A New Poly(ADP-Ribose) Polymerase Inhibitor, FR261529 [2-(4-Chlorophenyl)-5-quinoxalinecarboxamide], Ameliorates Methamphetamine-Induced Dopaminergic Neurotoxicity in Mice

Abstract

Methamphetamine (METH) administration in mice, results in a chronic dopamine (DA) depletion associated with nerve terminal damage, with DA oxidation and generation of reactive oxygen species (ROS) primarily mediating this neurotoxicity. The oxidative stress induced by METH putatively activates nuclear enzyme poly(ADPribose) polymerase (PARP), with excessive PARP activation eventually leading to cell death. In this study, we show that prevention of PARP activation by treatment with FR261529 [2-(4-chlorophenyl)-5-quinoxalinecarboxamide], the compound that was recently identified as a novel PARP inhibitor (IC 50 for PARP-1 ϭ 33 nM, IC 50 for PARP-2 ϭ 7 nM), protects against both ROS-induced cells injury in vitro and METH-induced dopaminergic neuronal damage in an in vivo Parkinson's disease (PD) model. In PC12 cells, exposure of hydrogen peroxide or METH markedly induced PARP activation, and treatment with FR261529 (1 M) significantly reduced PARP activation and attenuated cell death. In the mouse METH model, METH (15 mg/ kg ϫ 2 i.p., 2 h apart) intoxication accelerated DA metabolism and oxidation in the striatum, with subsequent cell damage in nigrostriatal dopaminergic neurons after 4 days. Oral administration of FR261529 (10 or 32 mg/kg) attenuated the damage of dopaminergic neurons via marked reduction of PARP activity and not via changes in dopamine metabolism or body temperature. These findings indicate that the neuroprotective effects of a novel PARP inhibitor, FR261529, were accompanied by inhibition of METH-induced PARP activation, suggesting that METH induces nigrostriatal dopaminergic neurodegeneration involving PARP activation and also orally active and brainpenetrable PARP inhibitor FR261529 could be a novel attractive therapeutic candidate for neurodegenerative disorders such as PD.

Levels of 4-Hydroxynonenal and Malondialdehyde Are Increased in Brain of Human Chronic Users of Methamphetamine

“…Brain (occipital cortex) drug levels for the high and low groups are 124 Ϯ 47 (range, 20 -319; median 90) and 10.0 Ϯ 1.3 (range, 2.8 -15.6; median 10) nmol/g tissue, respectively (p Ͻ 0.01, Mann-Whitney U tests). Dopamine levels (previously reported by Wilson et al, 1996 andMoszczynska et al, 2004) Kim et al, 1999;Kita et al, 2000;Wan et al, 2000;Gluck et al, 2001;Flora et al, 2002;Iwashita et al, 2004). Nevertheless, the possibility also has to be considered that chronic drug exposure (e.g., involving tolerance, sensitization) might also have modulated the effects of an acute exposure, as suggested by some animal data (Acikgoz et al, 1998(Acikgoz et al, , 2000.…”

“…We hypothesized that, as in most of the experimental animal studies in which MDA or MDA-like thiobarbituric acid reactive substances (TBARS) were reported to be increased in brain of MA-treated rodents (Acikgoz et al, 1998(Acikgoz et al, , 2000Jayanthi et al, 1998;Yamamoto and Zhu, 1998;Kim et al, 1999;Kita et al, 2000;Wan et al, 2000;Gluck et al, 2001;Flora et al, 2002;Iwashita et al, 2004), levels of both oxidative markers would be above-normal in the dopamine-rich caudate nucleus of human MA users but less markedly increased (if at all) in brain areas having very low (frontal and cerebellar cortices) concentrations of dopamine. Our human post mortem data provide additional support to the notion based on animal models that MA can cause oxidative damage in human brain.…”

Poly (ADP-ribose) polymerase-1 (PARP-1) genetic variants are protective against Parkinson's disease

“…Down-regulation of PARP-1 might be protective for PD by preventing oxidative stress, suppressing the inflammatory response associated with activated microglia, or by reducing α-synuclein expression level. In fact, inhibition of PARP-1 results in significant neuroprotection in the MPTP mouse model of Parkinson's disease [10]. Considering the interaction between PARP-1 and NACPRep1 polymorphic site upstream of the α-synuclein gene [4], it is tempting to speculate that the association between α-synuclein variants and PD risk has been controversial in the literature [11], probably, at least in part, because analysis of PARP-1 polymorphism has not been simultaneously included.…”

Thiamine and Parkinson's disease

“…MPTP is a neurotoxin that causes parkinsonism in humans and animals; mice lacking the PARP gene are dramatically spared from MPTP neurotoxicity [73]. Moreover, PARP inhibitors have been shown to be a valuable neuroprotective tool in models of PD [74,75]. PARP-1 variants are reported to be protective against PD [76].…”