Korean J Pain.  2020 Jul;33(3):216-225. 10.3344/kjp.2020.33.3.216.

Exploring the role and mechanisms of diallyl trisulfide and diallyl disulfide in chronic constriction-induced neuropathic pain in rats

• Wang G
• Yang Y
• Wang C
• Huang J
• Wang X
• Liu Y
• Wang H

• KMID: 2504067
• DOI: http://doi.org/10.3344/kjp.2020.33.3.216

Abstract

Background
Garlic oil is a rich source of organosulfur compounds including diallyl disulfide and diallyl trisulfide. There have been studies showing the neuroprotective actions of these organosulfur compounds. However, the potential of these organosulfur compounds in neuropathic pain has not been explored. The present study was aimed at investigating the pain attenuating potential of diallyl disulfide and diallyl trisulfide in chronic constriction injury (CCI)-induced neuropathic pain in rats. The study also explored their pain-attenuating mechanisms through modulation of H2S, brain-derived neurotrophin factor (BDNF) and nuclear factor erythroid 2-related factor 2 (Nrf2).
Methods
The rats were subjected to CCI injury by ligating the sciatic nerve in four places. The development of neuropathic pain was measured by assessing mechanical hyperalgesia (Randall–Selittotest), mechanical allodynia (Von Frey test), and cold allodynia (acetone drop test) on 14th day after surgery.
Results
Administration of diallyl disulfide (25 and 50 mg/kg) and diallyl trisulfide (20 and 40 mg/kg) for 14 days led to a significant reduction in pain in CCI-subjected rats. Moreover, treatment with these organosulfur compounds led to the restoration of H₂S, BDNF and Nrf2 levels in the sciatic nerve and dorsal root ganglia. Coadministration of ANA-12 (BDNF blocker) abolished pain attenuating actions as well as BDNF and the Nrf2 restorative actions of diallyl disulfide and diallyl trisulfide, without modulating H₂S levels.
Conclusions
Diallyl disulfide and diallyl trisulfide have the potential to attenuate neuropathic pain in CCI-subjected rats possibly through activation of H₂S-BDNF-Nrf2 signaling pathway.

Keyword

Allyl Compounds; Brain-Derived Neurotrophic Factor, Hyperalgesia; Neuralgia; Sciatic Nerve

Figure

• 

  Fig. 1 Effect of different interventions on paw withdrawal threshold (mechanical hyperalgesia) in Randall–Selitto test. The data were represented as percentage decrease in paw withdrawal threshold on 14th day of surgery in comparison to day 1 i.e., before surgery. CCI: chronic constriction injury, DADS: diallyl disulfide, DATS: diallyl trisulfide. aP < 0.05 vs. sham; bP < 0.05 vs. CCI; cP < 0.05 vs. DADS (50 mg/kg) in CCI; dP < 0.05 vs. DATS (40 mg/kg) in CCI.

• 

  Fig. 2 Effect of different interventions on paw withdrawal threshold (mechanical allodynia) in Von Frey test. The data were represented as percentage decrease in paw withdrawal threshold on 14th day of surgery in comparison to day 1 i.e., before surgery. CCI: chronic constriction injury, DADS: diallyl disulfide, DATS: diallyl trisulfide. aP < 0.05 vs. sham; bP < 0.05 vs. CCI; cP < 0.05 vs. DADS (50 mg/kg) in CCI; dP < 0.05 vs. DATS (40 mg/kg) in CCI.

• 

  Fig. 3 Effect of different interventions on paw withdrawal duration (cold allodynia) in cold acetone drop test. The data were represented as percentage increase in paw withdrawal threshold on 14th day of surgery in comparison to day 1 i.e., before surgery. CCI: chronic constriction injury, DADS: diallyl disulfide, DATS: diallyl trisulfide. aP < 0.05 vs. sham; bP < 0.05 vs. CCI; cP < 0.05 vs. DADS (50 mg/kg) in CCI; dP < 0.05 vs. DATS (40 mg/kg) in CCI.

• 

  Fig. 4 Effect of different interventions on the BDNF levels in the DRG and sciatic nerve. BDNF: brain-derived neurotrophin factor, DRG: dorsal root ganglia, CCI: chronic constriction injury, DADS: diallyl disulfide, DATS: diallyl trisulfide. aP < 0.05 vs. sham; bP < 0.05 vs. CCI; cP < 0.05 vs. DADS (50 mg/kg) in CCI; dP < 0.05 vs. DATS (40 mg/kg) in CCI.

• 

  Fig. 5 Effect of different interventions on the H2S levels in the DRG and sciatic nerve. DRG: dorsal root ganglia, CCI: chronic constriction injury, DADS: diallyl disulfide, DATS: diallyl trisulfide. aP < 0.05 vs. sham; bP < 0.05 vs. CCI.

• 

  Fig. 6 Effect of different interventions on the Nrf2 levels in the DRG and sciatic nerve. Nrf2: nuclear factor erythroid 2-related factor 2, DRG: dorsal root ganglia, CCI: chronic constriction injury, DADS: diallyl disulfide, DATS: diallyl trisulfide. aP < 0.05 vs. sham; bP < 0.05 vs. CCI; cP < 0.05 vs. DADS (50 mg/kg) in CCI; dP < 0.05 vs. DATS (40 mg/kg) in CCI.

Reference

1. Gierthmühlen J, Baron R. 2016; Neuropathic pain. Semin Neurol. 36:462–8. DOI: 10.1055/s-0036-1584950. PMID: 27704502.

2. Gilron I, Baron R, Jensen T. 2015; Neuropathic pain: principles of diagnosis and treatment. Mayo Clin Proc. 90:532–45. DOI: 10.1016/j.mayocp.2015.01.018. PMID: 25841257.

3. Xu L, Zhang Y, Huang Y. 2016; Advances in the treatment of neuropathic pain. Adv Exp Med Biol. 904:117–29. DOI: 10.1007/978-94-017-7537-3_9. PMID: 26900067.

4. Gupta R, Rowshan K, Chao T, Mozaffar T, Steward O. 2004; Chronic nerve compression induces local demyelination and remyelination in a rat model of carpal tunnel syndrome. Exp Neurol. 187:500–8. DOI: 10.1016/j.expneurol.2004.02.009. PMID: 15144876.

5. Shang A, Cao SY, Xu XY, Gan RY, Tang GY, Corke H, et al. 2019; Bioactive compounds and biological functions of garlic (Allium sativum L.). Foods. 8:246. DOI: 10.3390/foods8070246. PMID: 31284512. PMCID: PMC6678835.

6. Hayashida R, Kondo K, Morita S, Unno K, Shintani S, Shimizu Y, et al. 2017; Diallyl trisulfide augments ischemia-induced angiogenesis via an endothelial nitric oxide synthase-dependent mechanism. Circ J. 81:870–8. DOI: 10.1253/circj.CJ-16-1097. PMID: 28216514.

7. Miltonprabu S, Sumedha NC, Senthilraja P. 2017; Diallyl trisulfide, a garlic polysulfide protects against As-induced renal oxidative nephrotoxicity, apoptosis and inflammation in rats by activating the Nrf2/ARE signaling pathway. Int Immunopharmacol. 50:107–20. DOI: 10.1016/j.intimp.2017.06.011. PMID: 28648972.

8. Shin JY, Han JH, Ko JW, Park SH, Shin NR, Jung TY, et al. 2016; Diallyl disulfide attenuates acetaminophen-induced renal injury in rats. Lab Anim Res. 32:200–7. DOI: 10.5625/lar.2016.32.4.200. PMID: 28053613. PMCID: PMC5206226.

9. Shaaban AA, El-Agamy DS. 2017; Cytoprotective effects of diallyl trisulfide against valproate-induced hepatotoxicity: new anticonvulsant strategy. Naunyn Schmiedebergs Arch Pharmacol. 390:919–28. DOI: 10.1007/s00210-017-1393-0. PMID: 28646254.

10. Jeremic JN, Jakovljevic VL, Zivkovic VI, Srejovic IM, Bradic JV, Bolevich S, et al. 2019; The cardioprotective effects of diallyl trisulfide on diabetic rats with ex vivo induced ischemia/reperfusion injury. Mol Cell Biochem. 460:151–64. DOI: 10.1007/s11010-019-03577-w. PMID: 31280436.

11. Kiesel VA, Stan SD. 2017; Diallyl trisulfide, a chemopreventive agent from Allium vegetables, inhibits alpha-secretases in breast cancer cells. Biochem Biophys Res Commun. 484:833–8. DOI: 10.1016/j.bbrc.2017.01.184. PMID: 28161636.

12. Liu C, Leng B, Li Y, Jiang H, Duan W, Guo Y, et al. 2018; Diallyl trisulfide protects motor neurons from the neurotoxic protein TDP-43 via activating lysosomal degradation and the antioxidant response. Neurochem Res. 43:2304–12. DOI: 10.1007/s11064-018-2651-3. PMID: 30317421.

13. Guo Y, Zhang K, Wang Q, Li Z, Yin Y, Xu Q, et al. 2011; Neuroprotective effects of diallyl trisulfide in SOD1-G93A transgenic mouse model of amyotrophic lateral sclerosis. Brain Res. 1374:110–5. DOI: 10.1016/j.brainres.2010.12.014. PMID: 21147075.

14. Bennett GJ, Xie YK. 1988; A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain. 33:87–107. DOI: 10.1016/0304-3959(88)90209-6. PMID: 2837713.

15. Verma R, Sharma J, Singh N, Jaggi AS. 2019; Investigating the possible pain attenuating mechanisms of pregabalin in chronic constriction injury-induced neuropathic pain in rats. Int J Neurosci. 129:1155–65. DOI: 10.1080/00207454.2019.1638783. PMID: 31256739.

16. Khangura RK, Bali A, Kaur G, Singh N, Jaggi AS. 2017; Neuropathic pain attenuating effects of perampanel in an experimental model of chronic constriction injury in rats. Biomed Pharmacother. 94:557–63. DOI: 10.1016/j.biopha.2017.07.137. PMID: 28780471.

17. Kukkar A, Singh N, Jaggi AS. 2013; Neuropathic pain-attenuating potential of aliskiren in chronic constriction injury model in rats. J Renin Angiotensin Aldosterone Syst. 14:116–23. DOI: 10.1177/1470320312460899. PMID: 23087256.

18. Randall LO, Selitto JJ. 1957; A method for measurement of analgesic activity on inflamed tissue. Arch Int Pharmacodyn Ther. 111:409–19. PMID: 13471093.

19. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. 1994; Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 53:55–63. DOI: 10.1016/0165-0270(94)90144-9.

20. Choi Y, Yoon YW, Na HS, Kim SH, Chung JM. 1994; Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain. Pain. 59:369–76. DOI: 10.1016/0304-3959(94)90023-X.

21. Xiong JW, Wei B, Li YK, Zhan JQ, Jiang SZ, Chen HB, et al. 2018; Decreased plasma levels of gasotransmitter hydrogen sulfide in patients with schizophrenia: correlation with psychopathology and cognition. Psychopharmacology (Berl). 235:2267–74. DOI: 10.1007/s00213-018-4923-7. PMID: 29777287.

22. Shen X, Chakraborty S, Dugas TR, Kevil CG. 2014; Hydrogen sulfide measurement using sulfide dibimane: critical evaluation with electrospray ion trap mass spectrometry. Nitric Oxide. 41:97–104. DOI: 10.1016/j.niox.2014.06.002. PMID: 24932544. PMCID: PMC4413942.

23. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. 1951; Protein measurement with the Folin phenol reagent. J Biol Chem. 193:265–75.

24. Wang S, Li M, Wang X, Li X, Yin H, Jiang L, et al. 2017; Diallyl trisulfide attenuated n-hexane induced neurotoxicity in rats by modulating P450 enzymes. Chem Biol Interact. 265:1–7. DOI: 10.1016/j.cbi.2017.01.013. PMID: 28115069.

25. Yu L, Li S, Tang X, Li Z, Zhang J, Xue X, et al. 2017; Diallyl trisulfide ameliorates myocardial ischemia-reperfusion injury by reducing oxidative stress and endoplasmic reticulum stress-mediated apoptosis in type 1 diabetic rats: role of SIRT1 activation. Apoptosis. 22:942–54. DOI: 10.1007/s10495-017-1378-y. PMID: 28455824.

26. Pedraza-Chaverrí J, González-Orozco AE, Maldonado PD, Barrera D, Medina-Campos ON, Hernández-Pando R. 2003; Diallyl disulfide ameliorates gentamicin-induced oxidative stress and nephropathy in rats. Eur J Pharmacol. 473:71–8. DOI: 10.1016/S0014-2999(03)01948-4. PMID: 12877940.

27. Ren Q, Zhang JC, Fujita Y, Ma M, Wu J, Hashimoto K. 2013; Effects of TrkB agonist 7,8-dihydroxyflavone on sensory gating deficits in mice after administration of methamphetamine. Pharmacol Biochem Behav. 106:124–7. DOI: 10.1016/j.pbb.2013.03.016. PMID: 23567202.

28. Çivi S, Emmez G, Dere ÜA, Börcek AÖ, Emmez H. 2016; Effects of quercetin on chronic constriction nerve injury in an experimental rat model. Acta Neurochir (Wien). 158:959–65. DOI: 10.1007/s00701-016-2761-0. PMID: 26960544.

29. Flannigan KL, Agbor TA, Motta JP, Ferraz JG, Wang R, Buret AG, et al. 2015; Proresolution effects of hydrogen sulfide during colitis are mediated through hypoxia-inducible factor-1α. FASEB J. 29:1591–602. DOI: 10.1096/fj.14-266015. PMID: 25550470.

30. Zhang F, Jin H, Wu L, Shao J, Zhu X, Chen A, et al. 2017; Diallyl trisulfide suppresses oxidative stress-induced activation of hepatic stellate cells through production of hydrogen sulfide. Oxid Med Cell Longev. 2017:1406726. DOI: 10.1155/2017/1406726. PMID: 28303169. PMCID: PMC5337887.

31. Di Cesare Mannelli L, Lucarini E, Micheli L, Mosca I, Ambrosino P, Soldovieri MV, et al. 2017; Effects of natural and synthetic isothiocyanate-based H2S-releasers against chemotherapy-induced neuropathic pain: role of Kv7 potassium channels. Neuropharmacology. 121:49–59. DOI: 10.1016/j.neuropharm.2017.04.029. PMID: 28431970.

32. Kim JM, Chang HJ, Kim WK, Chang N, Chun HS. 2006; Structure-activity relationship of neuroprotective and reactive oxygen species scavenging activities for allium organosulfur compounds. J Agric Food Chem. 54:6547–53. DOI: 10.1021/jf060412c. PMID: 16939308.

33. Koh SH, Kwon H, Park KH, Ko JK, Kim JH, Hwang MS, et al. 2005; Protective effect of diallyl disulfide on oxidative stress-injured neuronally differentiated PC12 cells. Brain Res Mol Brain Res. 133:176–86. DOI: 10.1016/j.molbrainres.2004.10.006. PMID: 15710234.

34. Allen SJ, Watson JJ, Shoemark DK, Barua NU, Patel NK. 2013; GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol Ther. 138:155–75. DOI: 10.1016/j.pharmthera.2013.01.004. PMID: 23348013.

35. Pall ML, Levine S. 2015; Nrf2, a master regulator of detoxification and also antioxidant, anti-inflammatory and other cytoprotective mechanisms, is raised by health promoting factors. Sheng Li Xue Bao. 67:1–18. PMID: 25672622.

36. Chen H, Xie K, Chen Y, Wang Y, Wang Y, Lian N, et al. 2019; Nrf2/HO-1 signaling pathway participated in the protection of hydrogen sulfide on neuropathic pain in rats. Int Immunopharmacol. 75:105746. DOI: 10.1016/j.intimp.2019.105746. PMID: 31325725.

37. Sikandar S, Minett MS, Millet Q, Santana-Varela S, Lau J, Wood JN, et al. 2018; Brain-derived neurotrophic factor derived from sensory neurons plays a critical role in chronic pain. Brain. 141:1028–39. DOI: 10.1093/brain/awy009. PMID: 29394316. PMCID: PMC5888992.

38. Ishii T, Warabi E, Mann GE. 2019; Circadian control of BDNF-mediated Nrf2 activation in astrocytes protects dopaminergic neurons from ferroptosis. Free Radic Biol Med. 133:169–78. DOI: 10.1016/j.freeradbiomed.2018.09.002. PMID: 30189266.

39. Chen T, Wu Y, Wang Y, Zhu J, Chu H, Kong L, et al. 2017; Brain-derived neurotrophic factor increases synaptic protein levels via the MAPK/Erk signaling pathway and Nrf2/Trx axis following the transplantation of neural stem cells in a rat model of traumatic brain injury. Neurochem Res. 42:3073–83. DOI: 10.1007/s11064-017-2340-7. PMID: 28780733.

40. Kapczinski F, Frey BN, Andreazza AC, Kauer-Sant’Anna M, Cunha AB, Post RM. 2008; Increased oxidative stress as a mechanism for decreased BDNF levels in acute manic episodes. Braz J Psychiatry. 30:243–5. DOI: 10.1590/S1516-44462008000300011. PMID: 18833425.

41. Cheng PL, Song AH, Wong YH, Wang S, Zhang X, Poo MM. 2011; Self-amplifying autocrine actions of BDNF in axon development. Proc Natl Acad Sci U S A. 108:18430–5. DOI: 10.1073/pnas.1115907108. PMID: 22025720. PMCID: PMC3215064.

42. Wang L, Chang X, She L, Xu D, Huang W, Poo MM. 2015; Autocrine action of BDNF on dendrite development of adult-born hippocampal neurons. J Neurosci. 35:8384–93. DOI: 10.1523/JNEUROSCI.4682-14.2015. PMID: 26041908. PMCID: PMC6605324.

43. Hu M, Zou W, Wang CY, Chen X, Tan HY, Zeng HY, et al. 2016; Hydrogen sulfide protects against chronic unpredictable mild stress-induced oxidative stress in hippocampus by upregulation of BDNF-TrkB pathway. Oxid Med Cell Longev. 2016:2153745. DOI: 10.1155/2016/2153745. PMID: 27525050. PMCID: PMC4976147.

44. Bae J, Kumazoe M, Fujimura Y, Tachibana H. 2019; Diallyl disulfide potentiates anti-obesity effect of green tea in high-fat/high-sucrose diet-induced obesity. J Nutr Biochem. 64:152–61. DOI: 10.1016/j.jnutbio.2018.10.014. PMID: 30504007.