Neuroprotectant Activity of Novel Water-Soluble Synthetic Neurosteroids on Organophosphate Intoxication and Status Epilepticus-Induced Long-Term Neurological Dysfunction, Neurodegeneration, and Neuroinflammation.
Neuroprotectant Activity of Novel Water-Soluble Synthetic Neurosteroids on Organophosphate Intoxication and Status Epilepticus-Induced Long-Term Neurological Dysfunction, Neurodegeneration, and Neuroinflammation.
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DOI：
10.1124/jpet.123.001819
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发表时间：
2024-01-17
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有机磷酸酯 (OP) 和神经毒剂是强效神经毒性化合物，可导致癫痫发作、癫痫持续状态 (SE)、脑损伤或死亡。初次接触后数月至数年会出现持续的长期神经系统和神经退行性影响。目前的解毒剂无法有效预防这些长期的神经行为和神经病理学变化。此外，很少有有效的神经保护剂可以减轻急性OP中毒的长期影响。我们率先将神经类固醇作为新型抗惊厥药和神经保护剂，用于治疗 OP 中毒和癫痫发作。在这项研究中，我们评估了两种新型合成水溶性神经类固醇 Valaxanolone (VX) 和 lysaxanolone (LX) 在对抗急性 OP 中毒和 SE 引起的长期行为和神经病理学损伤方面的功效。动物暴露于 OP 神经毒剂替代二异丙基氟磷酸盐 (DFP)，并在暴露后 40 分钟除咪达唑仑外还接受 VX 或 LX 治疗。暴露后 3 个月评估神经退行性变的程度以及各种行为和记忆缺陷。 VX 显着降低了对照（DFP 暴露、咪达唑仑治疗）动物的攻击行为、焦虑、记忆和抑郁样特征的缺陷； VX 还显着阻止了 DFP 诱导的海马和其他区域 NeuN(+) 主要神经元和 PV(+) 抑制神经元的慢性损失。此外，VX治疗的动物表现出炎症反应减轻，海马、杏仁核和其他区域的GFAP(+)星形胶质细胞增生和IBA1(+)小胶质细胞增生减少。同样，LX 显着改善行为和记忆缺陷，并减少神经退行性变和细胞神经炎症。总之，这些结果证明了新型合成神经类固醇在减轻与 OP 暴露相关的长期神经功能障碍和神经变性方面的神经保护作用。神经毒剂和有机磷 (OP) 暴露的幸存者会遭受长期神经功能缺损。目前，没有特定的药物疗法可以减轻有机磷暴露的影响。然而，激活强直抑制的新型合成神经类固醇为治疗 OP 中毒提供了可行的选择。这项研究的数据表明，合成的水溶性神经类固醇对于减轻 OP 中毒后的长期神经功能缺损具有神经保护作用。这些研究结果表明，valaxanolone 和 lysaxanolone 是适合注射剂量的强效且有效的神经保护剂：
Organophosphates (OPs) and nerve agents are potent neurotoxic compounds that cause seizures, status epilepticus (SE), brain injury, or death. There are persistent long-term neurologic and neurodegenerative effects that manifest months to years after the initial exposure. Current antidotes are ineffective in preventing these long-term neurobehavioral and neuropathological changes. Additionally, there are few effective neuroprotectants for mitigating the long-term effects of acute OP intoxication. We have pioneered neurosteroids as novel anticonvulsants and neuroprotectants for OP intoxication and seizures. In this study, we evaluated the efficacy of two novel synthetic, water-soluble neurosteroids, valaxanolone (VX) and lysaxanolone (LX), in combating the long-term behavioral and neuropathological impairments caused by acute OP intoxication and SE. Animals were exposed to the OP nerve agent surrogate diisopropylfluorophosphate (DFP) and were treated with VX or LX in addition to midazolam at 40 minutes postexposure. The extent of neurodegeneration, along with various behavioral and memory deficits, were assessed at 3 months postexposure. VX significantly reduced deficits of aggressive behavior, anxiety, memory, and depressive-like traits in control (DFP-exposed, midazolam-treated) animals; VX also significantly prevented the DFP-induced chronic loss of NeuN(+) principal neurons and PV(+) inhibitory neurons in the hippocampus and other regions. Additionally, VX-treated animals exhibited a reduced inflammatory response with decreased GFAP(+) astrogliosis and IBA1(+) microgliosis in the hippocampus, amygdala, and other regions. Similarly, LX showed significant improvement in behavioral and memory deficits, and reduced neurodegeneration and cellular neuroinflammation. Together, these results demonstrate the neuroprotectant effects of the novel synthetic neurosteroids in mitigating the long-term neurologic dysfunction and neurodegeneration associated with OP exposure. Survivors of nerve agents and organophosphate (OP) exposures suffer from long-term neurological deficits. Currently, there is no specific drug therapy for mitigating the impact of OP exposure. However, novel synthetic neurosteroids that activate tonic inhibition provide a viable option for treating OP intoxication. The data from this study indicates the neuroprotective effects of synthetic, water-soluble neurosteroids for attenuation of long-term neurological deficits after OP intoxication. These findings establish valaxanolone and lysaxanolone as potent and efficacious neuroprotectants suitable for injectable dosing.:
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影响因子：
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通讯作者：
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影响因子：
4.8
作者：
Brandon, NJ;Delmas, P;Moss, SJ
通讯作者：
Moss, SJ
DOI：
10.1124/jpet.114.217299
发表时间：
2014-11-01
影响因子：
3.5
作者：
Apland, James P.;Aroniadou-Anderjaska, Vassiliki;Braga, Maria F. M.
通讯作者：
Braga, Maria F. M.
影响因子：
4.7
作者：
Adams JM;Thomas P;Smart TG
通讯作者：
Smart TG
DOI：
10.1073/pnas.1403285111
发表时间：
2014-05-13
影响因子：
11.1
作者：
Abramian, Armen M.;Comenencia-Ortiz, Eydith;Moss, Stephen J.
通讯作者：
Moss, Stephen J.