Benfotiamine relieves inflammatory and neuropathic pain in rats

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Abstract

Benfotiamine has shown therapeutic efficacy in the treatment of painful diabetic neuropathy in human beings. However, so far there is no evidence about the efficacy of this drug in preclinical models of pain. The purpose of this study was to assess the possible antinociceptive and antiallodynic effect of benfotiamine in inflammatory and neuropathic pain models in the rat. Inflammatory pain was induced by injection of formalin in non-diabetic and diabetic (2 weeks) rats. Reduction of flinching behavior was considered as antinociception. Neuropathic pain was induced by either ligation of left L5/L6 spinal nerves or administration of streptozotocin (50 mg/kg, i.p.) in Wistar rats. Benfotiamine significantly reduced inflammatory (10–300 mg/kg) and neuropathic (75–300 mg/kg) nociception in non-diabetic and diabetic rats. Results indicate that oral administration of benfotiamine is able to reduce tactile allodynia from different origin in the rat and they suggest the use of this drug to reduce inflammatory and neuropathic pain in humans.

Introduction

Neuropathic pain represents a chronic pain syndrome group with diverse etiology, but that shares some common underlying pathophysiologic mechanisms and clinical features. The clinical features of neuropathic pain include the paradox combination of sensory loss in the painful neuropathic area and hypersensitivity phenomena such as touch-evoked pain (allodynia) in the same area. The allodynia is assumed to reflect a neuronal hyperexcitability in the central nervous system (Koltzenburg et al., 1992).

Anticonvulsants and tricyclic antidepressants have become the mainstay in the treatment of chronic neuropathic pain (McQuay et al., 1996, Sindrup and Jensen, 1999). However, these drugs often have a limited effect and they may cause intolerable side effects. Therefore, other options of treatment have been explored. B vitamins have been proposed as possible drugs to treat neuropathic pain. In this sense, previous evidence showed that thiamine and pyridoxine are useful in the treatment of symptomatic diabetic peripheral neuropathy (Abbas and Swai, 1997). A recent study found evidence that the combination of thiamine, pyridoxine and cyanocobalamin improves the analgesic effect of gabapentin in the treatment of diabetic neuropathy (Medina-Santillán et al., 2004). Then, vitamins could be an alternative to treat neuropathic pain.

Benfotiamine was synthesized in early 1960s as a thiamine (vitamin B1) derivative with high bioavailability (Fujiwara, 1954, Bitsch et al., 1991). Previous studies have showed that thiamine or the mixture of thiamine, pyridoxine and cyanocobalamin could have a role in the treatment of painful neuropathy (Stracke et al., 1996); however, since these vitamins are water-soluble, the rate of absorption was relatively small. Benfotiamine is a lipid-soluble analogue of vitamin B1 with capacity to reach several organs in animals and humans (Woelk et al., 1998). This drug has shown therapeutic efficacy in the treatment of alcoholic polyneuropathy (Woelk et al., 1998) and painful diabetic neuropathy (Winkler et al., 1999) in human beings. However, so far there is no evidence about the efficacy of benfotiamine in preclinical models of neuropathic pain. B vitamins have also shown to reduce inflammatory pain in animals (França et al., 2001, Reyes-García et al., 2001). Therefore, the purpose of this study was to assess the possible antiallodynic and antinociceptive effect of benfotiamine in neuropathic and inflammatory pain, respectively, models in the rat.

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Animals

Experiments were performed on adult female Wistar rats. Female rats were used based on the fact that previous experiments in our conditions (Wistar rats, formalin concentration 1% and weight range 180–220 g) have not shown significant differences between males and females (unpublished data). Other authors have found differences only with other rat strains, greater weight or different formalin concentrations (Gaumond et al., 2002). The animals were obtained from our own breeding facilities and

Antinociceptive effect of benfotiamine in non-diabetic and diabetic rats

Subcutaneous formalin injection into the right hind paw of non-diabetic and diabetic (2 weeks) rats produced a typical pattern of flinching behavior characterized by a biphasic time course (Fig. 1). Phase 1 of the nociceptive response began immediately after formalin administration and then declined gradually in approximately 10 min. Phase 2 began about 15 min after formalin administration and lasted about 1 h (Dubuisson and Dennis, 1977, Porro and Cavazzuti, 1993). Diabetic rats injected with

Discussion

In the present study we have observed that oral administration of benfotiamine was able to reduce formalin-induced nociception in non-diabetic rats. Moreover, benfotiamine also reduced flinching behavior in diabetic rats (2 weeks). To our knowledge, this is the first report about the antinociceptive and anti-hyperalgesic effect of benfotiamine in a preclinical model of pain in non-diabetic and diabetic rats, respectively. Recent data have demonstrated that thiamine significantly reduces

Acknowledgements

The authors greatly appreciate the bibliographic assistance of Héctor Vázquez. Héctor I. Rocha-González and Nadia L. Caram-Salas are CONACYT fellows. This work is part of the B.Sc. dissertation of Gabriela M. Sánchez-Ramírez.

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