Objective: Present study was designed to delineate the neuroprotective epigenetic and DNA-damage-repair molecular mechanisms of acetyl-L-carnitine (ALC) and astaxanthin (ASX) against  6-OHDA-induced neurotoxicity in aged Sprague-Dawley (SD) rats.

Background: Aging is an ubiquitous biological phenomena characterized by ever increasing susceptibility to diseases, toxic effects of xenobiotic and an ultimate genome-instability and diminished DNA-damage-repair capacity and cell death which occurs in neurodegenerative diseases including PD. ROS play an important role in ageing and age-related neurodegenerative changes including PD. The neurotoxins  6-OHDA is thought to produce their dopaminergic neurodegeneration which leads to PD.

Method: Aged male rats were injected with 6-OHDA (300µg, intracisternal) and the damage was assessed by rotational test and molecular alterations. Aged male SD rats of 300-350g b.wt were divided into five groups as control, 6-OHDA alone, 6-OHDA+ALC, 6-OHDA+ASX and 6-OHDA+ALC+ASX (ALC: 300 mg/kg b.wt, i.p for 21 days; ASX: 100mg/kg b.wt, i.p for 21 days, ALC and ASX started 3-days prior to 6-OHDA lesion) groups. Effect of combined applications of ALC+ASX on biomarkers of inflammation and OS, neurotransmitters, total antioxidant status (TAS), DNA, the DNA-damage repair enzymes including PARP-1 levels in substantia nigra and corpus striatum was examined.

Results: Aged rats challenged with 6-OHDA elicited a significant increase (p<0.01) in IL-6, TNF-α, lipid hydroperoxides (LPO), PCC, HCy, XO, NOS, NOX and PARP-1 when compared with control rats. There was a significant decrease (p<0.001) in TAS, SOD, GPx, CAT, neurotransmitters (DA, Serotonin and NE), DNA content and a significant increase (p<0.001) in XO, NOS, NOX, PARP-1 activities with 6-OHDA treatment. Supplementation of ALC+ASX significantly reduced LPO, PCC, HCy, 8-OHdG levels and significantly increased (p<0.01) TAS, antioxidant enzyme activities, neurotransmitters and significantly decreased XO, NOS, NOX, PARP-1 activities in substantia nigra and corpus striatum.

Conclusion: Combined application of the iron-chelating antioxidants such as acetyl-L-carnitine and astaxanthin is beneficial in the treatment of Parkinson’s disease, which are due to its “Iron-chelating antioxidant, Antionflamamtory, Poly(ADP-Ribose)Polymerase Inhibitory (PARP-1-I) and Neuronal Genome Stabilizing Effects”.

References: [1]. Neethu Gopal, Sridharan Manavalan, Kumar Ponnusamy. Neuroprotective effects of astaxanthine and acetyl-L-carnitine against streptozotocin-induced neurotoxicity in aged mice. Alzheimer’s & Dementia, July 2018, Vol 14, Issue 7, Suppl, P1523. [2]. Kumar Ponnusamy* et al., Acetyl-L-Carnitine and Quercetin as PARP-1 Modulators: Implication on Alzheimer’s Disease. Poster Presntation, The Lancet Neurology Conference Preclinical neurodegenerative disease: towards prevention and early diagnosis Oct 19-21, 2016, Park Plaza Riverbank, London, UK. . [3]. Kumar Ponnusamy* et al., Impact of Poly(ADP-ribose)Polymerase (PARP-1) Modulators on the Biomarkers of Alzheimer’s Disease in Aged Mice. The Lancet Neurology Conference Preclinical neurodegenerative disease: towards prevention and early diagnosis Oct 19-21, 2016, Park Plaza Riverbank, London, UK. [4]. Kumar Ponnusamy, Siddarth Srigoku Kumar and Jegathambigai R Naidu (2017). Neuroprotective Epigenetic and DNA Damage Repairing Molecular Mechanisms of L-Carnitine and its Congeners Against Aging and Age-Related Neurodegenerative Diseases. Texila International Journal of Basic Medical Science, Vol 2 (1), Issue 1, Jul 2017, 1-22.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neuroprotective-epigenetic-and-dna-repair-molecular-mechanisms-of-acetyl-l-carnitine-and-astaxanthin-against-6-ohda-induced-parkinsonism-in-aged-rats/