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Blast-overpressure induced modulation of PARP-SIRT-NRF2 axis in stress signaling of astrocytes and microglia.
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  • VIJAYA PRAKASH KRISHNAN MUTHAIAH,
  • Kathiravan Kaliyappan,
  • Supriya Mahajan,
  • Ramkumar Thiyagarajan,
  • Krishnamoorthy Gunasekaran
VIJAYA PRAKASH KRISHNAN MUTHAIAH
University at Buffalo School of Public Health and Health Professions
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Kathiravan Kaliyappan
University at Buffalo School of Public Health and Health Professions
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Supriya Mahajan
University at Buffalo School of Medicine and Biomedical Sciences
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Ramkumar Thiyagarajan
The University of Kansas Medical Center
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Krishnamoorthy Gunasekaran
Dambi Dollo University

Corresponding Author:[email protected]

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Abstract

Background: The pathomechanism of blast TBI and blunt TBI is different. In blast injury, evidence indicate that a single blast exposure can often manifest long-term neurological impairments. However, its pathomechanism is still elusive and treatments were symptomatic. Poly ADP Ribose Polymerase-1 (PARP1) is being implicated in the parthanatos and secondary neuroinflammation. Animal studies indicate the over-activation of as a major downstream event underlying the neurological sequalae 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 NAD+ and ATP. As NAD+ is a substrate for sirtuins, it too has been implicated in the oxidative stress underlying TBI pathology. Hypothesis: 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 to be beneficial by attenuating oxidative stress. In this study, we hypothesized the involvement of the PARP1-SIRT-NRF2 axis following Blast induced PARP over-activation in glial cells for the manifestation of oxidative stress in BOP insults. Objective: Our 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. Results: As a result of NAD+ being a common substrate for PARP1 and Sirtuins, we found the decreased expression of SIRT1, SIRT3 and NRF2, a major 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 pro-inflammation post-BOP. Conclusion: This result shows that blast-induced PARP over-activation impacts the deacetylation activity of sirtuins and consequently impacts the regulation of antioxidant levels in astrocytes and microglia.
Submitted to Immunity, Inflammation and Disease
24 Jun 2024Review(s) Completed, Editorial Evaluation Pending
06 Jul 2024Editorial Decision: Revise Major
09 Aug 20241st Revision Received
12 Aug 2024Submission Checks Completed
12 Aug 2024Assigned to Editor
12 Aug 2024Review(s) Completed, Editorial Evaluation Pending
13 Aug 2024Reviewer(s) Assigned
26 Aug 2024Editorial Decision: Revise Minor
10 Oct 20242nd Revision Received
14 Oct 2024Submission Checks Completed
14 Oct 2024Assigned to Editor
14 Oct 2024Review(s) Completed, Editorial Evaluation Pending
15 Oct 2024Reviewer(s) Assigned