Vincristine-induced Painful Neuropathy Research Articles

Ameliorative Effect of Green Lipped Mussel Extract on Vincristine-Induced Painful Neuropathy in Rats

Ameliorative Effect of Green Lipped Mussel Extract on Vincristine-Induced Painful Neuropathy in Rats

Ameliorative potential of ferulic acid in vincristine-induced painful neuropathy in rats: An evidence of behavioral and biochemical examination

The present study was designed to investigate the effect of ferulic acid (FA) in vincristine-induced neuropathic pain in rats. Vincristine (50 µg/kg, i.p. for 10 consecutive days) was administered to induce painful neuropathy in rats. Various pain sensitive tests, viz., pinprick, hot plate, paint-brush, and acetone test were performed on different days (1, 6, 14, and 21) to assess the degree of mechanical hyperalgesia, heat hyperalgesia, mechanical dynamic allodynia, and cold allodynia, respectively. The electrophysiological and histopathological evaluations were also investigated. The tissue thiobarbituric acid reactive species (TBARS), reduced glutathione (GSH), myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-10 (IL-10), and total calcium were measured as the markers of inflammation and oxidative stress. FA (50 and 100 mg/kg, i.p.) and gabapentin (10 mg/kg, p.o.) were administered for 11 days. Administration of FA attenuated the vincristine-induced behavioral alteration along with electrophysiological and histopathological changes significantly (P < 0.05). FA also attenuated the vincristine-induced oxidative stress (TBARS, GSH, and total calcium levels) and inflammation (MPO, TNF-alpha, IL-6, and IL-10). It may be concluded that FA has ameliorative potential in mitigation of the painful states associated with vincristine-induced painful neuropathy that may further be attributed to anti-inflammatory actions with subsequent reduction in oxidative stress.

Ameliorative effect of Vernonia cinerea in vincristine-induced painful neuropathy in rats

The present study was designed to investigate the antinociceptive potential of Vernonia cinerea (VC) on vincristine-induced painful neuropathy in rats. A chemotherapeutic agent, vincristine (50 μg/kg intraperitoneally for 10 consecutive days), was administered for the induction of neuropathic pain in rats. The painful behavioral changes were assessed using hot plate, acetone drop, paw pressure, Von Frey hair and tail immersion tests to assess the degree of hyperalgesic and allodynic pain sensation in paw and tail. Tissue biomarker changes including thiobarbituric acid reactive substances (TBARSs), reduced glutathione (GSH) and total calcium levels were estimated in sciatic nerve tissue samples to assess the degree of oxidative stress. Histopathological changes were also observed in transverse sections of rat sciatic nerve tissue. Ethanolic extract of VC leaves and pregabalin were administered for 14 consecutive days from day 0 (day of surgery). Pregabalin served as a positive control in the present study. Vincristine administration resulted in a significant reduction in painful behavioral changes along with a rise in the levels of TBARS, total calcium and decrease in GSH levels when compared with the normal control group. Furthermore, significant histopathological changes were also observed. Pretreatment with VC significantly attenuated vincristine-induced development of painful behavioral, biochemical and histological changes in a dose-dependent manner, which is similar to that of pregabalin-pretreated group. The attenuating effect of VC in vincristine-induced nociceptive painful sensation may be due to its potential of antioxidative, neuroprotective and calcium channel inhibitory action.

Antinociceptive effect of Butea monosperma on vincristine-induced neuropathic pain model in rats

Neuropathic pain is a chronic neurodegenerative disease. It is well characterized by spontaneous pain, hyperalgesia, hypothesia, dysesthesia and allodynia. The present study was designed to investigate the antinociceptive potential of Butea monosperma on vincristine-induced painful neuropathy in rats. Vincristine was administered for induction of neuropathic pain in experimental animals. Hot plate, acetone drop, paw pressure, Von Frey hair and tail immersion tests were performed to assess the degree of thermal hyperalgesia, cold chemical allodynia, mechanical hyperalgesia and allodynia in the hind paw and tail thermal hyperalgesia, respectively, as an index of peripheral and central pain sensation. Tissue thiobarbituric acid reactive substances (TBARSs), reduced glutathione (GSH) and total calcium levels were estimated to assess the biochemical changes in the sciatic nerve tissue. Microscopically, histopathological changes were also observed in the sciatic nerve tissue. Ethanolic extract of B. monosperma leaves and pregabalin were administered for 14 consecutive days. Vincristine administration resulted in significant reduction in behavioural (i.e. hyperalgesia and allodynic pain sensation) changes along with a rise in the levels of TBARS, total calcium and decrease in GSH levels when compared with the normal control group. Moreover, significant histological changes were also observed. Pretreatment with B. monosperma significantly attenuated vincristine-induced development of painful behavioural, biochemical and histological changes in a dose-dependent manner, which is similar to that of pregabalin-pretreated group. B. monosperma ameliorated vincristine-induced painful neuropathy. It may be due to its potential of antioxidative, neuroprotective and calcium channel inactivation.

Protective effect of Acorus calamus L. in rat model of vincristine induced painful neuropathy: An evidence of anti-inflammatory and anti-oxidative activity

The study investigates the protective effect of Acorus calamus L. (AC) in vincristine-induced painful neuropathy. Vincristine (75μg/kg, i.p. for 10 consecutive days) was administered to induce painful neuropathy in rats. Various tests were performed to assess the degree of painful neuropathy at different days i.e., 0, 1, 7, 14, and 21st day. Sciatic nerve TNF-α, superoxide anion generation, total calcium, and myeloperoxidase activity level were also estimated after 21st day of study. Hydro-alcoholic extract of AC (HAE-AC, 100 and 200mg/kg, p.o.) and pregabalin (10mg/kg, p.o.) were administered for 14 consecutive days. Vincristine significantly induced neuropathic pain manifested in the terms of thermal hyperalgesia and allodynia (increase in hind paw licking, lifting or jumping from hot plate); mechanical hyperalgesia (increase in left hind paw lifting duration in pin-prick test) and allodynia (left hind paw withdrawal reflexes to non-noxious stimuli in Von Frey test); and sciatic functional index (analysis of footprints of the feet) along with rise in the levels of various biochemicals. HAE-AC attenuated vincristine induced behavioral, and biochemical changes comparable to that of pregabalin (positive control). HAE-AC attenuated vincristine induced painful neuropathy, which may be attributed to its multiple effects including anti-oxidative, anti-inflammatory, and calcium inhibitory actions.

Attenuating effect of hydroalcoholic extract of Acorus calamus in vincristine-induced painful neuropathy in rats

The present study was designed to investigate the attenuating potential of hydroalcoholic extract of Acorus calamus in vincristine-induced neuropathic pain in rats. Vincristine (50μg/kg, i.p. for 10 consecutive days) was administered to induce neuropathic pain in rats. Hot plate, plantar, Randall-Selitto and von Frey hair tests were performed to assess the degree of thermal and mechanical hyperalgesia and mechanical allodynia, respectively, at different time intervals, viz., 0, 1, 3, 6, 9, 12, 15, 18 and 21 days. Tissue myeloperoxidase, superoxide anion and total calcium levels were determined after day 21to assess biochemical alterations. Histopathological evaluations were also performed. Hydroalcoholic extract of Acorus calamus (HAE-AC, 100 and 200mg/kg, p.o.) and pregabalin (10mg/kg, p.o.) were administered for 14 consecutive days. Vincristine significantly induced peripheral neuropathic pain, manifested in thermal and mechanical hyperalgesia and mechanical allodynia, along with rises in the levels of superoxide anion, total calcium and myeloperoxidase activity. Moreover, significant histological changes were also observed. HAE-AC attenuated vincristine-induced development of painful behavioural, biochemical and histological changes in a dose-dependent manner comparable to that of pregabalin, serving as positive control. Acorus calamus prevented vincristine-induced neuropathic pain, which may be attributed to its anti-oxidative, anti-inflammatory, neuroprotective and calcium inhibitory actions, among others.

Effect of mexiletine on vincristine-induced painful neuropathy in mice

In the present study, we examined the effect of mexiletine on vincristine-induced thermal hyperalgesia in mice. Mice were intraperitoneally treated with vincristine at a dose of 0.05 mg/kg one day after the measurement of the pre-drug latency in the tail-flick test, and then treated with a dose of 0.125 mg/kg twice a week for 6 weeks. In vincristine-treated mice, a significant decrease in tail-flick latency developed at 6 weeks after treatment. Pretreatment with mexiletine, at doses of 3, 10 and 30 mg/kg, i.p., dose-dependently increased the tail-flick latency in vincristine-treated mice. A significant reduction of the tail-flick latency was observed when the tail-flick latency was examined 60 min after i.t. administration of N G-nitro- l-arginine methyl ester ( l-NAME, 30 nmol), a nitric oxide synthase (NOS) inhibitor, in naive mice. This l-NAME-induced thermal hyperalgesia was dose-dependently attenuated by pretreatment with mexiletine (10 and 30 mg/kg, i.p.), 10 min before the injection of l-NAME. The duration of nociceptive behavioral response induced by fenvalerate, at a dose of 0.1 μg, i.t., was significantly increased by pretreatment with l-NAME (30 nmol, i.t.). Intrathecal pretreatment with l-arginine (300 pmol) significantly reversed the l-NAME-induced enhancement of fenvalerate-induced nociceptive responses. The present study demonstrates that systemic mexiletine can effectively attenuate vincristine-induced thermal hyperalgesia. Furthermore, these results suggest that blockade of nitric oxide-induced enhancement of nociceptive transmission, in which tetrodotoxin-resistant sodium channels play an important role, may participate in the antinociceptive effect of mexiletine on vincristine-induced thermal hyperalgesia.

Possible involvement of the spinal nitric oxide/cGMP pathway in vincristine-induced painful neuropathy in mice

The mechanisms that underlie the development of vincristine-induced painful neuropathy are poorly understood. The nitric oxide (NO)-cGMP pathway has been reported to be involved in the spinal transmission of nociceptive information. In the present study, we examined whether alterations in spinal nociceptive processing via the NO-cGMP pathway contribute to vincristine-induced painful neuropathy in mice. Mice were intraperitoneally treated with vincristine at a dose of 0.05 mg/kg 1 day after the measurement of pre-drug latency in the tail-flick test, and then treated with a dose of 0.125 mg/kg twice a week for 6 weeks. In vincristine-treated mice, a significant decrease in tail-flick latencies developed at 4 weeks after treatment. Pretreatment with l-arginine (30–300 mg/kg, s.c.), a substrate of NO synthase (NOS), dose-dependently increased the tail-flick latencies in vincristine-treated mice. The l-arginine-induced increase in tail-flick latencies in vincristine-treated mice was completely reversed by i.t. pretreatment with N G-nitro- l-arginine methyl ester ( l-NAME, 3–30 nmol), a NOS inhibitor. Furthermore, i.t. pretreatment with 8-bromoguanosine 3′, 5′-cyclic monophosphate (8-Br-cGMP, 0.3–3.0 nmol), a membrane-permeable cGMP analog, dose-dependently increased the tail-flick latencies in vincristine-treated mice. The contents of NO metabolites, cGMP and protein levels of neuronal NOS in the spinal cord in vincristine-treated mice were significantly reduced compared to those in vehicle-treated naive mice. These results indicate that dysfunction of the l-arginine/NO/cGMP cascade in the spinal cord may trigger vincristine-induced thermal hyperalgesia in mice.

A New Animal Model of Vincristine-Induced Nociceptive Peripheral Neuropathy

Using doses close to those used clinically, we have developed an animal model of vincristine-induced nociceptive sensory neuropathy after repeated intravenous injection in male Sprague–Dawley rats. In order to validate the model, three different doses (50, 100 and 150 μg/kg) of vincristine were injected every 2nd day until five injections had been given. The sensory behavioural assessment revealed mechanical hyperalgesia and allodynia associated with cold thermal hyperalgesia and allodynia. With regard to electrophysiological evaluation, we observed a decrease in the nerve conduction velocity in the highest dose group. Morphological studies revealed few degenerated fibers in the sciatic nerve and many degenerated myelinated axons in the fine nerve fibers of the subcutaneous paw tissue. Finally, to develop an animal model, we chose the 150 μg/kg dose because of the good general clinical status of the rats without motor function changes associated with severe sensation disorders like hyperalgesia and allodynia. This model of vincristine-induced painful neuropathy will be used to explore physiopathological mechanisms implied in the genesis of neuropathic pain and also to test new analgesic and neuroprotective drugs.

Microtubule disorientation and axonal swelling in unmyelinated sensory axons during vincristine-induced painful neuropathy in rat

Neuropathic pain accompanies peripheral nerve injury following a variety of insults including metabolic disorders, traumatic injury, and exposure to neurotoxins such as vincristine and taxol. Vincristine, a microtubule depolymerizing drug, produces a peripheral neuropathy in humans that is accompanied by painful paresthesias and dysesthesias (Sandler et al., [1969] Neurology 19:367-374; Holland et al. [1973] Cancer Res. 33:1258-1264). The recent development of an animal model of vincristine-induced neuropathy provides an opportunity to investigate mechanisms underlying this form of neuropathic pain. Systemic vincristine (100 microg/kg) produces hyperalgesia to mechanical stimuli during the second week of administration, which persists for more than a week (Aley et al. [1996] Neuroscience 73:259-265). To test the hypothesis that changes in microtubule structure in nociceptive sensory neurons accompany vincristine-induced hyperalgesia, we analyzed unmyelinated axons in saphenous nerves of vincristine-treated rats. This study constitutes the first quantitative ultrastructural analysis of the cytoskeleton of unmyelinated axons in peripheral nerve during neuropathic hyperalgesia. There was no evidence of unmyelinated fiber loss or a decrease in the number of microtubules per axons. There was, however, a significant decrease in microtubule density in unmyelinated axons from vincristine-treated rats. This decrease in microtubule density was due to a significant increase in the cross-sectional area of unmyelinated axons, suggesting swelling of axons. In addition, vincristine-treated axons had significantly fewer microtubules cut in cross-section and significantly more tangentially oriented microtubules per axon compared to controls. These results suggest that vincristine causes disorganization of the axonal microtubule cytoskeleton, as well as an increase in the caliber of unmyelinated sensory axons.