NEUROPROTECTIVE EFFECTS OF ASTAXANTHINE AND ACETYL-L-CARNITINE AGAINST STREPTOZOTOCIN-INDUCED NEUROTOXICITY IN AGED MICE

Oxidative stress (OS), increased inflammation and an ultimate non-repairable membrane molecular and mitochondrial damages are implicated in aging and age-related progressive neurodegenerative diseases (NDDs) such as Parkinsonism, Senile Dementia and Alzheimer's Disease (AD). AD is the common form of dementia characterized by loss of neurons in the brain. Astaxanthin (ASX) is a potent iron-chelating antioxidant and ALC is a potent iron-chelating antioxidant and a potent anti-inflammatory vasodilatory bi-phasic osmolyte ergogenic aid, which plays an essential role in mitochondrial ATP synthesis and exerts cytoprotective effect against innumerable NDDs. Intracerebroventricular (ICV) injection of Streptozotocin (STZ) produces reduced cognition and increased cerebral-Aβ-deposits coupled with neuroinflammation, OS and neuronal DNA damages coupled with mitochondrial-damage and ATP-depletion. Poly(ADP-ribose) polymerase-1 (PARP-1) is DNA-nick-sensor enzyme and activated PARP-1 repairs the damaged DNA with NAD+. OS-induced over-activation of PARP-1 exerts double-edged sword role in DNA damage-repair signaling cascade, consumes NAD+ and consequently ATP, protects the cells from repairable DNA-damages, maintains genome stability and/or culminating in necrosis due to NAD+ / ATP-deprivation. The aim of this study is to investigate the neuroprotective effect of ASX and ALC on oxidative stress, DNA-repair mechanisms of STZ-induced neurotoxicity in a mice model of AD. Aged-male Swiss mice were pretreated with ASX (3-days prior to STZ) (100mg/kg b.wt, i.p for 21-days,) and/or ALC (300mg/kg b.wt, i.p for 21-days), followed by bilateral i.c.v injection with the DNA-destabilizing genotoxin STZ (100mg/kg b.wt). At the end of the 21-days, the hippocampus were dissected out from sacrificed animals for the estimation of MDA, 8-OHdG, acetyl-cholinesterase (AChE) activity, TNF-α, ATP and DNA contents and the DNA-repair enzymes. Combined application of ASX+ALC mitigated the toxic onslaught of SZN-induced neurotoxicity and exerted neuroprotective effect by significantly reducing MDA, 8-OHdG, AChE-activity, TNF-α, XO, NOS and augmentation of TAS, ATP and DNA contents and modulation of PARP-1 and the activity of PARP-1 was found to be regulated differently, PARP-1 expression increased significantly in acute toxicity and significantly decreased in chronic OS. Administration of acetyl-L-carnitine and astaxanthin was effective against STZ-induced neurotoxicity based on the severity of oxidative DNA-damage and cellular ATP-status and beneficial in the prevention and/or progression of Alzheimer's disease.