title: PARP inhibition attenuates neuroinflammation and oxidative stress in chronic constriction injury induced peripheral neuropathy.
abstract: OBJECTIVE
  Peripheral nerve degeneration after nerve injury is accompanied with oxidative stress that may activate poly ADP-ribose polymerase (PARP, DNA repair enzyme). PARP overactivation amplifies the neuronal damage either due to energy crisis or through inflammatory process by facilitating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Hence investigated the role of PARP inhibitors, 3-Aminobenzamide (3-AB) and 1,5-isoquinolinediol (ISO) in the attenuation of chronic constriction injury (CCI) induced peripheral neuropathy in rats.
  
  
  METHODS
  3-AB and ISO (at doses 30 and 3mg/kg i.p., respectively) were tested in rats subjected to standard tests for evaluating hyperalgesia and allodynia. Sciatic functional index (SFI) was assessed by performing walking track analysis. Oxidative stress and inflammation induced biochemical alterations were estimated after 14 days in sciatic nerve and lumbar spinal cord. Molecular changes were explored by immunohistochemistry and DNA fragmentation by TUNEL assay.
  
  
  RESULTS
  Treatment significantly improved sensorimotor responses (p<0.001), SFI (p<0.001) and foot posture. PARP inhibition significantly (p<0.01 and p<0.001) reduced the elevated levels of nitrite, inflammatory markers and also normalized the depleted NAD(total) levels. The protein expression of poly (ADP-ribose) (PAR), NF-κB, cyclooxygenase-2 (COX-2) and nitrotyrosine were significantly (p<0.01 and p<0.001) decreased in both sciatic nerve and lumbar spinal cord, evident through immunohistochemistry.
  
  
  CONCLUSIONS
  Present study outcomes fortify the pathological role of PARP overactivation in CCI induced neuropathy and PARP inhibition ameliorated oxidative stress and neuroinflammation associated with CCI induced nerve injury. Therefore, the current study suggests the PARP inhibitors can further be evaluated for designing futuristic strategies for the management of trauma induced neuropathy.
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India.
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 Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Balanagar, India.
authors.forename: Veera Ganesh
authors.initials: VG
authors.lastname: Yerra
authors.affiliation: Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India.
authors.forename: P K
authors.initials: PK
authors.lastname: Ruby
authors.affiliation: Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India.
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Sharma
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: Medicinal Chemistry and 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: D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D003251:Constriction, Pathologic / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D006930:Hyperalgesia / Q000188:drug therapy; D007249:Inflammation / Q000378:metabolism; D008297:Male; D009243:NAD / Q000378:metabolism; D009443:Neuritis / Q000188:drug therapy* / Q000209:etiology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects*; D010147:Pain Measurement / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy* / Q000209:etiology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012677:Sensation / Q000187:drug effects; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D016138:Walking
chemical_list: D001549:Benzamides; D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009243:NAD; C002744:3-nitrotyrosine; D014443:Tyrosine; C025160:3-aminobenzamide; D051546:Cyclooxygenase 2
keywords: 1,5-Isoquinolinediol; 3-Aminobenzamide; NF-κB; Neuroinflammation; Nitrotyrosine and PAR