Elsevier

Life Sciences

Volume 90, Issues 19–20, 22 May 2012, Pages 755-762
Life Sciences

Ameliorative potential of montelukast on ischemia–reperfusion injury induced vasculitic neuropathic pain in rat

https://doi.org/10.1016/j.lfs.2012.03.010Get rights and content

Abstract

Aims

Ischemia -reperfusion (I/R) event in vascular and nervous system has been documented to rising ischemic and vasculitic neuropathic pain, clinically resembles the complex regional pain syndrome (CRPS). The present study evaluated the effect of montelukast, a cysteinyl leukotriene receptor (Cys-LTC4 and Cys-LTD4) antagonist on ischemia -reperfusion (I/R) induced vasculitic neuropathic pain in rats.

Main Methods

Behavioral parameters were assessed at different time intervals (i.e. 0, 1, 7, 14 and 21st day) and biochemical analysis in sciatic nerve tissue samples were also performed along with histopathological studies.

Key Findings

Behavioral pain assessment has shown increase in paw and tail withdrawal threshold in montelukast treated groups against thermal and mechanical stimuli as compared to I/R control group. We observed a decrease in the total calcium, thiobarbituric acid reactive substance (TBARS) and myeloperoxidase (MPO) activity levels, whereas there is rise in reduced glutathione level in montelukast treated groups as compared to I/R control group. However, significant behavioral and biochemical results were observed only in medium and high dose of treated groups which were comparable to normal control group. Moreover, histopathological study has revealed the reduction of I/R induced neuronal edema and axonal degeneration due to montelukast.

Significance

Montelukast has ameliorated I/R induced vasculitic neuropathic pain, these effects may be due to inhibition of lipid peroxidation, reduction of oxidative stress, release of inflammatory mediators and neuroprotective actions. Hence, it could be used as a novel therapeutic agent for the management of vasculitic inflammation related neuropathic pain.

Introduction

Neuropathic pain associated with peripheral nerve injury is characterized by the sensory abnormalities such as unpleasant abnormal sensation (dysesthesia), an increased response to painful stimuli (hyperalgesia) and pain in response to a stimulus that does not normally provoke pain (allodynia) (Woolf and Mannion, 1999). Peripheral neuropathic pain has been frequently observed in patients with cancer, AIDS, long standing diabetes, lumbar disc syndrome, herpes infection, traumatic spinal cord injury, multiple sclerosis and stroke (Schmader, 2002, Verma et al., 2005, Werhagen et al., 2004). It has also been documented that ischemic insult of vascular and nervous system in vascular occlusive diseases, necrotizing vasculitides, diabetes mellitus and trauma play a major key role in the development of ischemic pain, vasculitic neuropathic pain in complex regional pain syndrome (CRPS) (Kihara et al., 1996, Kwak et al., 2009). Moreover, it is also known that ischemic–reperfusion event induces potent tissue injury due to change in the microvascular environment of the targeted organ which in turn causes neuronal edema, breakdown of blood–nerve barrier, nerve fiber degeneration, neuronal excitation, decreased nerve conduction velocity, membranous lipid peroxidation, accumulation of free radical, alteration of enzymatic reaction and ion fluxes (Coderre et al., 2004, Koban et al., 2003, Nouri et al., 2008). The pathophysiology of ischemia–reperfusion injury include platelet aggregation, immune cell activation, free radical generation and leukocyte–endothelial cell interactions which lead to the injury of the endothelium and obstruction of capillaries, thus impairing oxygen supply to the nerve tissue, tissue and neuronal inflammation (Droge, 2002, Kannan, 2002, Kirschner et al., 1997).

During inflammatory condition, various cell components i.e., eosinophils, mast cells, monocytes, and macrophages readily secrete the chemical mediators such as cysteinyl leukotrienes and their derivatives which enhance the further pathogenic process (Nayak, 2004). Montelukast (leukotriene receptor antagonist) is a new anti-inflammatory drug, which directly interferes with leukotriene production and their receptors (Drazen et al., 1999). Leukotrienes are an important mediator of inflammation, vascular injury, ischemia, obstructive pulmonary disease (Freiberg et al., 2009), asthma, peptic ulcer (Singh et al., 2008, Sood and Muthuraman, 2009) and neuroinflammation as well as neuropathic pain (Gholami et al., 2008, Zandman-Goddard et al., 2007). This selective reversible cysteinyl leukotriene D4 (CysLTD4) receptor antagonist property helps to treat such illness and inflammation. Montelukast also provide a significant improvement from the inflammatory conditions and symptoms, along with high safety profile (Wenzel, 1999).

Montelukast is clinically used for the treatment of bronchial asthma by antagonizing the leukotriene receptor in bronchial smooth muscle. The same receptor also plays a key role in the pathogenesis of neuroinflammation as well as neuropathic pain via leukocyte–endothelial cell interactions process (Honjo et al., 2002, Nakamura et al., 2009, Zandman-Goddard et al., 2007). Therefore, the present study was designed to investigate the role of montelukast on femoral ischemia–reperfusion injury induced painful vasculitic neuropathy in rats.

Section snippets

Chemicals

Montelukast (Cadila Pharma Pvt. Ltd. Gujarat), 1,1,3,3-tetra methoxy propane and thiobarbituric acid (Loba Chemie) were obtained from the respective companies. Chemicals such as Folin-Ciocalteu's Phenol reagent (Merck Limited, Mumbai), 5,5′-dithiobis(2-nitrobenzoic acid) [DTNB], reduced glutathione (GSH) and bovine serum albumin (BSA), (Sisco Research Laboratories Pvt. Ltd. Mumbai) were procured for the present study. All the reagents used in the present study were of analytical grade.

Animals

Wistar

Effect of montelukast on peripheral behavioral test

Peripheral thermal (conduction, radiant and mechanical) sensitivity was assessed by right hind paw withdrawal threshold and lifting duration, as an index of heat and mechanical hyperalgesia by using hot plate (Fig. 1), plantar (Fig. 2), and pin prick test (Fig. 3) respectively. Ischemia–reperfusion of femoral artery showed significant decrease in paw withdrawal threshold at different days and maximum effect was observed on 7th day as compared to sham control group. Whereas, montelukast treated

Discussion

The present study evaluated the neuroprotective effect of montelukast on ischemia–reperfusion induced vasculitic neuropathic pain in rats. Literature revealed that ischemia followed by reperfusion can cause severe damage in heart, intestine, kidney, stomach and brain as well as in peripheral nerve tissue (Gholami et al., 2008). It is also well known that neuronal cellular reperfusion induced damage is caused by enhancement of the reactive oxygen species generation, lipid peroxidation, calcium

Conclusion

The support from literature and data in hand, evident that montelukast exert beneficial effects in ischemia–reperfusion of femoral artery induced vasculitic neuropathic pain probably due to its potential of anti-oxidative, anti-inflammatory, neuroprotective and calcium inhibitory actions. Hence, it can be concluded that montelukast can act as a novel therapeutic molecule for the treatment of ischemia–reperfusion associated vasculitic neuropathic pain due to its leukotriene receptor (CysLTC4 and

Conflict of interest statement

There was no conflict of interest in the present study.

Funding source

There was no financial support from any funding agency for the completion of this research work.

Acknowledgements

Thanks to all faculty members of Rayat Institute of Pharmacy for their encouragement and support. We are also grateful to Rayat & Bahra Educational and Research Trust for their unconditional helps to carryout this project.

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