Protective effect of co-administration of curcumin and sildenafil in alcohol induced neuropathy in rats

Abstract

Neuropathic pain associated with chronic alcohol consumption is a medico-socioeconomical problem that affects both central and peripheral nervous system and has no satisfactory treatment till date. The present study was designed to investigate the protective effect of co-administration of curcumin and sildenafil on alcohol induced neuropathic pain in rats. In order to carry out this, ethanol (35% v/v, 10 g/kg, p.o.) was administered for 10 weeks to induce neuropathic pain. Curcumin (30 and 60 mg/kg, i.p.) and sildenafil (5 and 10 mg/kg, i.p.) were given alone and in combination at their lower doses (30 mg/kg curcumin and 5 mg/kg, sildenafil, i.p.) to investigate the changes in thermal and mechanical hyperalgesia, allodynia and histopathological parameters. Biochemical estimations of thiobarbituric acid reactive species, glutathione and protein was also carried out to evaluate oxidative stress. The results revealed that chronic alcohol consumption for 10 weeks caused significant thermal and mechanical hyperalgesia, allodynia and increased oxidative stress. Individual administration of both the drugs at their low as well as high doses were able to improve the symptoms of alcohol induced neuropathic pain. Whereas co-administration of curcumin and sildenafil at their lower doses itself were found to significantly improve nerve functions, biochemical and histopathological parameters as compared to their individual administration. It is therefore proposed that co-administration of curcumin and sildenafil may bring new dimension towards attenuation of alcohol induced neuropathic pain affecting central as well as peripheral nervous system.

Introduction

Neuropathic pain is caused due to damage of neurons, direct damage to the nervous system or disease of somatosensory nervous system (Pasero, 2004, Costigan et al., 2009, Dworkin et al., 2010, Xu et al., 2012). It is characterized by allodynia, hyperalgesia, and paraesthesia (Shields et al., 2003; Campbell and Meyer, 2006; Grovle et al., 2013). Peripheral neuropathic pain is most commonly reported aberration in patients with chronic alcoholism (Dina et al., 2007, Misra and Kalita, 2009, Ferrari and Levine, 2010). Painful peripheral polyneuropathy, Wernicke encephalopathy, cortical and motility dysfunction, psychosis and delirium tremens are some of the neurological aberrations reported in chronic alcoholic patients (Yerdelen et al., 2008, Kandhare et al., 2012). In addition, chronic alcohol consumption produces a sustained increase in stress hormones, epinephrine and glucocorticoids, that are exacerbated through withdrawal of alcohol (Dina et al., 2008, Fu et al., 2015). Alcohol is a well-known promoter of oxidative stress by decreasing endogenous antioxidants like α-tocopherol, ascorbate and vitamin E concentration (McDonough, 2003, Kandhare et al., 2012). Moreover, it is reported that neuropathic effect of alcohol is exerted either via direct damage to DNA, cellular protein and lipid or, indirect damage to signaling pathway that regulates oxidative stress and exerts vicious effects (Cheesman, 1993, Kandhare et al., 2012). This causes significant decrease in velocity of nerve conduction, impairment in neural function, changes in vascular permeability and endoneural hypoxia (McDonough, 2003, Kandhare et al., 2012). Combination of gabapentin and extended release morphine, gabapentin and extended release oxycodone, pregabalin and oxycodone, pregabalin and lidocaine (5% w/w, topical) as well as sodium valproate and nitroglycerin (spray) (Xu et al., 2012) are reported to provide satisfactory pain relief with reduced side effects. Despite several efforts made in past to investigate the effect of synthetic drugs in peripheral neuropathy, significant clinical success has been limited and successful therapy is still a farfetched dream (Gloria et al., 1997, Peters et al., 2006).

Curcumin, an alkaloid from plant Curcuma longa, is widely used as an additive in Indian food. Its antioxidant, antiarthritic, antirheumatic, analgesic and gastro-protective effects are well documented (Ahmad, 2013, Díaz-triste et al., 2014, Zanjani et al., 2014). It is reported to have inhibitory effect over mitogen protein kinase (Jeon et al., 2013), cyclooxygenase 2 (COX-2) pathway and neuropathic pain induced by diabetes (Li et al., 2013). The antidepressant effect of curcumin is also reported by increasing serotonin, norepinephrine and dopamine levels in the brain that inhibit monoamino oxidase (Sanmukhani et al., 2013). Sildenafil is (mainly) known mainly for the treatment of erectile dysfunction (Boolell et al., 1996). It is also reported to have antidepressant and gastro-protective effects (Díaz-triste et al., 2014). It has been found to alleviate insulin sensitivity via attenuating oxidative stress (Aboryag et al., 2013) and inhibit selective phosphodiesterase-5 (Patil et al., 2004). The use of sildenafil in neuropathic pain is well reported (Huang et al., 2010, Wang et al., 2015).

In the previous study, curcumin has been reported to attenuate alcohol induced neuropathic pain in rat model (Kandhare et al., 2012). As mentioned above, sildenafil has been reported in reduction of neuropathic pain in rat model (Huang et al., 2010). In the present study, an effort has, therefore, been made to investigate the advantages of co-administration of curcumin and sildenafil at their sub-effective doses over their individual treatments on ethanol induced neuropathic pain. It is important to note that the protective response of co-administration of curcumin and sildenafil for attenuation of alcohol induced neuropathy in rats has been reported for the first time.