Inhibiting Inducible Nitric Oxide Synthase with 1400W Reduces Soman (GD)-Induced Ferroptosis in Long-Term Epilepsy-Associated Neuropathology: Structural and Functional Magnetic Resonance Imaging Correlations with Neurobehavior and Brain Pathology.
Inhibiting Inducible Nitric Oxide Synthase with 1400W Reduces Soman (GD)-Induced Ferroptosis in Long-Term Epilepsy-Associated Neuropathology: Structural and Functional Magnetic Resonance Imaging Correlations with Neurobehavior and Brain Pathology.
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DOI：
10.1124/jpet.123.001929
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发表时间：
2024-01-17
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有机磷（OP）神经毒剂（OPNA）中毒会导致长期脑功能障碍。目前对 OPNA 中毒的治疗无效，促使人们寻求对其机制的研究和替代有效的治疗方法。我们之前对 1400W（一种高选择性诱导型一氧化氮合酶 (iNOS) 抑制剂）的研究表明，红藻氨酸和 OP 中毒大鼠模型的癫痫和癫痫发作诱发的脑部病理学有所改善。在这项研究中，对大鼠模型中索曼（GD）中毒后大脑异常的磁共振成像（MRI）模式、行为结果和生物标志物进行了全面研究。 T1 和 T2 MRI 有力地识别了与 GD 毒性相关的大脑结构的病理性微变化，而 1400W 抑制了这些异常改变。此外，GD暴露后，皮质、海马和丘脑的功能网络明显减少，1400W挽救了除丘脑以外的损失。行为测试显示 1400W 可以防止 GD 引起的记忆功能障碍，这也与结构和功能 MRI 中观察到的大脑病理程度相关。 GD暴露上调了大脑和血清中的铁负载神经胶质细胞和铁蛋白水平，1400W降低了大脑中癫痫病灶的铁蛋白水平，但不降低血清中的铁蛋白水平。脑铁蛋白水平也与 MRI 参数相关。此外，1400W 缓解了 GD 暴露后硝基氧化标记物的过量产生。总体而言，这项研究为结构和功能 MRI 模式与 GD 暴露后行为和分子异常以及 iNOS 抑制剂 1400W 的神经保护作用之间的关系提供了直接证据。我们的研究证明了 GD 毒性后大脑中的 MRI 微变化，这与神经行为表现和铁稳态密切相关。用 1400W 抑制 iNOS 可减轻 GD 引起的认知衰退、铁失调和异常脑部 MRI 结果。
Organophosphate (OP) nerve agent (OPNA) intoxication leads to long-term brain dysfunctions. The ineffectiveness of current treatments for OPNA intoxication prompts a quest for the investigation of the mechanism and an alternative effective therapeutic approach. Our previous studies on 1400W, a highly selective inducible nitric oxide synthase (iNOS) inhibitor, showed improvement in epilepsy and seizure-induced brain pathology in rat models of kainate and OP intoxication. In this study, magnetic resonance imaging (MRI) modalities, behavioral outcomes, and biomarkers were comprehensively investigated for brain abnormalities following soman (GD) intoxication in a rat model. T1 and T2 MRI robustly identified pathologic microchanges in brain structures associated with GD toxicity, and 1400W suppressed those aberrant alterations. Moreover, functional network reduction was evident in the cortex, hippocampus, and thalamus after GD exposure, and 1400W rescued the losses except in the thalamus. Behavioral tests showed protection by 1400W against GD-induced memory dysfunction, which also correlated with the extent of brain pathology observed in structural and functional MRIs. GD exposure upregulated iron-laden glial cells and ferritin levels in the brain and serum, 1400W decreased ferritin levels in the epileptic foci in the brain but not in the serum. The levels of brain ferritin also correlated with MRI parameters. Further, 1400W mitigated the overproduction of nitroxidative markers after GD exposure. Overall, this study provides direct evidence for the relationships of structural and functional MRI modalities with behavioral and molecular abnormalities following GD exposure and the neuroprotective effect of an iNOS inhibitor, 1400W. Our studies demonstrate the MRI microchanges in the brain following GD toxicity, which strongly correlate with neurobehavioral performances and iron homeostasis. The inhibition of iNOS with 1400W mitigates GD-induced cognitive decline, iron dysregulation, and aberrant brain MRI findings.:
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