PARP inhibition attenuates neuroinflammation and oxidative stress in chronic constriction injury induced peripheral neuropathy.
AIM
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.


KEY FINDINGS
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.


SIGNIFICANCE
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.
['Komirishetty|Prashanth|P|', 'Areti|Aparna|A|', 'Yerra|Veera Ganesh|VG|', 'Ruby|P K|PK|', 'Sharma|Shyam S|SS|', 'Gogoi|Ranadeep|R|', 'Sistla|Ramakrishna|R|', 'Kumar|Ashutosh|A|']
D000818:Animals D001549:Benzamides D003251:Constriction, Pathologic D051546:Cyclooxygenase 2 D006930:Hyperalgesia D007249:Inflammation D008297:Male D009243:NAD D009443:Neuritis D018696:Neuroprotective Agents D018384:Oxidative Stress D010147:Pain Measurement D010523:Peripheral Nervous System Diseases D000067856:Poly(ADP-ribose) Polymerase Inhibitors D051381:Rats D017207:Rats, Sprague-Dawley D012677:Sensation D014443:Tyrosine D016138:Walking
Neuroinflammation NF-κB 3-Aminobenzamide 1,5-Isoquinolinediol Nitrotyrosine and PAR