FeTMPyP a peroxynitrite decomposition catalyst ameliorated functional and behavioral deficits in chronic constriction injury induced neuropathic pain in rats

Abstract

Neuropathic pain is a maladaptive pain phenotype that results from injury or damage to the somatosensory nervous system and is proposed to be linked to a cascade of events including excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation and apoptosis. Oxidative/nitrosative stress is a critical link between neuroinflammation and neurodegeneration through poly (ADP) ribose polymerase (PARP) overactivation. Hence, the present study investigated the antioxidant and anti-inflammatory effects of peroxynitrite decomposition catalyst; FeTMPyP in chronic constriction injury (CCI) of sciatic nerve-induced neuropathy in rats. CCI of the sciatic nerve manifested significant deficits in behavioral, biochemical, functional parameters and was markedly reversed by administration of FeTMPyP. After 14 days of CCI induction, oxidative/nitrosative stress and inflammatory markers such as iNOS, NF-kB, TNF-α and IL-6 were elevated in sciatic nerves of CCI rats along with depleted levels of ATP and elevated levels of poly (ADP) ribose (PAR) in both sciatic nerves in ipsilateral (L4-L5) dorsal root ganglions (DRG’s), suggesting over activation of PARP. Additionally, CCI resulted in aberrations in mitochondrial function as evident by decreased Mn-SOD levels and respiratory complex activities with increased mitochondrial fission protein DRP-1. These changes were reversed by treatment with FeTMPyP (1 & 3 mg/kg, p.o.). Findings of this study suggest that FeTMPyP, by virtue of its antioxidant properties, reduced both PARP over-activation and subsequent neuroinflammation resulted in protection against CCI-induced functional, behavioral and biochemical deficits.

Graphical Abstract

Schematic representation of the effect of FeTMPyP in attenuating the nerve injury-induced neuropathic pain.

Keywords:

• FeTMPyP
• chronic constriction injury (CCI)
• peroxynitrite
• poly (ADP) ribose polymerase (PARP)
• neuroinflammation

Acknowledgement

Authors would like to acknowledge the financial support from the Department of Pharmaceuticals, Ministry of Chemical and fertilizers, NIPER Kolkata, NIPER Hyderabad and Director, CSIR, IICT for encouragement (IICT/Pubs./2020/369) and support to carry out the study.

Author contributions

Prashanth Komirishetty, Aparna Areti, Vijay Kumar Arruri: Performed experiments, analyzed data, and manuscript writing. Ramakrishna Sistla, RanadeepGogoi, Ashutosh Kumar: Conception, study design, editing and reviewing the manuscript. All authors read and approved the final manuscript.

Disclosure statement

The authors would like to declare no conflicts of interest.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.