Abstract

Inhibition of poly(ADP-ribose) polymerase (PARP) activity is protective against inflammation, ischemia and neurodegeneration [1]. Although other PARP-1 mediated mechanisms (e.g. control of integrins expression in microglia [2]) can be involved in perpetuation of neuronal death, energy depletion via PARP-1 overactivation represents a major cause of cell demise in brain injury [3]. Protection against MPTP neurotoxicity in C57Bl/6N mice with benzamide PARP inhibitors is associated with preservation of cellular energy status [4,5]. Lesioning of the rat striatum with kainic acid (KA) produces time-dependent changes in striatal PARP activity in vivo [6]. Here, we investigated the effects of the PARP inhibitor benzamide on striatal lesions and changes in NAD+ and ATP levels, induced by KA, AMPA and NMDA in C57Bl/6N mice. The KA lesion volume was dependent on the amount of toxin injected, was well-developed at 48h and was almost undetectable after one week, at which time an extensive astrogliosis was apparent. Benzamide partially prevented both KA- and NMDA- but not AMPA-induced lesions when measured at 48h; protection against KA correlated with changes in energy metabolism, since KA-induced decreases in striatal NAD+ and ATP were partially prevented by benzamide at 48h, and were normalized after one week. NMDA did not affect NAD+ and produced only a small decrease in ATP levels. Benzamide had no effect on AMPA-induced changes in NAD+ and ATP. Results indicate that PARP differentially participates in excitatory amino acid-induced neurotoxicity through mechanisms not exclusively related to energy depletion, and provide further evidence supporting PARP-1 as a novel target for new drug treatments against neurodegenerative disorders. References: 1.Cosi C: Expert Opin Ther Patents, 2002; 12(7): 1047-1071. Review 2.Ullrich O, Diestel A, Eyupoglu YI, Nitsch R: Nat Cell Biol, 2001; 3: 1035-1042 3.Ha HC, Snyder SH: Neurobiol Dis, 2000; 7: 225-239. Review 4.Cosi C, Colpaert F, Koek W, Degryse A, Marien M: Brain Res, 1996; 729: 264-269 5.Cosi C, Marien M: 1998; 809: 58-67 6.Cosi C, Cavalieri E, Marien M, Carcereri de Prati A, Suzuki H: Amino Acids, 2000; 19(1): 229-237

Keywords: PARP inhibitors, MPTP, Kainic Acid, neurotoxicity in vivo