PARP-1 Inhibition Is Neuroprotective in the R6/2 Mouse Model of Huntington's Disease

• Published in: PloS one 2015-08, Vol.10 (8), p.e0134482-e0134482
• Main Authors: Cardinale, Antonella, Paldino, Emanuela, Giampà, Carmela, Bernardi, Giorgio, Fusco, Francesca R
• Format: Article
• Language: English
• Subjects: Adenosine diphosphate; Analysis; Animals; Apoptosis; Atrophy; Autophagy; Blotting, Western; Body Weight - drug effects; Brain; Brain damage; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Care and treatment; Cell death; Chemotherapy; Corpus Striatum - drug effects; Corpus Striatum - pathology; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - metabolism; Deoxyribonucleic acid; Development and progression; Disease; Disease Models, Animal; DNA; DNA damage; DNA repair; Female; Gene expression; Genetic aspects; Genetic engineering; Glial cells; Huntington Disease - drug therapy; Huntington Disease - pathology; Huntington Disease - physiopathology; Huntington's disease; Huntingtons disease; Immunohistochemistry; Immunoreactivity; Inclusion bodies; Indoles - pharmacology; Indoles - therapeutic use; Inhibition; Inhibitors; Ischemia; Kaplan-Meier Estimate; Male; Mice; Mice, Transgenic; Motor Activity - drug effects; Neostriatum; Neurodegeneration; Neurological complications; Neuronal-glial interactions; Neurons; Neuroprotection; Neuroprotection - drug effects; Oxidative stress; Pathogenesis; Patient outcomes; Perfusion; Physiological aspects; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Poly(ADP-ribose) Polymerases - metabolism; Ribose; Rodents; Rotarod Performance Test; Spinal cord; Spiny neurons; Studies; Transgenic mice; Trauma
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0134482

Poly (ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that is involved in physiological processes as DNA repair, genomic stability, and apoptosis. Moreover, published studies demonstrated that PARP-1 mediates necrotic cell death in response to excessive DNA damage under certain pathological conditions. In Huntington's disease brains, PARP immunoreactivity was described in neurons and in glial cells, thereby suggesting the involvement of apoptosis in HD. In this study, we sought to determine if the PARP-1 inhibitor exerts a neuroprotective effect in R6/2 mutant mice, which recapitulates, in many aspects, human HD. Transgenic mice were treated with the PARP-1 inhibitor INO-1001 mg/Kg daily starting from 4 weeks of age. After transcardial perfusion, histological and immunohistochemical studies were performed. We found that INO 1001-treated R6/2 mice survived longer and displayed less severe signs of neurological dysfunction than the vehicle treated ones. Primary outcome measures such as striatal atrophy, morphology of striatal neurons, neuronal intranuclear inclusions and microglial reaction confirmed a neuroprotective effect of the compound. INO-1001 was effective in significantly increasing activated CREB and BDNF in the striatal spiny neurons, which might account for the beneficial effects observed in this model. Our findings show that PARP-1 inhibition could be considered as a valid therapeutic approach for HD.