|Year : 2011 | Volume
| Issue : 1 | Page : 28-34
Non-beneficial effects of rosiglitazone in oxaliplatin-induced cold hyperalgesia in rats
Vivek Jain, Amteshwar Singh Jaggi, Nirmal Singh
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
|Date of Web Publication||15-Jul-2011|
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147 002, Punjab
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Studies have suggested the ameliorative potential of PPAR g agonist in attenuating the nerve injury-induced neuropathic pain. However, their role in chemotherapy-induced neuropathic pain is not explored yet. Aims: To investigate the potential of rosiglitazone, a PPAR g agonist, in oxaliplatin-induced cold hyperalgesia in rats. Settings and Design: All animals were divided in nine groups and single administration of oxaliplatin (6 mg/kg ip) used for induction of neuropathy. Material and Methods : The pinprick, cold immersion, hot plate and hot immersion tests were performed to assess the degree of mechanical hyperalgesia, cold hyperalgesia, heat hyperalgesia, and heat allodynia, respectively. The levels of thiobarbituric acid reactive species (TBARS) and reduced glutathione (GSH) were measured as an index of oxidative stress. The myeloperoxidase (MPO) activity (a specific marker of inflammation) and calcium levels were also determined. Statistical analysis: Two-way analysis of variance (ANOVA) followed by Bonferroni's post test for behavioral assessment and one-way ANOVA followed by Tukey's multiple range tests for biochemical assessment were performed. Results: Single administration of oxaliplatin resulted in significant development of cold hyperalgesia without altering the nociceptive threshold for mechanical and heat stimuli. Furthermore, oxaliplatin increased the oxidative stress and decreased calcium levels without affecting inflammation. Treatment with rosiglitazone (2.5, 5, and 10 mg/kg po) for 11 days did not modulate oxaliplatin-induced cold hyperalgesia. Moreover, rosiglitazone did not modulate oxaliplatin-induced biochemical changes. Conclusions: PPAR g agonists are ineffective in attenuating the state of cold hyperalgesia during oxaliplatin administration.
Keywords: Cold hyperalgesia, oxaliplatin, PPAR γ, rosiglitazone
|How to cite this article:|
Jain V, Jaggi AS, Singh N. Non-beneficial effects of rosiglitazone in oxaliplatin-induced cold hyperalgesia in rats. J Pharm Negative Results 2011;2:28-34
|How to cite this URL:|
Jain V, Jaggi AS, Singh N. Non-beneficial effects of rosiglitazone in oxaliplatin-induced cold hyperalgesia in rats. J Pharm Negative Results [serial online] 2011 [cited 2020 Jul 14];2:28-34. Available from: http://www.pnrjournal.com/text.asp?2011/2/1/28/82985
| Introduction|| |
A third-generation novel platinum-derived compound, oxaliplatin, has received much importance in the treatment of advanced metastatic colorectal cancer, ovarian, breast, and lung cancer.  The toxicity profile of this new drug is favourable, in comparison with earlier platinum derivatives, with lesser nephrotoxicity, ototoxicity, and hematotoxicity. However, it produces unusual toxicity with regard to peripheral sensory nerves.  About 85-95% of oxaliplatin-treated patients rapidly develop significant pain signs without motor dysfunction within first 24-48 h of drug administration. Oxaliplatin-induced neuropathy is characterised by rapid onset of cold distal dysesthesia, paraesthesia, hypoesthesia, dysesthesia of the hands, feet, perioral area, or throat. ,
There are currently very few truly effective, well-tolerated therapies for effective management of chemotherapy-induced neuropathic pain. All clinically used drugs have limited efficacy and are associated with a number of intolerable side effects. Thus, chemotherapy-induced neuropathic pain represents a substantial unmet medical need for the development of novel therapies or extending the spectrum of clinically available drugs for effective management of cancer patients.
Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor super-family,  and PPAR γ agonists are employed for the management of type 2 diabetes. Recently, the interest in PPAR γ ligands has increased because they represent a potential therapeutic strategy for other diseases as well, including atherosclerosis, cancer, cardiovascular complications, inflammation, Parkinson's, and Alzheimer's disease. ,,, Immunohistochemical studies indicate that the presence of PPAR γ in the dorsal horns of the spinal cord and microglia cell culture indicates their important role in pain perception and pain transmission pathway. , Furthermore, PPAR g agonists have been documented to ameliorate the painful state in diabetic neuropathy, , and carrageenan-induced inflammation. , Moreover, PPAR g agonist has been shown to prevent several consequences of spinal cord injury (SCI), including neuronal damage, motor dysfunction, myelin loss, inflammation, and thermal hyperalgesia.  A recent study has shown that intrathecal administration of rosiglitazone inhibits spared nerve injury-induced neuropathic pain in
rats.  Furthermore, pioglitazone has been documented to attenuate tactile allodynia and hyperalgesia in mice subjected to peripheral nerve injury.  At our laboratory, it has been demonstrated that rosiglitazone attenuates tibial and sural nerve transection-induced neuropathic pain.  Therefore, the present study was designed to investigate the ameliorative potential of rosiglitazone, a PPAR g agonist, in oxaliplatin-induced cold hyperalgesia in rats.
| Materials and Methods|| |
Wistar albino rats of either sex weighing 250-300 g (procured from Punjab Agriculture University, Ludhiana) were employed in present study. They were housed in animal house with free access of water and standard laboratory pellet chow diet (Kisan Feeds Ltd, Mumbai, India). The rats were exposed to12 h light and 12 h dark cycle. The experimental protocol was duly approved by Institutional Animal Ethics Committee (IAEC) and care of the animals was carried out as per the guidelines of Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Ministry of Environment and Forest, Government of India (Reg. No.- 107/ 2007/ CPCSEA).
Drugs and reagent
Rosiglitazone was obtained as a generous gift from Torrent Pharma Ltd, Ahmedabad, India. Oxaliplatin was generous gift from Venus Remedies, Panchkula. 1, 1, 3, 3 tetramethoxy propane (Sigma Aldrich, USA), DTNB [5,5'-dithio, bis (2-nitrobenzoic acid)], reduced glutathione (GSH), Bovine Serum Albumin (BSA; Sisco Research Laboratories Pvt Ltd, Mumbai, India), Thiobarbituric acid (Loba Chem, Mumbai), Hexadecyl trimethyl ammonium bromide (HETAB), o-dianisidine hydrochloride (S.D. Fine, Mumbai, India), and Folin-Ciocalteu's Phenol reagent (Merck Ltd Mumbai, India) were procured for the present study. All chemicals used were of analytical grade.
Induction of neuropathy by single injection of oxaliplatin
Oxaliplatin was dissolved in a 5% glucose solution and single dose of 6 mg/kg was administered ip for inducing neuropathy as described by Ling and co-workers. 
Heat hyperalgesia (Hot plate test)
Thermal nociceptive threshold, as an index of thermal hyperalgesia, was assessed by the hot plate test. Eddy's hot plate was preheated and maintained at temperature of 52.5 ± 0.5°C. Rats were placed on the hot plate and nociceptive threshold, with respect to hind paw licking, was recorded in seconds. The cut-off time of 20 second was maintained. 
Mechanical hyperalgesia (Pinprick test)
Mechanical hyperalgesia was assessed by a pinprick test as described by Erichsen and Blackburn-Munro.  Both hind paws were touched with the point of the bent needle (at 90 o to the syringe) at an intensity sufficient to produce a reflex withdrawal response in normal animals, but at an intensity that was insufficient to penetrate the skin. The duration of the paw withdrawal was recorded in seconds with a stopwatch. A cut-off time of 20 second was maintained.
Heat allodynia test (Tail immersion test)
Spinal heat thermal sensitivity was assessed by the tail immersion test as described by Necker and Hellon.  Tail heat allodynia was noted with the immersion of terminal part of the tail (1 cm) in water, maintained at a temperature of 42.5 ± 0.5 °C. The tail withdrawal latency was recorded, as a response of heat thermal sensation and a cut-off time of 20 second was maintained.
Cold hyperalgesia test (Tail immersion test)
Spinal cold thermal sensitivity was assessed by tail immersion method as described by Necker and
Hellon.  Tail cold hyperalgesia was noted with the immersion of terminal part of the tail (1 cm) in water maintained at a temperature of 0-4°C. The tail withdrawal latency was recorded as a response of cold thermal sensation and a cut-off time of 20 second was maintained.
All animals were sacrificed after 11 th day of oxaliplatin administration by high-dose anaesthesia (diethyl ether). The sciatic nerve and the tissue beneath the sciatic nerve were isolated immediately. The sciatic nerve homogenate (10%) was prepared with 0.1 M Tris HCl buffer (pH 7.4). The tubes with homogenate were kept in ice water for 30 minute and centrifuged at 4°C (2,000 g, 10 min). The supernatant of homogenate was separated and used to estimate total protein content, thiobarbituric acid reactive species (TBARS), GSH, and total calcium content. The tissue beneath the sciatic nerve was homogenised at 5,000 rpm for 10 min. The supernatant was discarded and the pellet collected to measure myeloperoxidase (MPO) activity. The blood was collected from retro-orbital sinus on days 0, 5, and 11 to estimate the glucose levels.
Estimation of total protein content
The protein concentration was estimated according to the method of Lowry et al,  using bovine serum albumin as a standard.
Estimation of TBARS level
Lipid peroxidation was estimated by measuring the TBARS by the method of Ohokawa et al. The concentration was expressed in terms of nanomoles of TBARS per milligram of protein.
Estimation of GSH level
The GSH levels were measured according to the method of Beutler et al. The concentration of GSH was expressed as μg/mg of protein.
Estimation of total calcium
Total calcium levels were estimated in the sciatic nerve as described earlier. , Briefly, the sciatic nerve homogenate was mixed with 1 ml of trichloroacetic acid (4%) in ice cold conditions and centrifuged at 1,500 g for 10 minutes. The clear supernatant was used for estimation of total calcium ion by atomic emission spectroscopy at 556 nm.
Estimation of MPO activity
The MPO activity was measured by a method described by Krawisz et al and Grisham et al.  The tissue beneath the sciatic nerve was taken, rinsed with ice-cold saline, blotted dry and weighed. The minced tissue was homogenised in 10 volumes of ice-cold potassium phosphate buffer (pH 7.4), using the tissue homogeniser. The homogenate was centrifuged at 5,000 g for 10 min at 4°C. The supernatant was discarded, and 10 ml of ice-cold 50 mM potassium phosphate buffer (pH 6.0) containing 0.5% hexadecyl trimethyl ammonium bromide (HETAB) and l0 mM EDTA was then added to the pellet. It was then subjected to one cycle of freezing and thawing and brief period (l5 second) of sonication. After sonication, the solution was centrifuged at 19,000 g for 15 min. The MPO activity was measured spectrophotometerically at 460 nm. One unit of MPO activity was defined as that which would produce a change in absorbance of 1.0 unit/min at pH 7.0 and 25°C, calculated from the initial rate of reaction with peroxide (1 μM) as the substrate. The results were expressed as MPO units per gram of tissue.
Estimation of blood glucose level
The blood glucose levels were estimated by glucose oxidase-peroxidase (GOD-POD) method.
Nine groups, each comprising eight Wistar albino rats, were used in the present study. The dose selection of rosiglitazone was according to Kavak et al. 
Group I (Normal control)
The rats were not subjected to oxaliplatin administration and kept for 11 days. The behavioral tests were employed on different days, ie, day 0, 1, 3, 5, 7, 9, and 11. Thereafter, all animals were sacrificed and the biochemical analysis was done for estimating the total protein content, TBARS, GSH, total calcium and MPO activity. The blood glucose level was measured on days 0, 5, and 11.
Group II (Oxaliplatin control)
A single injection of oxaliplatin (6 mg/kg, ip) was administered to rats. The behavioral tests and biochemical parameters were assessed as mentioned in group I.
Group III (Vehicle in oxaliplatin)
Carboxy methyl cellulose (0.5% w/v, orally) was administered for 11 days in rats subjected to oxaliplatin injection. The behavioral tests and the biochemical parameters were assessed as mentioned in group I.
Group IV, V, and VI (Rosiglitazone 2.5, 5, and 10 mg/kg)
Rosiglitazone (2.5, 5, and 10 mg/kg po) was administered to normal rats for 11 days. The behavioral tests and biochemical parameters were assessed as mentioned in group I.
Group VII, VIII, and IX (Rosiglitazone 2.5, 5, and 10 mg/kg in oxaliplatin treated rats)
Rosiglitazone (2.5, 5, and 10 mg/kg po) was administered for 11 consecutive days, starting from day one after oxaliplatin administration. The behavioral tests and the biochemical parameters were assessed as mentioned in group I.
| Statistical Analysis|| |
All results were expressed as mean ± standard error of means (SEM). The data obtained from behavioral tests were statistically analysed by two-way analysis of variance (ANOVA) followed by Bonferroni's post test by using Graph pad prism Version 5.0 software. The data obtained from biochemical tests were statistically analysed by one-way ANOVA followed by Tukey's multiple range tests by using Graph pad prism Version 5.0 software. P < 0.05 was considered statistically significant.
| Results|| |
Effect of rosiglitazone on thermal hyperalgesia and allodynia in oxaliplatin-induced neuropathy
Administration of oxaliplatin resulted in significant development of cold hyperalgesia [Figure 1], as reflected by a marked decrease in withdrawal latency in a tail immersion test. However, no significant changes were observed in heat hyperalgesia [Figure 2] and heat allodynia [Figure 3] tests. Administration of rosiglitazone (2.5, 5, and 10 mg/kg po) did not modulate oxaliplatin-induced decrease in tail withdrawal latency in a cold immersion test [Figure 1].
|Figure 1: Effect of rosiglitazone on cold hyperalgesia, assessed by the tail immersion test, in oxaliplatin-induced neuropathic pain. Values are mean ± SEM, n=8 rats per group. a = P<0.05 vs control group|
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|Figure 2: Effect of rosiglitazone on heat hyperalgesia, assessed by the hot plate test, oxaliplatin-induced neuropathic pain. Values are mean ± SEM, n=8 rats per group|
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|Figure 3: Effect of rosiglitazone on heat allodynia, assessed by tail immersion test, oxaliplatin-induced neuropathic pain. Values are mean ± SEM, n=8 rats per group|
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Effect of rosiglitazone on mechanical hyperalgesia in oxaliplatin-induced neuropathy
Administration of oxaliplatin did not result in a significant development of mechanical hyperalgesia as in a pinprick test. Administration of rosiglitazone (2.5, 5, and 10 mg/kg dose) also did not make any changes in nociceptive threshold for mechanical noxious stimuli [Figure 4].
|Figure 4: Effect of rosiglitazone on mechanical hyperalgesia, assessed by the pin-prick test, oxaliplatin-induced neuropathic pain. Values are mean ± SEM, n=8 rats per group|
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Effect of rosiglitazone on oxidative stress markers and total calcium in oxaliplatin-induced neuropathy
Oxaliplatin resulted in significant decrease in the levels of GSH, total calcium, and increase in TBARS level when compared to control group. However, administration of rosiglitazone (2.5, 5, and 10 mg/kg dose) did not modulate oxaliplatin-induced decrease in calcium and GSH levels, and an increase in TBARS levels significantly [Table 1].
|Table 1: Effect of rosiglitazone on oxidative stress markers and total calcium in oxaliplatin-induced neuropathy|
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Effect of rosiglitazone on MPO activity (inflammatory marker) in oxaliplatin-induced neuropathy
Oxaliplatin did not produce significant changes in MPO activity compared to those in control group. Administration of the rosiglitazone (2.5, 5, and 10 mg/kg) also did not modify MPO activity significantly [Figure 5].
|Figure 5: Effect of rosiglitazone on myeloperoxidase activity in oxaliplatin-induced Neuropathy. Values are mean ± SEM, n=8 rats per group|
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Effect of rosiglitazone on total glucose level in oxaliplatin-induced neuropathy
Oxaliplatin did not produce significant changes in the blood glucose levels. Further, administration of rosiglitazone (2.5, 5, and 10 mg/kg) also did not make any significant change in glucose level (data not shown).
| Discussion|| |
In the present investigation, oxaliplatin administration significantly reduced nociceptive threshold for noxious cold stimuli, indicating the development of cold hyperalgesia. The behavioral alterations started on day 1 after oxaliplatin administration and reached peak within five days. However, it is noteworthy that oxaliplatin did not alter the nociceptive threshold for mechanical hyperalgesia and heat noxious, and non-noxious stimuli. Oxaliplatin-induced behavioral alterations observed in the present study are consistent with the findings in an earlier report. 
Treatment with rosiglitazone (2.5, 5, and 10 mg/kg) for 11 days did not attenuate oxaliplatin-induced cold hyperalgesia, suggesting the ineffectiveness of PPAR γ agonists in modulating oxaliplatin-induced neuropathic pain. Earlier reports have documented beneficial effects of PPAR γ agonists in attenuating the painful state in carrageenan-induced inflammation,, diabetic neuropathy, , spinal cord injury,  and spared nerve injury-induced neuropathy.  Furthermore, pioglitazone has been documented to attenuate tactile allodynia and hyperalgesia in mice subjected to peripheral nerve
injury.  From our laboratory, it has been demonstrated that rosiglitazone attenuates tibial and sural nerve transection-induced neuropathic pain.  These reports boosted us to hypothesise that perhaps PPAR γ receptors also have a role in oxaliplatin-induced neuropathy. However, contrary to our hypothesis, it was noted that rosiglitazone failed to modify oxaliplatin-induced alteration in pain perception for cold stimuli.
Oxaliplatin administration did not affect MPO activity significantly. The MPO activity has been well documented as a specific marker of inflammation.  This observation suggests that oxaliplatin-induced neurotoxicity is not a consequence of inflammation. Inflammation has been documented to play a crucial role in the pathophysiology of diabetic neuropathy,  chronic constriction injury (CCI), partial sciatic nerve ligation (PSL), , and tibial and sural nerve transection-induced neuropathy.  However, inflammation does not seem to be involved in oxaliplatin-induced neuropathy.
In the present investigation, oxaliplatin administration was noted to decrease calcium levels, which may possibly
be attributed to oxaliplatin-mediated chelation of calcium ions.  Further, oxaliplatin resulted in an increase in oxidative stress in terms of decrease in GSH and an increase in TBARS level. Earlier, oxaliplatin has been documented to increase the oxidative stress, which may be due to irreversible binding to glutathione, and hence depletion of potent antioxidant substances. , Earlier findings from our laboratory as well as from other researchers have documented that oxidative stress and calcium ion level play a critical role in chemotherapy-induced neuropathy. , These findings suggest that oxaliplatin-induced decrease in calcium levels and an increase in oxidative stress may be crucial in the development of neuropathy.
However, pretreatment with rosiglitazone did not modulate oxaliplatin-induced alterations in calcium levels and oxidative stress. Based on these observations, it may be suggested that the lack of effectiveness of rosiglitazone is due to of non-involvement of PPAR γ receptors and inflammation in oxaliplatin-induced neuropathy. Therefore, it may be concluded that PPAR γ and inflammation do not have a role in oxaliplatin-induced neuropathy, and hence PPAR γ ligands are ineffective in attenuating the state of neuropathic pain during oxaliplatin administration. The limitation of the present study is that it does not reveal the mechanisms involved in oxaliplatin-induced neuropathic pain. The measurement of more specific inflammatory mediators such as TNF-α could also have been included. Furthermore, future studies are required to investigate the potential of PPAR γ agonists in other types of chemotherapy-induced neuropathic pain, including vincristine and cisplatin-induced neuropathic pain.
| Conclusions|| |
It may be concluded that PPAR γ receptors and inflammation do not play a significant role in oxaliplatin-induced neuropathic pain. Further, rosiglitazone is ineffective in attenuating the alterations in perception for cold stimuli in oxaliplatin-induced neuropathy.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]