title: Combination strategy of PARP inhibitor with antioxidant prevent bioenergetic deficits and inflammatory changes in CCI-induced neuropathy.
abstract: Neuropathic pain, a debilitating pain condition and the underlying pathogenic mechanisms are complex and interwoven amongst each other and still there is scant information available regarding therapies which promise to treat the condition. Evidence indicate that oxidative/nitrosative stress induced poly (ADP-ribose) polymerase (PARP) overactivation initiate neuroinflammation and bioenergetic crisis culminating into neurodegenerative changes following nerve injury. Hence, we investigated the therapeutic effect of combining an antioxidant, quercetin and a PARP inhibitor, 4-amino 1, 8-naphthalimide (4-ANI) on the hallmark deficits induced by chronic constriction injury (CCI) of sciatic nerve in rats. Quercetin (25 mg/kg, p.o.) and 4-ANI (3 mg/kg, p.o.) were administered either alone or in combination for 14 days to examine sciatic functional index, allodynia and hyperalgesia using walking track analysis, Von Frey, acetone spray and hot plate tests respectively. Malondialdehyde, nitrite and glutathione levels were estimated to detect oxidative/nitrosative stress; mitochondrial membrane potential and cytochrome c oxidase activity to assess mitochondrial function; NAD & ATP levels to examine the bioenergetic status and levels of inflammatory markers were evaluated in ipsilateral sciatic nerve. Quercetin and 4-ANI alone improved the pain behaviour and biochemical alterations but the combination therapy demonstrated an appreciable reversal of CCI-induced changes. Nitrotyrosine and Poly ADP-Ribose (PAR) immunopositivity was decreased and nuclear factor erythroid 2-related factor (Nrf-2) levels were increased significantly in micro-sections of the sciatic nerve and dorsal root ganglion (DRG) of treatment group. These results suggest that simultaneous inhibition of oxidative stress-PARP activation cascade may potentially be useful strategies for management of trauma induced neuropathic pain.
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India; Division of Neurology, Department of Medicine, University of Alberta, 2E3.26 Walter C Mackenzie, Health Sciences Center, Edmonton, AB, T6G 2B7, Canada.
authors.forename: Prashanth
authors.initials: P
authors.lastname: Komirishetty
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India.
authors.forename: Aparna
authors.initials: A
authors.lastname: Areti
authors.affiliation: Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, India.
authors.forename: Ranadeep
authors.initials: R
authors.lastname: Gogoi
authors.affiliation: Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad, India.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Sistla
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India. Electronic address: ashutosh.niperhyd@gov.in.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Kumar
mesh_terms: D015057:1-Naphthylamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage* / Q000627:therapeutic use; D004660:Encephalitis / Q000150:complications / Q000201:enzymology / Q000517:prevention & control*; D006930:Hyperalgesia / Q000517:prevention & control; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D053644:Naphthalimides / Q000008:administration & dosage* / Q000627:therapeutic use; D009437:Neuralgia / Q000150:complications / Q000201:enzymology / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011794:Quercetin / Q000008:administration & dosage* / Q000627:therapeutic use; D015363:Quinolones / Q000008:administration & dosage* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000293:injuries
chemical_list: D000975:Antioxidants; D053644:Naphthalimides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015363:Quinolones; D009243:NAD; C086538:4-amino-1,8-naphthalimide; D000255:Adenosine Triphosphate; D015057:1-Naphthylamine; D011794:Quercetin; D011065:Poly(ADP-ribose) Polymerases
keywords: 4-ANI; Bioenergetic crisis; Chronic constriction injury; Oxidative stress; PARP; Quercetin