Licofelone attenuates MPTP-induced neuronal toxicity: behavioral, biochemical and cellular evidence

Abstract

Neuroinflammation and oxidative stress play critical role in the pathophysiology of neurodegenerative diseases including Parkinson's disease (PD). Recent reports indicate the beneficial effect of anti-inflammatory drugs in attenuating the progression of PD. Therefore, the present study is aimed to evaluate the possible role of licofelone, a dual COX/LOX-inhibitor against MPTP-induced neurotoxicity in mice. Administration of MPTP (40 mg/kg in divided doses of four injections of 10 mg/kg, i.p. each at 1 h interval) significantly impaired locomotor activity and induced catatonia, oxidative damage (elevated levels of lipid peroxidation, superoxide anion and nitrite, and decreased levels of non-protein thiols) as compared with vehicle-treated animals. Biochemical studies revealed significant alterations in mitochondrial enzyme complex activities (decreased complex-I activity and mitochondrial viability) and increased levels of caspase-3 and NF-κB/p65 as compared to vehicle treated group. Licofelone (2.5, 5 or 10 mg/kg/day, p.o.) treatment for 7 days significantly improved locomotor activity, attenuated the severity of catatonia, oxidative damage and restored mitochondrial enzyme complex activity as compared to MPTP-treated group. Licofelone treatment also attenuated the expression of apoptotic factor (caspase-3) and transcription factor (NF-κB/p65) as compared to MPTP-treated group. The findings of the present study suggest that licofelone (dual inhibitor of COX and LOX) represents a new class of anti-inflammatory agent which may provide a novel therapeutic alternative for the treatment and management of PD.

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

“…Such encouraging results may constitute an important breakthrough not only to enrich the quality of life of NSAIDs chronic users, but also to allow the use of these medicines in the therapy of a wider spectrum of diseases. In fact, diverse preclinical studies have been showing the efficacy of phospho‐NSAIDs, NO‐NSAIDs, H 2 S‐NSAIDs, NOSH‐NSAIDs, dual COX/5‐LOX inhibitors, and mPGES‐1 inhibitors as antitumor and/or neuroprotective agents . Therefore, the development of safer anti‐inflammatory drugs may additionally provide valuable options for the long‐term treatment of cancer and neurodegenerative diseases.…”

Differential contribution of lipoxygenase isozymes to nigrostriatal vulnerability

“…While extensively studied for pro- and anti-inflammatory effects in other conditions such as diabetes, cancer, asthma, cardiovascular disorders and most recently AD (Marks et al, 2000; Werz, 2002; Yao et al, 2005; Gubitosi-Klug et al, 2008; Ikonomovic et al, 2008; Planaguma et al, 2008; Liu et al, 2009; Menna et al, 2010; Neilson et al, 2012), LOX enzymes have not been widely explored in the context of PD etiology and progression (Mosca et al, 1996; Li et al, 1997; Mytilineou et al, 1999, 2002; Klegeris and McGeer, 2002; Canals et al, 2003; de Bernardo et al, 2004; Kramer et al, 2004; Scholz et al, 2008; Gupta et al, 2010; Dobrian et al, 2011). Further, although products of distinct LOX-mediated metabolism have differential effects on activation pro- and anti-inflammatory cellular pathways, no study has compared isozyme-specific effects on nigrostriatal dopamine regulation and vulnerability.…”