title: PARP-1 Inhibition Is Neuroprotective in the R6/2 Mouse Model of Huntington's Disease.
abstract: 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.
authors.affiliation: Fondazione Santa Lucia IRCCS, Laboratorio di Neuroanatomia, Roma, Italia; Università degli studi Roma 3, Roma, Italia.
authors.forename: Antonella
authors.initials: A
authors.lastname: Cardinale
authors.affiliation: Fondazione Santa Lucia IRCCS, Laboratorio di Neuroanatomia, Roma, Italia.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Paldino
authors.affiliation: Fondazione Santa Lucia IRCCS, Laboratorio di Neuroanatomia, Roma, Italia; Università Cattolica del Sacro Cuore, Dipartimento di Anatomia e Biologia, Roma, Italia.
authors.forename: Carmela
authors.initials: C
authors.lastname: Giampà
authors.affiliation: Fondazione Santa Lucia IRCCS, Laboratorio di Neuroanatomia, Roma, Italia; Università di Roma Tor Vergata, Dipartimento di Neuroscienze, Roma, Italia.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.affiliation: Fondazione Santa Lucia IRCCS, Laboratorio di Neuroanatomia, Roma, Italia.
authors.forename: Francesca R
authors.initials: FR
authors.lastname: Fusco
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006816:Huntington Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D000066829:Neuroprotection / Q000187:drug effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D045442:Rotarod Performance Test
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; C491685:INO 1001; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases