TRPV1 receptor-mediated expression of Toll-like receptors 2 and 4 following permanent middle cerebral artery occlusion in rats

Document Type: Original Article

Authors

1 Physiology-Pharmacology Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

2 Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

3 Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

4 Department of Laboratory Sciences, School of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

5 Molecular Medicine Research Center, Department of Biochemistry, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

6 Department of Anatomy, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

7 Department of Neurology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

Abstract

Objective(s): Stroke is known as a main cause of mortality and prolonged disability in adults. Both transient receptor potential V1 (TRPV1) channels and toll-like receptors (TLRs) are involved in mediating the inflammatory responses. In the present study, the effects of TRPV1 receptor activation and blockade on stroke outcome and gene expression of TLR2 and TLR4 were assessed following permanent middle cerebral artery occlusion in rats
Materials and Methods: Eighty male Wistar rats were divided into four groups as follows: sham, vehicle, AMG9810 (TRPV1 antagonist) -treated and capsaicin (TRPV1 agonist) -treated. For Stroke induction, the middle cerebral artery was permanently occluded and then behavioral functions were evaluated 1, 3 and 7 days after stroke.
Results: TRPV1 antagonism significantly reduced the infarct volume compared to the stroke group. Also, neurological deficits were decreased by AMG9810 seven days after cerebral ischemia. In the ledged beam-walking test, the slip ratio was enhanced following ischemia. AMG9810 decreased this index in stroke animals. However, capsaicin improved the ratio 3 and 7 days after cerebral ischemia. Compared to the sham group, the mRNA expression of TLR2 and TLR4 was significantly increased in the stroke rats. AMG9810 Administration significantly reduced the mRNA expression of TLR2 and TLR4. However, capsaicin did not significantly affect the gene expression of TLR2 and TLR4.
Conclusion: Our results demonstrated that TRPV1 antagonism by AMG9810 attenuates behavioral function and mRNA expression of TLR2 and TLR4. Thus, it might be useful to shed light on future therapeutic strategies for the treatment of ischemic stroke.

Keywords


1. Wang XH, You YP. Epigallocatechin gallate extends therapeutic window of recombinant tissue plasminogen activator treatment for brain ischemic stroke: a randomized double-blind and placebo-controlled trial. Clin Neuropharmacol 2017; 40:24-28.

2. Aidar FJ, de Oliveira RJ, de Matos DG, Mazini Filho ML, Moreira OC, de Oliveira CE, et al. A Randomized trial investigating the influence of strength training on quality of life in ischemic stroke. Top Stroke Rehabil 2016; 23:84-89.

3. Doyle KP, Simon RP, Stenzel-Poore MP. Mechanisms of ischemic brain damage. Neuropharmacology 2008; 55:310-318.

4. Crack PJ, Taylor JM. Reactive oxygen species and the modulation of stroke. Free Radic Biol Med 2005; 38:1433-1444.

5. Wang Z, Wei X, Liu K, Zhang X, Yang F, Zhang H, et al. NOX2 deficiency ameliorates cerebral injury through reduction of complexin II-mediated glutamate excitotoxicity in experimental stroke. Free Radic Biol Med 2013; 65:942-951.

6. Ramos-Cabrer P, Campos F, Sobrino T, Castillo J. Targeting the ischemic penumbra. Stroke 2011; 42:S7-11.

7. Darabi S, Mohammadi MT. Fullerenol nanoparticles decrease ischaemia-induced brain injury and oedema through inhibition of oxidative damage and aquaporin-1 expression in ischaemic stroke. Brain Inj 2017:1-9.

8. Zhu M, Xing D, Lu Z, Fan Y, Hou W, Dong H, et al. DDR1 may play a key role in destruction of the blood-brain barrier after cerebral ischemia-reperfusion. Neurosci Res 2015; 96:14-19.

9. Leker RR, Shohami E. Cerebral ischemia and trauma-different etiologies yet similar mechanisms: neuroprotective opportunities. Brain Res Brain Res Rev 2002; 39:55-73.

10. del Zoppo G, Ginis I, Hallenbeck JM, Iadecola C, Wang X, Feuerstein GZ. Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. Brain Pathol 2000; 10:95-112.

11. Tureyen K, Kapadia R, Bowen KK, Satriotomo I, Liang J, Feinstein DL, et al. Peroxisome proliferator-activated receptor-gamma agonists induce neuroprotection following transient focal ischemia in normotensive, normoglycemic as well as hypertensive and type-2 diabetic rodents. J Neurochem 2007; 101:41-56.

12. Shichita T, Ago T, Kamouchi M, Kitazono T, Yoshimura A, Ooboshi H. Novel therapeutic strategies targeting innate immune responses and early inflammation after stroke. J Neurochem 2012; 123:29-38.

13. Zielinska M, Jarmuz A, Wasilewski A, Salaga M, Fichna J. Role of transient receptor potential channels in intestinal inflammation and visceral pain: novel targets in inflammatory bowel diseases. Inflamm Bowel Dis 2015; 21:419-427.

14. Moran MM, McAlexander MA, Biro T, Szallasi A. Transient receptor potential channels as therapeutic targets. Nat Rev Drug Discov 2011; 10:601-620.

15. Rubino T, Realini N, Castiglioni C, Guidali C, Vigano D, Marras E, et al. Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex. Cereb Cortex 2008; 18:1292-1301.

16. Kauer JA, Gibson HE. Hot flash: TRPV channels in the brain. Trends Neurosci 2009; 32:215-224.

17. Okun E, Griffioen KJ, Mattson MP. Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci 2011; 34:269-281.

18. Kawai T, Akira S. TLR signaling. Semin Immunol 2007; 19:24-32.

19. Zare-Bidaki M, Tsukiyama-Kohara K, Arababadi MK. Toll-like receptor 4 and hepatitis B infection: molecular mechanisms and pathogenesis. Viral Immunol 2014; 27:321-326.

20. Downes CE, Crack PJ. Neural injury following stroke: are Toll-like receptors the link between the immune system and the CNS? Br J Pharmacol 2010; 160:1872-1888.

21. Lehnardt S. Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia 2010; 58:253-263.

22. Abbadie C. Chemokines, chemokine receptors and pain. Trends Immunol 2005; 26:529-534.

23. Lehnardt S, Lehmann S, Kaul D, Tschimmel K, Hoffmann O, Cho S, et al. Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia. J Neuroimmunol 2007; 190:28-33.

24. Caso JR, Pradillo JM, Hurtado O, Lorenzo P, Moro MA, Lizasoain I. Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation 2007; 115:1599-1608.

25. Tang SC, Arumugam TV, Xu X, Cheng A, Mughal MR, Jo DG, et al. Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proc Natl Acad Sci U S A 2007;  104:13798-13803.

26. Lu YC, Yeh WC, Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine 2008; 42:145-151.

27. Diogenes A, Ferraz CC, Akopian AN, Henry MA, Hargreaves KM. LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons. J Dent Res 2011; 90:759-764.

28. Ferraz CC, Henry MA, Hargreaves KM, Diogenes A. Lipopolysaccharide from Porphyromonas gingivalis sensitizes capsaicin-sensitive nociceptors. J Endod 2011; 37:45-48.

29. Qi J, Buzas K, Fan H, Cohen JI, Wang K, Mont E, et al. Painful pathways induced by TLR stimulation of dorsal root ganglion neurons. J Immunol 2011; 186:6417-6426.

30. Gonder JC, Laber K. A renewed look at laboratory rodent housing and management. ILAR J 2007; 48:29-36.

31. Khatibi NH, Jadhav V, Charles S, Chiu J, Buchholz J, Tang J, et al. Capsaicin pre-treatment provides neurovascular protection against neonatal hypoxic-ischemic brain injury in rats. Acta Neurochir Suppl 2011; 111:225-230.

32. Fu J, Bottegoni G, Sasso O, Bertorelli R, Rocchia W, Masetti M, et al. A catalytically silent FAAH-1 variant drives anandamide transport in neurons. Nat Neurosci 2012; 15:64-69.

33. Allahtavakoli M, Amin F, Esmaeeli-Nadimi A, Shamsizadeh A, Kazemi-Arababadi M, Kennedy D. Ascorbic acid reduces the adverse effects of delayed administration of tissue plasminogen activator in a rat stroke model. Basic Clin Pharmacol Toxicol 2015; 117:335-339.

34. Xing B, Chen H, Zhang M, Zhao D, Jiang R, Liu X, et al. Ischemic postconditioning inhibits apoptosis after focal cerebral ischemia/reperfusion injury in the rat. Stroke 2008; 39:2362-2369.

35. Esmaeeli-Nadimi A, Kennedy D, Allahtavakoli M. Opening the window: Ischemic postconditioning reduces the hyperemic response of delayed tissue plasminogen activator and extends its therapeutic time window in an embolic stroke model. Eur J Pharmacol 2015; 764:55-62.

36. Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke 1986; 17:472-476.

37. Allahtavakoli M, Jarrott B. Sigma-1 receptor ligand PRE-084 reduced infarct volume, neurological deficits, pro-inflammatory cytokines and enhanced anti-inflammatory cytokines after embolic stroke in rats. Brain Res Bull 2011; 85:219-224.

38. Wang H, Zhou M, Brand J, Huang L. Inflammation and taste disorders: mechanisms in taste buds. Ann N Y Acad Sci 2009; 1170:596-603.

39. Hua F, Ha T, Ma J, Li Y, Kelley J, Gao X, et al. Protection against myocardial ischemia/reperfusion injury in TLR4-deficient mice is mediated through a phosphoinositide 3-kinase-dependent mechanism. J Immunol 2007; 178:7317-7324.

40. Hamanaka J, Hara H. Involvement of Toll-like receptors in ischemia-induced neuronal damage. Cent Nerv Syst Agents Med Chem 2011; 11:107-113.

41. Hua F, Tang H, Wang J, Prunty MC, Hua X, Sayeed I, et al. TAK-242, an antagonist for Toll-like receptor 4, protects against acute cerebral ischemia/reperfusion injury in mice. J Cereb Blood Flow Metab 2015; 35:536-542.

42. Brady JD, Mohr C, Rossi DJ. Vesicular GABA release delays the onset of the Purkinje cell terminal depolarization without affecting tissue swelling in cerebellar slices during simulated ischemia. Neuroscience 2010; 168:108-117.

43. Chiba Y, Sasayama T, Miyake S, Koyama J, Kondoh T, Hosoda K, et al. Anti-VEGF receptor antagonist (VGA1155) reduces infarction in rat permanent focal brain ischemia. Kobe J Med Sci 2008; 54:E136-146.

44. Gu Y, Xi G, Liu W, Keep RF, Hua Y. Estrogen reduces iron-mediated brain edema and neuronal death. Acta Neurochir Suppl 2010; 106:159-162.

45. Hua F, Ma J, Ha T, Kelley JL, Kao RL, Schweitzer JB, et al. Differential roles of TLR2 and TLR4 in acute focal cerebral ischemia/reperfusion injury in mice. Brain Res 2009; 1262:100-108.

46. Stevens SL, Ciesielski TM, Marsh BJ, Yang T, Homen DS, Boule JL, et al. Toll-like receptor 9: a new target of ischemic preconditioning in the brain. J Cereb Blood Flow Metab 2008; 28:1040-1047.

47. Ji RR, Samad TA, Jin SX, Schmoll R, Woolf CJ. p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 2002; 36:57-68.

48. Miyanohara J, Shirakawa H, Sanpei K, Nakagawa T, Kaneko S. A pathophysiological role of TRPV1 in ischemic injury after transient focal cerebral ischemia in mice. Biochem Biophys Res Commun 2015; 467:478-483.

49. Li Y, Adamek P, Zhang H, Tatsui CE, Rhines LD, Mrozkova P, et al. The Cancer chemotherapeutic paclitaxel increases human and rodent sensory neuron responses to TRPV1 by activation of TLR4. J Neurosci 2015; 35:13487-13500.

50. Ozturk A, Yildiz L. Expression of transient receptor potential vanilloid receptor 1 and toll-like receptor 4 in aggressive periodontitis and in chronic periodontitis. J Periodontal Res 2011; 46:475-482.

51. Wang Z, Yang H, Wolosin JM, Reinach PS. In human corneal epithelial cells TLR2/4 innate immune responses are fully dependent on TRPV1 activity mediated through both MyD88-dependent and independent signaling pathways. Invest Ophthalmol  Visual Sci 2012; 53:1832-1832.