Abstract：
OBJECTIVE: Niacin (NIA) supplementation showed effectiveness against Parkinson\'s disease (PD) in clinical trials. The depletion of NAD and endoplasmic reticulum stress response (ERSR) are implicated in the pathogenesis of PD, but the potential role for NAD precursors on ERSR is not yet established. This study was undertaken to decipher NIA molecular mechanisms against PD-accompanied ERSR, especially in relation to PKC.
METHODS: Alternate-day-low-dose-21 day-subcutaneous exposure to rotenone (ROT) in rats induced PD. Following the 5th ROT injection, rats received daily doses of either NIA alone or preceded by the PKC inhibitor tamoxifen (TAM). Extent of disease progression was assessed by behavioral, striatal biochemical and striatal/nigral histopathological/immunohistochemical analysis.
RESULTS: Via activating PKC/LKB1/AMPK stream, NIA post-treatment attenuated the ERSR reflected by the decline in ATF4, ATF6 and XBP1s to downregulate the apoptotic markers, CHOP/GADD153, p-JNK and active caspase-3. Such amendments congregated in motor activity/coordination improvements in open field and rotarod tasks, enhanced grid test latency and reduced overall PD scores, while boosting nigral/striatal tyrosine hydroxylase immunoreactivity and increasing intact neurons (Nissl stain) in both SNpc and striatum that showed less neurodegeneration (H&E stain). To different extents, TAM reverted all the NIA-related actions to prove PKC as a fulcrum in conveying the drug neurotherapeutic potential.
CONCLUSIONS: PKC activation is a pioneer mechanism in the drug ERSR inhibitory anti-apoptotic modality to clarify NIA promising clinical and potent preclinical anti-PD efficacy. This kinase can be tagged as a druggable target for future add-on treatments that can assist dopaminergic neuronal aptitude against this devastating neurodegenerative disease.
METHODS: Alternate-day-low-dose-21 day-subcutaneous exposure to rotenone (ROT) in rats induced PD. Following the 5th ROT injection, rats received daily doses of either NIA alone or preceded by the PKC inhibitor tamoxifen (TAM). Extent of disease progression was assessed by behavioral, striatal biochemical and striatal/nigral histopathological/immunohistochemical analysis.
RESULTS: Via activating PKC/LKB1/AMPK stream, NIA post-treatment attenuated the ERSR reflected by the decline in ATF4, ATF6 and XBP1s to downregulate the apoptotic markers, CHOP/GADD153, p-JNK and active caspase-3. Such amendments congregated in motor activity/coordination improvements in open field and rotarod tasks, enhanced grid test latency and reduced overall PD scores, while boosting nigral/striatal tyrosine hydroxylase immunoreactivity and increasing intact neurons (Nissl stain) in both SNpc and striatum that showed less neurodegeneration (H&E stain). To different extents, TAM reverted all the NIA-related actions to prove PKC as a fulcrum in conveying the drug neurotherapeutic potential.
CONCLUSIONS: PKC activation is a pioneer mechanism in the drug ERSR inhibitory anti-apoptotic modality to clarify NIA promising clinical and potent preclinical anti-PD efficacy. This kinase can be tagged as a druggable target for future add-on treatments that can assist dopaminergic neuronal aptitude against this devastating neurodegenerative disease.
摘要：
目的：在临床试验中，补充烟酸（NIA）对帕金森病（PD）有效。NAD的耗竭和内质网应激反应(ERSR)与PD的发病机制有关,但NAD前体对ERSR的潜在作用尚未确定。这项研究旨在破译NIA对抗PD伴ERSR的分子机制，尤其是与PKC有关。
方法：在诱发PD的大鼠中，交替日低剂量21天皮下暴露于鱼藤酮（ROT）。在第5次ROT注射之后,大鼠每天单独接受NIA或之前接受PKC抑制剂他莫昔芬（TAM）。通过行为评估疾病进展的程度，纹状体生化和纹状体/黑色组织病理学/免疫组织化学分析。
结果：通过激活PKC/LKB1/AMPK流，NIA后处理减弱了由ATF4，ATF6和XBP1的下降所反映的ERSR，以下调凋亡标志物，CHOP/GADD153、p-JNK和活性胱天蛋白酶-3。这些修正集中在空场和旋转任务中的运动活动/协调改进中，增强网格测试延迟并降低总体PD分数，同时增强SNpc和纹状体中的黑质/纹状体酪氨酸羟化酶免疫反应性并增加完整的神经元（Nissl染色），显示较少的神经变性（H＆E染色）。在不同程度上，TAM恢复了所有与NIA相关的行动，以证明PKC是传达药物神经治疗潜力的支点。
结论：PKC激活是药物ERSR抑制性抗凋亡模式的先驱机制，以阐明NIA有希望的临床和有效的临床前抗PD功效。这种激酶可以被标记为未来的附加治疗的药物靶标，可以帮助多巴胺能神经元抵抗这种破坏性的神经退行性疾病。
方法：在诱发PD的大鼠中，交替日低剂量21天皮下暴露于鱼藤酮（ROT）。在第5次ROT注射之后,大鼠每天单独接受NIA或之前接受PKC抑制剂他莫昔芬（TAM）。通过行为评估疾病进展的程度，纹状体生化和纹状体/黑色组织病理学/免疫组织化学分析。
结果：通过激活PKC/LKB1/AMPK流，NIA后处理减弱了由ATF4，ATF6和XBP1的下降所反映的ERSR，以下调凋亡标志物，CHOP/GADD153、p-JNK和活性胱天蛋白酶-3。这些修正集中在空场和旋转任务中的运动活动/协调改进中，增强网格测试延迟并降低总体PD分数，同时增强SNpc和纹状体中的黑质/纹状体酪氨酸羟化酶免疫反应性并增加完整的神经元（Nissl染色），显示较少的神经变性（H＆E染色）。在不同程度上，TAM恢复了所有与NIA相关的行动，以证明PKC是传达药物神经治疗潜力的支点。
结论：PKC激活是药物ERSR抑制性抗凋亡模式的先驱机制，以阐明NIA有希望的临床和有效的临床前抗PD功效。这种激酶可以被标记为未来的附加治疗的药物靶标，可以帮助多巴胺能神经元抵抗这种破坏性的神经退行性疾病。
