敏感性及認知障礙的發展具有促進之作用。因此抑制 NOX2 可能是一種具有潛力作為減少敗血症相關之中樞發炎反應、 神經元過度興奮及癲癇發作之有效治療策略。此外，抑制 NOX2 也可以是進一步防止敗血症後產生漸進性神經元失調和認知功能之損害。

Systemic inflammation associated with sepsis can induce neuronal hyperexcitability, leading to enhanced seizure predisposition and increase the process of cognitive impairment. Brain microglia are rapidly activated in response to systemic inflammation and, in this activated state, release multiple cytokines and signaling factors that amplify the inflammatory response and increase neuronal dysfunction. NADPH oxidase (NOX) enzymes promote microglial activation through the generation of reactive oxygen species (ROS), such as superoxide anion. We hypothesized that NOX isoforms, particularly NOX2, are potential targets for prevention of sepsis-associated seizures and cognition deficits.
In order to reduce NADPH oxidase 2-derived ROS production, mice with deficits of NOX regulatory subunit/NOX2 organizer p47phox (p47phox−/−) or NOX2 major subunit gp91phox (gp91phox−/−) were used or the NOX2-selective inhibitor diphenyleneiodonium (DPI) was used to treat wild-type (WT) mice. Systemic inflammation was induced by intraperitoneal injection of lipopolysaccharide (LPS). Seizure susceptibility was compared among mouse groups in response to intraperitoneal injection of pentylenetetrazole (PTZ). Spatial learning and memory was then compared among mouse groups using RAM task. We found that increased susceptibility to PTZ-induced seizures following sepsis was significantly attenuated in gp91phox−/− and p47phox−/− mice compared with WT mice. Both gp91phox−/− and p47phox−/− mice exhibited reduced microglia activation and lower brain induction of multiple proconvulsive cytokines, including tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), interleukin-6 (IL-6) and chemokine (C-C motif) ligand 2 (CCL2), compared with WT mice. Administration of DPI following LPS injection significantly attenuated the increased susceptibility to PTZ-induced seizures and reduced both microglia activation and brain proconvulsive cytokine concentrations compared with vehicle-treated controls. DPI also inhibited the upregulation of gp91phox transcripts following LPS injection. Moreover, cognitive impairment following sepsis was significantly attenuated in p47phox-/- mice compared to WT mice. Similar to p47phox knockout, DPI administration significantly attenuated the cognitive impairment and reduced glia activation and brain cytokine concentrations as well as loss of synaptic protein, compared to vehicle-treated controls within 10 days following LPS injection.
In conclusion, our results suggest that NADPH oxidases can contribute to the development of increased seizure susceptibility and the progression of cognitive impairment in mice after sepsis. Pharmacologic inhibition of NOX may be a promising therapeutic approach to reducing sepsis-associated neuroinflammation, neuronal hyperexcitability, and seizures. In addition, pharmacologic inhibition of NOX2 would be a potential therapeutic strategy to prevent progressive neuronal dysregulation, and hippocampal cognitive impairment after sepsis.

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