Krishnan Muthaiah Vijaya Prakash, Kaliyappan Kathiravan, Thiayagarajan Ramkumar, Mahajan Supriya, Gunasekaran Krishnamoorthy
Department of Rehabilitation Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York, USA.
Department of Geriatric Medicine, Kansas University Medical Center, The University of Kansas, Kansas City, Kansas, USA.
Immun Inflamm Dis. 2025 Jan;13(1):e70106. doi: 10.1002/iid3.70106.
The pathomechanism of blast traumatic brain injury (TBI) and blunt TBI is different. In blast injury, evidence indicates that a single blast exposure can often manifest long-term neurological impairments. However, its pathomechanism is still elusive, and treatments have been symptomatic. Poly adenosine diphosphate (ADP) ribose polymerase-1 (PARP1) is implicated in the parthanatos and secondary neuroinflammation. Animal studies indicate the over-activation of PARP1 as a significant downstream event underlying the neurological sequelae of several traumatic and neurodegenerative disorders, irrespective of the mode of cell death. PARP over-activation forms ADP polymers on several nuclear proteins, known as trans-PARylation, by consuming nicotinamide adenine dinucleotide (NAD) and ATP. As NAD is a substrate for sirtuins, ithas also been implicated in the oxidative stress underlying TBI pathology.
We recently established the implication of PARP1 following blast overpressure (BOP) and its differential response on astrocytes and microglial cells. We found that the inhibition of PARP is proven beneficial by attenuating oxidative stress. In this study, we hypothesized the involvement of the PARP1-SIRT-NRF2 axis following induced blast-induced PARP over-activation in glial cells for the manifestation of oxidative stress in BOP insults.
The objective is to determine the downstream modulation of the PARP-SIRT-NRF2 axis and changes in ATP levels following blast exposure in astrocytes and microglia cell lines.
As a result of NAD being a common substrate for PARP1 and Sirtuins, we found the decreased expression of SIRT1, SIRT3, and NRF2, a central transcriptional regulator for the expression of antioxidant genes. We found that ATP levels were elevated post-BOP from both glycolysis and oxidative phosphorylation (OXPHOS), an increase of ATP by glycolysis more significant than OXPHOS source, indicating the proinflammation post-BOP.
This result shows that blast-induced PARP1 over-activation impacts the deacetylation activity of sirtuins and consequently impacts the regulation of antioxidant levels in astrocytes and microglia.
爆炸所致创伤性脑损伤（TBI）与钝性TBI的发病机制不同。在爆炸伤中，有证据表明单次爆炸暴露往往会表现出长期的神经功能障碍。然而，其发病机制仍不清楚，治疗也只是对症治疗。聚二磷酸腺苷（ADP）核糖聚合酶-1（PARP1）与细胞程序性坏死和继发性神经炎症有关。动物研究表明，PARP1的过度激活是几种创伤性和神经退行性疾病神经后遗症的一个重要下游事件，与细胞死亡方式无关。PARP过度激活通过消耗烟酰胺腺嘌呤二核苷酸（NAD）和三磷酸腺苷（ATP），在几种核蛋白上形成ADP聚合物，即反式PAR化。由于NAD是去乙酰化酶的底物，它也与TBI病理中的氧化应激有关。
我们最近确定了爆炸超压（BOP）后PARP1的作用及其对星形胶质细胞和小胶质细胞的不同反应。我们发现抑制PARP可通过减轻氧化应激而被证明是有益的。在本研究中，我们假设在胶质细胞中诱导爆炸诱导的PARP过度激活后，PARP1-去乙酰化酶-NRF2轴参与BOP损伤中氧化应激的表现。
目的是确定星形胶质细胞和小胶质细胞系爆炸暴露后PARP-去乙酰化酶-NRF2轴的下游调节以及ATP水平的变化。
由于NAD是PARP1和去乙酰化酶的共同底物，我们发现抗氧化基因表达的核心转录调节因子SIRT1、SIRT3和NRF2的表达降低。我们发现BOP后糖酵解和氧化磷酸化（OXPHOS）产生的ATP水平均升高，糖酵解产生的ATP增加比OXPHOS来源更显著，表明BOP后存在促炎反应。
该结果表明，爆炸诱导的PARP1过度激活影响去乙酰化酶的去乙酰化活性，从而影响星形胶质细胞和小胶质细胞中抗氧化水平的调节。
