Attenuation of oxidative stress after contusion spinal cord injury through inhibition of Poly ADP Ribose Polymerase involves glutamate cysteine ligase. (September 2019)

• Record Type: Journal Article
• Authors: Krishnan Muthaiah, Vijaya Prakash; Palaniappan, Tamilselvi; Rajan, Sridhar Skylab; Chandrasekar, Kirubhanand; Venkatachalam, Sankar
• Is Part Of: Process biochemistry. Volume 84(2019)
• Page Start: 180
• Page End: 185
• Publication Date: 2019-09
• Subjects: Oxidative stress -- Spinal cord injury -- Parp1 overactivation -- Parp1 inhibition -- 3-aminobenzamide; Biochemical engineering -- Periodicals; Biotechnology -- Periodicals; Biochemistry -- periodicals; Biotechnology -- periodicals; Chemical Engineering -- periodicals; Génie biochimique -- Périodiques; Biotechnologie -- Périodiques; Biochemical engineering; Biotechnology; Periodicals; 660.63
• DOI: 10.1016/j.procbio.2019.05.030
• Languages: English
• ISSNs: 1359-5113

Abstract

Graphical abstract: Highlights: PARP1 mediated DNA repair utilizes NAD + and therefore can cause energy depletion. 3-aminobenzamide inhibit Parp1 due to its structural similarity to NAD+. Replenished NAD + levels regenerate glutathione (GSH) from its oxidized form (GSSH). Together these changes increase GSH synthesis through upregulating Gclc . These may the mechanism behind PARP1inhibition mediated beneficial effects. Abstract: Oxidative stress-induced DNA damage in cells activates Poly ADP Ribose Polymerase 1 (PARP1) as a part of the repair process. Since it is an energy-dependent process, overactivation of PARP1 results in energy depletion and as a consequence causes parthanatos – a subtype of necrosis. Beneficial effects of inhibiting PARP1 using chemicals such as 3-aminobenzamide (3-AB) has been well documented and were shown to mitigate oxidative stress and increase anti-oxidants levels in the cells. However, the exact molecular mechanism responsible for the increased anti-oxidants levels during inhibition of PARP1 overactivation has not been established. Under these circumstances, PARP1 inhibition using 3-aminobenzamide after a contusion spinal cord injury in rats was found to increase the levels of both glutamate–cysteine ligase catalytic unit (GCLC) and glutathione (GSH). GCLC being the rate-limiting enzyme in the synthesis of GSH, the increase of GSH levels might be because of increased synthesis as well as regeneration of GSH from its oxidized state (GSSH); both the processes favored by the energy replenishment. Given that GSH is pivotal in the antioxidant defense mechanism, the observations of increased expression of Gclc as reported here might be the plausible molecular mechanism responsible for the increased anti-oxidants levels in PARP1 inhibition by 3-AB.