Combination strategy of PARP inhibitor with antioxidant prevent bioenergetic deficits and inflammatory changes in CCI-induced neuropathy.

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.

Boswellia ovalifoliolata abrogates ROS mediated NF-κB activation, causes apoptosis and chemosensitization in Triple Negative Breast Cancer cells.

The present study was aimed to evaluvate the apoptogenic potential of ethanolic extract of leaves from Boswellia ovalifoliolata (BL EthOH) and to unravel the molecular mechanisms implicated in apoptosis of Triple Negative Breast Cancer (TNBC) cells. BL EthOH was cytotoxic against TNBC cells like MDA-MB-231 and MDA-MB-453 with IC50 concentrations 67.48 ± 5.45 and 70.03 ± 4.76 µg/ml, respectively. Apoptotic studies showed that BL EthOH was able to induce apoptosis and western blot studies demonstrated that BL EthOH significantly decreased the Phospho-NF-κB (ser536), PCNA, anti-apoptotic protein Bcl-2 expression and increased the expression of pro-apoptotic protein Bax, in MDA-MB-231 and MDA-MB-453 cell lines when compared with untreated cells. Besides, BL EthOH has synergistic chemosensitizing effects on TNBC cells and increased the cytotoxicity of doxorubicin and cisplatin.

Oxidative stress and nerve damage: role in chemotherapy induced peripheral neuropathy.

Peripheral neuropathy is a severe dose limiting toxicity associated with cancer chemotherapy. Ever since it was identified, the clear pathological mechanisms underlying chemotherapy induced peripheral neuropathy (CIPN) remain sparse and considerable involvement of oxidative stress and neuroinflammation has been realized recently. Despite the empirical use of antioxidants in the therapy of CIPN, the oxidative stress mediated neuronal damage in peripheral neuropathy is still debatable. The current review focuses on nerve damage due to oxidative stress and mitochondrial dysfunction as key pathogenic mechanisms involved in CIPN. Oxidative stress as a central mediator of apoptosis, neuroinflammation, metabolic disturbances and bioenergetic failure in neurons has been highlighted in this review along with a summary of research on dietary antioxidants and other nutraceuticals which have undergone prospective controlled clinical trials in patients undergoing chemotherapy.