Poly(ADP‐ribose)polymerase inhibitor can attenuate the neuronal death after 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced neurotoxicity in mice

Abstract

An excessive expression of poly(ADP-ribose)polymerase (PARP) has been demonstrated to play a key role in the pathogenesis of Parkinson's disease (PD). Here we investigated the therapeutic effect of the PARP inhibitor benzamide against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice. In our HPLC and Western blot analysis, pretreatment with benzamide showed a neuroprotective effect against MPTP neurotoxicity in mice. Posttreatment with benzamide also attenuated MPTP neurotoxicity in mice. Furthermore, our immunohistochemical study showed that posttreatment with benzamide significantly prevented neuronal damage by suppressing overexpression of neuronal, microglial, and astroglial PARP after MPTP treatment. These findings have important implications for the therapeutic time window and choice of PARP inhibitors in PD patients. Our present findings provide further evidence that PARP inhibitor may offer a novel therapeutic strategy for PD.

Neurological Disorders of Purine and Pyrimidine Metabolism

“…NAD plays an important role in brain physiopathologic events, like neuronal death [7], ischemic injury [8,9], neurodegenerative diseases [10], Alzheimer's disease [11] and Parkinson's disease [12]. In particular, polyADPribose polymerase 1 (PARP-1) is directly involved in neuronal cell death and in neurotoxicity and its inhibitors are proposed as therapeutic agents [12,13]. Recently the sponta- neous chimeric protein Wld S , containing the whole sequence of a protein involved in NAD synthesis (nicotinamide mononucleotide adenylyltransferase 1: NMNAT1, E.C.2.7.7.1), has been demonstrated to protect axons from Wallerian degeneration [14].…”

“…NAD is known to play an essential role in oxidative metabolism but it is also involved in nonredox reactions critical for the regulation of cellular metabolism, such as protein poly-and mono-ADP-ribosylation, cyclic ADP-ribose formation, and deacetylation reactions catalyzed by sirtuins. NAD plays an important role in brain physiopathologic events, like neuronal death [7], ischemic injury [8,9], neurodegenerative diseases [10], Alzheimer's disease [11] and Parkinson's disease [12]. In particular, polyADPribose polymerase 1 (PARP-1) is directly involved in neuronal cell death and in neurotoxicity and its inhibitors are proposed as therapeutic agents [12,13].…”

Programmed Cell Death in Parkinson's Disease

“…MPTP/MPPþ involves PARP-1 and AIF nuclear translocation (Mandir et al 1999;Wang et al 2003;Liou et al 2005 (Perier et al 2010). And finally, PARP-1 inhibition prevents MPTP/MPPþ-induced cell death (Cosi et al 1996;Outeiro et al 2007;Yokoyama et al 2010), and a-synuclein cytotoxicity (Outeiro et al 2007). …”

Poly(ADP-ribosylation) and neurodegenerative disorders

“…Analogously, in PD rodent models, PARP inhibitors were described as neuroprotective, able to attenuate neuronal death (Outeiro et al, 2007;Yokoyama et al, 2010;Kim et al, 2013;Wu et al, 2014). The different interconnected pathways/routes finally leading to cell death (apoptosis, parthanatos, necrosis/necroptosis, autophagy/mitophagy, in bold) are drawn in different colors.…”