Original Article
The effect of thioctic acid on allodynia in a rat vincristineinduced neuropathy model
Journal of International Medical Research 2015, Vol. 43(3) 350–355 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0300060515569287 imr.sagepub.com
Jimin Kahng1, Tae kwan Kim2, Eun Yong Chung2, Yee Suk Kim2 and Jeong Yeon Moon2
Abstract Objective: To investigate the antiallodynic effects of thioctic acid in vincristine-induced neuropathy in rats. Methods: Neuropathy was induced in Sprague–Dawley rats via vincristine intraperitoneal injection. After 15 days, rats were investigated for the presence of mechanical and cold allodynia, and those with allodynia received intraperitoneal injection with normal saline or 1, 5, or 10 mg/kg thioctic acid. Mechanical and cold allodynia were assessed before treatment and at 15, 30, 60, 90, 150 and 180 min after treatment. Results: Mechanical and cold allodynia were reduced by thioctic acid injection. The duration of effect increased with thioctic acid dose. Conclusion: Thioctic acid may be an effective treatment for vincristine-induced neuropathy.
Keywords Thioctic acid, neuropathy, pain, vincristine Date received: 23 September 2014; accepted: 31 December 2014
Introduction The anticancer agent vincristine induces painful distal sensorimotor neuropathy in 60% of patients, resulting in discontinuation of treatment and reduced healthrelated quality-of-life.1,2 Since the pathogenesis of vincristine induced neuropathy is not clearly understood, various treatments are prescribed empirically, including tricyclic antidepressants, anticonvulsants, opioids, nonsteroidal anti-inflammatory agents and a-adrenergic agonists.3-5 The efficacy of these drugs in the treatment of neuropathy
is limited, however, and some have poor safety profiles.6-8 1
Department of Laboratory Medicine, Bucheon St Mary’s Hospital, The Catholic University of Korea, Bucheon, Republic of Korea 2 Department of Anaesthesia and Pain Medicine, Bucheon St Mary’s Hospital, The Catholic University of Korea, Bucheon, Republic of Korea Corresponding author: Yee Suk Kim, Department of Anaesthesia and Pain Medicine, Bucheon St Mary’s Hospital, 2 Sosa-dong, Wonmi-gu, Bucheon City, Kyunggido, Republic of Korea. Email: [email protected]
Creative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided original workbyisguest attributed as specified Downloaded fromthe imr.sagepub.com on October 5, 2015 on the SAGE and Open Access page (http://www.uk.sagepub.com/aboutus/openaccess.htm).
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Thioctic acid (a-lipoic acid) is a biological antioxidant9 that has been shown to improve nerve blood flow and distal nerve conduction velocity in a rat model of diabetic neuropathy.10 Thioctic acid is an effective treatment for diabetic sensorimotor polyneuropathy11 and diabetic peripheral neuropathy,12 and also has been shown to improve functional activity in patients with chronic low back pain.13 Vincristine-induced polyneuropathy and diabetic polyneuropathy develop in similar ways, as both involve inflammation and oxidative stress.14–16 The aim of the present study was to investigate the antiallodynic effects of thioctic acid in a vincristine-induced rat neuropathy model.
Materials and methods Animals Sprague–Dawley rats (n ¼ 40; body weight 200–250 g) were housed and fed according to guidelines on the care and use of laboratory animals, as adopted by the Institutional Animal Care and Use Committee, Department of Laboratory Animals, Bucheon St Mary’s Hospital, Catholic University of Korea, Bucheon City, Republic of Korea, who approved the study. Rats were housed (2–3 animals per plastic cage) and maintained on a 12-h light/dark cycle, with free access to food and water.
Neuropathy model Vincristine was used to induce neuropathy as described.10 Briefly, 0.1 ml/kg per day vincristine sulphate (Hopira, Lake Forest, IL, USA) was injected intraperitoneally for 5 days, paused for 2 days, then resumed for an additional 5 days. Allodynia was assessed on day 15 from the beginning of the injections via Semmes–Weinstein aesthesiometer (Stoelting, Wood Dale, IL, USA). Rats that showed a foot withdrawal response when a 4 -g filament was applied to the hindpaw were considered allodynic.
Treatment Allodynic rats were allocated between four groups: normal saline (n ¼ 6; 1 ml/kg normal saline intraperitoneal injection); TA1 (n ¼ 8; 1 mg/kg thioctic acid intraperitoneal injection [ThiotacidÕ injection; Dai han, Kyeongido, Korea]); TA 5 (n ¼ 8; 5 mg/kg thioctic acid intraperitoneal injection); and TA 10 (n ¼ 8; 10 mg/kg thioctic acid intraperitoneal injection). The volume of all injections was 1 ml/kg. Thioctic acid dose was determined by preliminary experiments. Mechanical and cold allodynia were assessed before treatment and at 15, 30, 60, 90, 120, 150 and 180 min after treatment.
Mechanical allodynia Mechanical allodynia was assessed using a series of von Frey filaments (1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 15.0 and 26.0 g), as described.17 The left hind paw of each animal was stimulated and the withdrawal threshold was defined as the minimal pressure level (in g) that elicited a withdrawal response (lifting, shaking or licking). If there was no response to any filament, the withdrawal threshold was recorded as 26.0 g.
Cold allodynia Cold allodynia was assessed using acetone, as described.17 Acetone was applied to the plantar surfaces of the left hind paw and withdrawal responses were noted. Testing was repeated 5 times with 3–5 min between each test. The intensity of cold allodynia was expressed as withdrawal frequency: (n paw withdrawal responses/n trials) 100.
Statistical analyses Data were presented as mean SD. Between-group and between-timepoint differences were evaluated using repeated-measures analysis of variance followed by post hoc Dunn’s test. Statistical analyses were
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Table 1. Effect of intraperitoneal injection with normal saline or thioctic acid on mechanical allodynia withdrawal threshold in vincristine-induced neuropathy in a rat model. Thioctic acid Timepoint
Normal saline n ¼ 6
1 mg/kg n ¼ 8
5 mg/kg n ¼ 8
10 mg/kg n ¼ 8
Before injection After injection, min 15 30 60 90 120 150 180
1.2 0.1
1.2 0.3
1.1 0.2
1.0 0.0
3.1 1.3 1.5 0.4 1.6 0.7 1.4 0.7 1.4 0.5 1.2 0.2 1.0 0.0
10.6 9.2* 2.0 1.4 1.2 0.3 1.1 0.2 1.0 0.2 1.0 0.0 1.1 0.1
20.3 7.4* 14.1 8.9* 10.6 9* 1.7 1.8 1.1 0.1 1.1 0.2 1.0 0.0
24.3 3.8* 15.9 8.9* 12.3 8.9* 11.2 9.5* 7.1 9.1 7.3 11.6 7.3 11.6
Data presented as mean SD. *P < 0.05 vs normal saline; repeated measures analysis of variance.
performed using SAS version 9.3 (SAS Institute, Cary, NC, USA), and Pvalues < 0.05 were considered statistically significant.
Results The effects of thioctic acid on mechanical allodynia are shown in Table 1. There was no significant change in withdrawal threshold in the normal saline group at any timepoint after injection. Withdrawal frequency was significantly higher at 15 min after1 mg/kg thioctic acid injection compared with normal saline. Compared with normal saline, 5 mg/ kg thioctic acid significantly increased withdrawal threshold for 60 min, and 10 mg/kg thioctic acid significantly increased withdrawal threshold for 90 min (P < 0.05 for each comparison; Table 1). The effects of thioctic acid on cold allodynia are shown in Table 2. There was no significant change in withdrawal threshold in the normal saline or 1 mg/kg thioctic acid groups at any timepoint after injection. Compared with normal saline, 5 mg/kg thioctic acid significantly decreased withdrawal frequency for 30 min, and 10 mg/kg thioctic acid significantly decreased
withdrawal frequency for 90 min (P < 0.05 for each comparison; Table 2).
Discussion The present study showed that thioctic acid has antiallodynic properties in a vincristineinduced neuropathy model, in accordance with findings in oxaliplatin-induced neuropathy.18,19 Thioctic acid has no effect on cisplatin-induced mechanical hyperalgesia,20 suggesting that treatment should be tailored for each chemotherapeutic drug. We used relatively small doses of thioctic acid (1, 5 and 10 mg/kg) compared with other researchers (50 and 100 mg/kg),18 due to differences in pain intensity incurred by oxaliplatin and vincristine. The antiallodynic action of thioctic acid has not been fully elucidated. Oxidative stress has an important role in several neuropathic pain models, including vincristine induced neuropathy, and spinal or sciatic nerve ligation.21,22 Concentrations of thiobarbituric acid reactive substances (TBARS) and superoxide anions were increased by vincristine treatment.23,24 It has been reported that lipoic acid treatment reversed indices of oxidative stress,
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Table 2. Effect of intraperitoneal injection with normal saline or thioctic acid on cold allodynia withdrawal frequency in vincristine induced neuropathy in a rat model. Thioctic acid Timepoint
Normal saline n ¼ 6
1 mg/kg n ¼ 8
5 mg/kg n ¼ 8
10 mg/kg n ¼ 8
Before injection After injection, min 15 30 60 90 120 150 180
90.0 11.0
87.5 10.4
92.5 10.4
95.0 9.3
80.0 12.6 80.0 17.9 80.0 21.9 83.3 15.1 83.3 15.1 86.7 10.3 90.0 11.0
62.5 12.8 70.0 26.2 80.0 26.2 82.5 16.7 85.0 20.7 87.5 14.9 90.0 10.7
35.0 20.7* 46.3 31.6* 52.5 30.1 70.0 21.4 82.5 12.8 85.0 14.1 92.5 10.4
17.5 27.1* 30.0 15.1* 40.0 23.9* 50.0 21.4* 62.5 31.1 65.0 23.3 87.5 21.2
Data presented as mean SD. *P < 0.05 vs normal saline; repeated measures analysis of variance.
including TBARS.25 It is possible that the antioxidant properties of thioctic acid are responsible for its antiallodynic effects. Inflammatory processes play an important role in the development of vincristineinduced neuropathy.26 In rats, vincristine treatment resulted in significantly increased tumour necrosis factor (TNF)-a concentrations in sciatic nerve tissue.27 Concentrations of nitric oxide (NO) metabolites, neuronal nitric oxide synthase (nNOS) and cyclic guanosine monophosphate (cGMP) were decreased in spinal cord tissue from vincristine-induced hyperalgesic mice,28 suggesting that changes in NO and cGMP may induce thermal hyperaglesia in vincristine-induced neuropathic pain. Thioctic acid has known anti-inflammatory effects:29,30 it significantly reduces interleukin-1b and TNF-a levels in experimental acute pancreatitis (in rats) and inhibits the increase in inducible NO synthase expression and activity in morphine-dependent rat brain.31,32 These anti-inflammatory actions may be responsible for the antiallodynic effects of thioctic acid in neuropathy. In conclusion, intraperitoneal administration of thioctic acid reduced mechanical
and cold allodynia in a vincristine-induced rat neuropathy model. It is possible that the antioxidant and anti-inflammatory properties of thioctic acid are responsible for its antiallodynic effects. Further studies are required to elucidate the mechanism of action of thioctic acid fully, and clinical studies must be conducted before this agent is used to treat patients with neuropathy.
Declaration of conflicting interest The authors declare that there are no conflicts of interest.
Funding The statistical consultation of our study was supported by Catholic Research Coordinating Centre of the Korea Health 21 R&D Project (A070001), Ministry of Health & Welfare, Republic of Korea.
References 1. Wolf S, Barton D, Kottschade L, et al. Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies. Eur J Cancer 2008; 44: 1507–1515.
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2. Quaschoff S and Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol 2002; 249: 9–17. 3. Anghelescu DL, Fauhnan LG, Jeha S, et al. Neuropathic pain during treatment for childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 2011; 57: 1147–1153. 4. Rasmussen FV, Lundberg V, Jespersen TW, et al. Extreme doses of intravenous methadone for severe pain in two children with cancer. Pediatr Blood Cancer 2015 Jan 13. doi: 10.1002/pbc.25392. [Epub ahead of print]. 5. Kanbayashi Y, Hosokawa T, Okamoto K, et al. Statistical identification of predictions for peripheral neuropathy associated with administration of bortezomib, taxanes, oxaliplatin or vincristine using ordered logistic regression analysis. Anticancer Drugs 2010; 21: 877–881. 6. Park BY, Park SH, Kim WM, et al. Antinociceptive Effect of Memantine and Morphine on Vincristine-induced Peripheral Neuopathy in Rats. Korean J Pain 2010; 23: 179–185. 7. Lynch 3rd JJ, Wade CL, Zhong CM, et al. Attenuation of mechanical allodynia by clinically utilized drugs in a rat chemotherapy-induced neuropathic pain model. Pain 2004; 110: 56–63. 8. Friedrichsdorf SJ and Nugent AP. Management of neuropathic pain in children with cancer. Curr Opin Support Palliat Care 2013; 7: 131–138. 9. Packer L, Witt EH and Tritschler HJ. a-Lipoic acid as a biological antioxidant. Free Radic Biol Med 1995; 19: 227–250. 10. Nagamatsu M, Nickander KK, Schmelzer JD, et al. Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve conduction in experimental diabetic neuropathy. Diabetes Care 1995; 18: 1160–1167. 11. Mcllduff CE and Rutkove SB. Critical appraisal of the use of alpha lipoic acid (thioctic acid) in the treatment of symptomatic diabetic polyneuropathy. Ther Clin Risk Manag 2011; 7: 377–385. 12. Mijnhout GS, Kollen BJ, Alkhalaf A, et al. Alpha lipoic Acid for symptomatic peripheral neuropathy in patients with diabetes: a
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meta-analysis of randomized controlled trials. Int J Endocrinol 2012; 2012: 456279Epub ahead of print 26 Jan 2012. DOI: 10.1155/2201/456279. Battisti E, Albanese A, Guerra L, et al. Alpha lipoic acid and superoxide dismutase in the treatment of chronic low back pain. Eur J Phys Rehabil Med 2013; 49: 659–664. Sandireddy R, Yerra VG, Areti A, et al. Neuroinflammation and oxidative stress in diabetic neuropathy: futuristic strategies based on these targets. Int J Endocrinol 2014; 2014: 674987. Kiguchi N, Maeda T, Kobayashi Y, et al. Involvement of inflammatory mediators in neuropathic pain caused by vincristine. Int Rev Neurobiol 2009; 85: 179–190. Kaur G, Jaggi AS and Singh N. Exploring the potential effect of Ocimum sanctum in vincristine-induced neuropathic pain in rats. J Brachial Plex Peripher Nerve Inj 2010; 5:3. Park HJ, Lee HG, Kim YS, et al. Ginkgo biloba extract attenuates hyperalgesia in a rat model of vincristine-induced peripheral neuropathy. Anesth Analg 2012; 115: 1228–1233. Joseph EK and Levine JD. Comparison of oxaliplatin- and cisplatin-induced painful peripheral neuropathy in the rat. J Pain 2009; 10: 534–541. Joseph EK, Chen X, Bogen O, et al. Oxaliplatin acts on IB4-positive nociceptors to induce an oxidative stress-dependent acute painful peripheral neuropathy. J Pain 2008; 9: 463–472. Kaley TJ and Deangelis LM. Therapy of chemotherapy-induced peripheral neuropathy. Br J Haematol 2009; 145: 3–14. Muthuraman A, Jaggi AS, Singh N, et al. Ameliorative effects of amiloride and pralidoxime in chronic constriction injury and vincristine induced neuropathy in rats. Eur J Pharmacol 2008; 587: 104–111. Yowtak J, Lee KY, Kim HK, et al. Reactive oxygen species contribute to neuropathic pain by reducing spinal GABA release. Pain 2011; 152: 844–852. Thiagarajan VR, Shanmugam P, Krishnan UM, et al. Antinociceptive effect of Butea monosperma on vincristine-induced
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The effect of thioctic acid on allodynia in a rat vincristineinduced neuropathy model
Journal of International Medical Research 2015, Vol. 43(3) 350–355 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0300060515569287 imr.sagepub.com
Jimin Kahng1, Tae kwan Kim2, Eun Yong Chung2, Yee Suk Kim2 and Jeong Yeon Moon2
Abstract Objective: To investigate the antiallodynic effects of thioctic acid in vincristine-induced neuropathy in rats. Methods: Neuropathy was induced in Sprague–Dawley rats via vincristine intraperitoneal injection. After 15 days, rats were investigated for the presence of mechanical and cold allodynia, and those with allodynia received intraperitoneal injection with normal saline or 1, 5, or 10 mg/kg thioctic acid. Mechanical and cold allodynia were assessed before treatment and at 15, 30, 60, 90, 150 and 180 min after treatment. Results: Mechanical and cold allodynia were reduced by thioctic acid injection. The duration of effect increased with thioctic acid dose. Conclusion: Thioctic acid may be an effective treatment for vincristine-induced neuropathy.
Keywords Thioctic acid, neuropathy, pain, vincristine Date received: 23 September 2014; accepted: 31 December 2014
Introduction The anticancer agent vincristine induces painful distal sensorimotor neuropathy in 60% of patients, resulting in discontinuation of treatment and reduced healthrelated quality-of-life.1,2 Since the pathogenesis of vincristine induced neuropathy is not clearly understood, various treatments are prescribed empirically, including tricyclic antidepressants, anticonvulsants, opioids, nonsteroidal anti-inflammatory agents and a-adrenergic agonists.3-5 The efficacy of these drugs in the treatment of neuropathy
is limited, however, and some have poor safety profiles.6-8 1
Department of Laboratory Medicine, Bucheon St Mary’s Hospital, The Catholic University of Korea, Bucheon, Republic of Korea 2 Department of Anaesthesia and Pain Medicine, Bucheon St Mary’s Hospital, The Catholic University of Korea, Bucheon, Republic of Korea Corresponding author: Yee Suk Kim, Department of Anaesthesia and Pain Medicine, Bucheon St Mary’s Hospital, 2 Sosa-dong, Wonmi-gu, Bucheon City, Kyunggido, Republic of Korea. Email: [email protected]
Creative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided original workbyisguest attributed as specified Downloaded fromthe imr.sagepub.com on October 5, 2015 on the SAGE and Open Access page (http://www.uk.sagepub.com/aboutus/openaccess.htm).
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Thioctic acid (a-lipoic acid) is a biological antioxidant9 that has been shown to improve nerve blood flow and distal nerve conduction velocity in a rat model of diabetic neuropathy.10 Thioctic acid is an effective treatment for diabetic sensorimotor polyneuropathy11 and diabetic peripheral neuropathy,12 and also has been shown to improve functional activity in patients with chronic low back pain.13 Vincristine-induced polyneuropathy and diabetic polyneuropathy develop in similar ways, as both involve inflammation and oxidative stress.14–16 The aim of the present study was to investigate the antiallodynic effects of thioctic acid in a vincristine-induced rat neuropathy model.
Materials and methods Animals Sprague–Dawley rats (n ¼ 40; body weight 200–250 g) were housed and fed according to guidelines on the care and use of laboratory animals, as adopted by the Institutional Animal Care and Use Committee, Department of Laboratory Animals, Bucheon St Mary’s Hospital, Catholic University of Korea, Bucheon City, Republic of Korea, who approved the study. Rats were housed (2–3 animals per plastic cage) and maintained on a 12-h light/dark cycle, with free access to food and water.
Neuropathy model Vincristine was used to induce neuropathy as described.10 Briefly, 0.1 ml/kg per day vincristine sulphate (Hopira, Lake Forest, IL, USA) was injected intraperitoneally for 5 days, paused for 2 days, then resumed for an additional 5 days. Allodynia was assessed on day 15 from the beginning of the injections via Semmes–Weinstein aesthesiometer (Stoelting, Wood Dale, IL, USA). Rats that showed a foot withdrawal response when a 4 -g filament was applied to the hindpaw were considered allodynic.
Treatment Allodynic rats were allocated between four groups: normal saline (n ¼ 6; 1 ml/kg normal saline intraperitoneal injection); TA1 (n ¼ 8; 1 mg/kg thioctic acid intraperitoneal injection [ThiotacidÕ injection; Dai han, Kyeongido, Korea]); TA 5 (n ¼ 8; 5 mg/kg thioctic acid intraperitoneal injection); and TA 10 (n ¼ 8; 10 mg/kg thioctic acid intraperitoneal injection). The volume of all injections was 1 ml/kg. Thioctic acid dose was determined by preliminary experiments. Mechanical and cold allodynia were assessed before treatment and at 15, 30, 60, 90, 120, 150 and 180 min after treatment.
Mechanical allodynia Mechanical allodynia was assessed using a series of von Frey filaments (1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 15.0 and 26.0 g), as described.17 The left hind paw of each animal was stimulated and the withdrawal threshold was defined as the minimal pressure level (in g) that elicited a withdrawal response (lifting, shaking or licking). If there was no response to any filament, the withdrawal threshold was recorded as 26.0 g.
Cold allodynia Cold allodynia was assessed using acetone, as described.17 Acetone was applied to the plantar surfaces of the left hind paw and withdrawal responses were noted. Testing was repeated 5 times with 3–5 min between each test. The intensity of cold allodynia was expressed as withdrawal frequency: (n paw withdrawal responses/n trials) 100.
Statistical analyses Data were presented as mean SD. Between-group and between-timepoint differences were evaluated using repeated-measures analysis of variance followed by post hoc Dunn’s test. Statistical analyses were
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Table 1. Effect of intraperitoneal injection with normal saline or thioctic acid on mechanical allodynia withdrawal threshold in vincristine-induced neuropathy in a rat model. Thioctic acid Timepoint
Normal saline n ¼ 6
1 mg/kg n ¼ 8
5 mg/kg n ¼ 8
10 mg/kg n ¼ 8
Before injection After injection, min 15 30 60 90 120 150 180
1.2 0.1
1.2 0.3
1.1 0.2
1.0 0.0
3.1 1.3 1.5 0.4 1.6 0.7 1.4 0.7 1.4 0.5 1.2 0.2 1.0 0.0
10.6 9.2* 2.0 1.4 1.2 0.3 1.1 0.2 1.0 0.2 1.0 0.0 1.1 0.1
20.3 7.4* 14.1 8.9* 10.6 9* 1.7 1.8 1.1 0.1 1.1 0.2 1.0 0.0
24.3 3.8* 15.9 8.9* 12.3 8.9* 11.2 9.5* 7.1 9.1 7.3 11.6 7.3 11.6
Data presented as mean SD. *P < 0.05 vs normal saline; repeated measures analysis of variance.
performed using SAS version 9.3 (SAS Institute, Cary, NC, USA), and Pvalues < 0.05 were considered statistically significant.
Results The effects of thioctic acid on mechanical allodynia are shown in Table 1. There was no significant change in withdrawal threshold in the normal saline group at any timepoint after injection. Withdrawal frequency was significantly higher at 15 min after1 mg/kg thioctic acid injection compared with normal saline. Compared with normal saline, 5 mg/ kg thioctic acid significantly increased withdrawal threshold for 60 min, and 10 mg/kg thioctic acid significantly increased withdrawal threshold for 90 min (P < 0.05 for each comparison; Table 1). The effects of thioctic acid on cold allodynia are shown in Table 2. There was no significant change in withdrawal threshold in the normal saline or 1 mg/kg thioctic acid groups at any timepoint after injection. Compared with normal saline, 5 mg/kg thioctic acid significantly decreased withdrawal frequency for 30 min, and 10 mg/kg thioctic acid significantly decreased
withdrawal frequency for 90 min (P < 0.05 for each comparison; Table 2).
Discussion The present study showed that thioctic acid has antiallodynic properties in a vincristineinduced neuropathy model, in accordance with findings in oxaliplatin-induced neuropathy.18,19 Thioctic acid has no effect on cisplatin-induced mechanical hyperalgesia,20 suggesting that treatment should be tailored for each chemotherapeutic drug. We used relatively small doses of thioctic acid (1, 5 and 10 mg/kg) compared with other researchers (50 and 100 mg/kg),18 due to differences in pain intensity incurred by oxaliplatin and vincristine. The antiallodynic action of thioctic acid has not been fully elucidated. Oxidative stress has an important role in several neuropathic pain models, including vincristine induced neuropathy, and spinal or sciatic nerve ligation.21,22 Concentrations of thiobarbituric acid reactive substances (TBARS) and superoxide anions were increased by vincristine treatment.23,24 It has been reported that lipoic acid treatment reversed indices of oxidative stress,
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Table 2. Effect of intraperitoneal injection with normal saline or thioctic acid on cold allodynia withdrawal frequency in vincristine induced neuropathy in a rat model. Thioctic acid Timepoint
Normal saline n ¼ 6
1 mg/kg n ¼ 8
5 mg/kg n ¼ 8
10 mg/kg n ¼ 8
Before injection After injection, min 15 30 60 90 120 150 180
90.0 11.0
87.5 10.4
92.5 10.4
95.0 9.3
80.0 12.6 80.0 17.9 80.0 21.9 83.3 15.1 83.3 15.1 86.7 10.3 90.0 11.0
62.5 12.8 70.0 26.2 80.0 26.2 82.5 16.7 85.0 20.7 87.5 14.9 90.0 10.7
35.0 20.7* 46.3 31.6* 52.5 30.1 70.0 21.4 82.5 12.8 85.0 14.1 92.5 10.4
17.5 27.1* 30.0 15.1* 40.0 23.9* 50.0 21.4* 62.5 31.1 65.0 23.3 87.5 21.2
Data presented as mean SD. *P < 0.05 vs normal saline; repeated measures analysis of variance.
including TBARS.25 It is possible that the antioxidant properties of thioctic acid are responsible for its antiallodynic effects. Inflammatory processes play an important role in the development of vincristineinduced neuropathy.26 In rats, vincristine treatment resulted in significantly increased tumour necrosis factor (TNF)-a concentrations in sciatic nerve tissue.27 Concentrations of nitric oxide (NO) metabolites, neuronal nitric oxide synthase (nNOS) and cyclic guanosine monophosphate (cGMP) were decreased in spinal cord tissue from vincristine-induced hyperalgesic mice,28 suggesting that changes in NO and cGMP may induce thermal hyperaglesia in vincristine-induced neuropathic pain. Thioctic acid has known anti-inflammatory effects:29,30 it significantly reduces interleukin-1b and TNF-a levels in experimental acute pancreatitis (in rats) and inhibits the increase in inducible NO synthase expression and activity in morphine-dependent rat brain.31,32 These anti-inflammatory actions may be responsible for the antiallodynic effects of thioctic acid in neuropathy. In conclusion, intraperitoneal administration of thioctic acid reduced mechanical
and cold allodynia in a vincristine-induced rat neuropathy model. It is possible that the antioxidant and anti-inflammatory properties of thioctic acid are responsible for its antiallodynic effects. Further studies are required to elucidate the mechanism of action of thioctic acid fully, and clinical studies must be conducted before this agent is used to treat patients with neuropathy.
Declaration of conflicting interest The authors declare that there are no conflicts of interest.
Funding The statistical consultation of our study was supported by Catholic Research Coordinating Centre of the Korea Health 21 R&D Project (A070001), Ministry of Health & Welfare, Republic of Korea.
References 1. Wolf S, Barton D, Kottschade L, et al. Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies. Eur J Cancer 2008; 44: 1507–1515.
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