Table 2.

Effects of PARP-1 inhibitors in animal models of human neurological and neurodegenerative conditions linked to parthanatos

Relevant neurological condition(s) or neurodegenerative disease (s)	Evidence of parthanatos involvement in human disease	Animal models (rodents)	Inhibitors	Outcome of PARP-1 or parthanatos pathway inhibition in animal models/observation
Stroke, brain ischaemia, brain trauma (Pacher and Szabo, 2008)	PARP activated in brain sections from patients dying from stroke, brain ischaemia (from cardiac arrest) and brain trauma (Love et al., 199b; 2000)	Focal cerebral ischaemia (rat) (Strosznajder et al., 2010)	DPQ	Decrease in infarct volume (Takahashi et al., 1997)
			3-AB	Decrease in infarct volume after MCAO, reduction in NMDA-induced glutamate elevation, improvement in neurological outcome and motor function, marked decrease in the volume of damaged tissue (Ding et al., 2001; Lo et al., 1998; Takahashi and Greenberg, 1999; Tokime et al., 1998; Yap et al., 2008)
			Cilostazol	Reduction in infarct size, nuclear AIF translocation and apoptosis after MCAO followed by reperfusion (Lee et al., 2007a)
		Focal cerebral ischaemia (mouse) (Strosznajder et al., 2010)	3-AB	Neuroprotection, decrease in infarct volume, improvement of neurological score (Couturier et al., 2003)
		Global cerebral ischaemia (rat) (Strosznajder et al., 2010)	PJ34	Inhibition of microglia/macrophage activation, decrease in CA1 neuronal death after forebrain ischaemia (Hamby et al., 2007)
		Global cerebral ischaemia (gerbil) (Strosznajder et al., 2010)	DPQ	No improvement of CA1 neuronal survival after bilateral carotid artery occlusion (Moroni et al., 2001)
			Benzamide
			3-AB	Robust neuroprotection in CA1 neurones after 3-min ischaemia, reduced forebrain ischaemia (Strosznajder et al., 2003)
Neurodegenerative diseases (Pacher and Szabo, 2008)	Evidence of poly (ADP-ribosyl)ation in brain sections from patients with Alzheimer's disease, Parkinson's disease and ALS (Love et al., 1999a; Kim et al., 2003; 2004; Soos et al., 2004)	Middle cerebral artery occlusion, global brain ischaemia, ischaemic reperfusion, hypoxia-ischaemia, MPTP intoxication, hypothermia, cortical trauma (mouse, rat, gerbil, guinea pig) (Komjati et al., 2005)	3-AB	Reduced infarct size, maintained or improved NAD, improved neurological function or status, attenuation in glutamate release, reduced neutrophil infiltration, reduced nitrosative stress, sustained ATP, decrease in water content, reduction in number of TUNEL-positive cells, decrease in immunoreactivity of PAR, CD11B, ICAM-1 and COX2, enhanced neuroprotection (in combination with melatonin), improved neuronal conductance, decrease in production of inflammatory mediator, improved survival and CNS function (Barc et al., 2001; Chiang and Lam, 2000; Couturier et al., 2003; Ding et al., 2001; Ducrocq et al., 2000; Eliasson et al., 1997; Endres et al., 1997; Goto et al., 2002; Iwashita et al., 2004; Koedel et al., 2002; Koh et al., 2004b; Lam, 1997; Lo et al., 1998; Nagayama et al., 2000; Plaschke et al., 2000; Sun and Cheng, 1998; Tabuchi et al., 2001; Tokime et al., 1998)
			PJ34	Reduced infarct size, improved neurological status (Abdelkarim et al., 2001; Iwashita et al., 2004)
			DPQ	Reduced infarct size, reduced infarct size but not DNA damage, improved neurological status (high doses may cause protective effect to be lost) (Takahashi et al., 1997; 1999; Giovannelli et al., 2002)
			Benzamide	Reduced neuronal death, reduced hyperalgesia and mechano-allodynia, reduced neuronal deficit, improved survival, maintained striatal NAD+ and ATP, protection against dopamine loss (Cosi et al., 1994; 1996; Mao et al., 1997; Meier et al., 1999)
			INO-1001	Reduced infarct volume, improved neurological outcome
				Reduced immunoreactivity of PAR, NT and APP, immunoreactivity changes of AIF restored.
				Entered clinical trial for myocardial ischaemia (Komjati et al., 2004; Lorenzo and Susin, 2007)

Animal models of neurological and neurodegenerative diseases in which parthanatos is implicated and the observed effects of selected PARP-1 inhibitors, most of which are currently at the experimental stage, except INO-1001 that entered clinical trial for myocardial ischaemia. Abbreviations: 3-AB, 3-aminobenzamide; AIF, apoptosis-inducing factor; ALS, amyotrophic lateral sclerosis; APP, amyloid precursor protein; DPQ, 3,4-Dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone; MCAO, middle cerebral artery occlusion; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NAD⁺, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; NT, nitrotyrosine; PAR, poly (ADP-ribose) polymer; PJ34, N-(-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide. Table was adapted from references (Komjati et al., 2005; Pacher and Szabo, 2008; Strosznajder et al., 2010).