Melatonin and calpeptin synergistically protect against post-reperfusion injury in a rat middle cerebral artery occlusion stroke model
Melatonin and calpeptin in post-reperfusion injury
Keywords:
melatonin, calpeptin, ischemic stroke, neuroprotection, ischemia, reperfusion
Abstract
Cerebral ischemia induces oxidative injury and increases the intracellular calcium ion concentration to activate several calcium-dependent proteases such as calpains. Calpain activation leads to various necrotic and apoptotic processes. Calpeptin is a potent, cell-permeable calpain inhibitor. As a strong antioxidant and free radical scavenger, melatonin shows beneficial effect in rodent models of focal cerebral ischemia when given prior to ischemia or reperfusion. This study was focused on the neuroprotective effects of melatonin and/or calpeptin given after onset of reperfusion. For this purpose, right-sided middle cerebral artery occlusion (MCAO) for 90 minutes followed by 24 or 72 hours of reperfusion was performed in male Sprague Dawley rats, then, melatonin 50 or 150 µg/kg, calpeptin 10, 15 or 50 µg/kg or a combination of melatonin 50 µg/kg plus calpeptin 15 or 50 µg/kg were injected via an intracerebroventricular route at 15 minutes after onset of reperfusion. Melatonin or calpeptin tended to reduce the relative infarct volume and significantly decreased the neurological deficit at 24 hours. The combination achieved a greater protection than each of them alone. Melatonin, calpeptin or the combination all decreased Fluoro-Jade B (FJB)+ degenerative neurons and cleaved/total caspase-3 ratio at 24 hours. These treatments did not significantly impact the density of surviving neurons and ED-1+ macrophage/activated microglia. At the 72-hour-reperfusion, melatonin or the combination decreased the relative infarct volume and neurological deficit. Nevertheless, only the combination reduced FJB+ degenerating neurons at 72 hours. In conclusion, a combination of melatonin and calpeptin exerted synergistic protection against post-reperfusion injury in a rat MCAO stroke model.
References
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3. Musuka TD, Wilton SB, Traboulsi M, Hill MD (2015) Diagnosis and management of acute ischemic stroke: speed is critical. CMAJ 187: 887–893.
4. Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, Brott T, Cohen G, Davis S, Donnan G, Grotta J, Howard G, Kaste M, Koga M, von Kummer R, Lansberg M, Lindley RI, Murray G, Olivot JM, Parsons M, Tilley B, Toni D, Toyoda K, Wahlgren N, Wardlaw J, Whiteley W, del Zoppo GJ, Baigent C, Sandercock P, Hacke W, Stroke Thrombolysis Trialists' Collaborative Group (2014) Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 384: 1929–1935.
5. Goyal M, Almekhlafi M, Dippel DW, Campbell BCV, Muir K, Demchuk AM, Bracard S, Davalos A, Guillemin F, Jovin TG, Menon BK, Mitchell PJ, Brown S, White P, Majoie CBLM, Saver JL, Hill MD, HERMES Collaborators (2019) Rapid alteplase administration improves functional outcomes in patients with stroke due to large vessel occlusions. Stroke 50: 645–651.
6. Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, Albers GW, Kaste M, Marler JR, Hamilton SA, Tilley BC, Davis SM, Donnan GA, Hacke W; ECASS, ATLANTIS, NINDS and EPITHET rt-PA Study Group, Allen K, Mau J, Meier D, del Zoppo G, De Silva DA, Butcher KS, Parsons MW, Barber PA, Levi C, Bladin C, Byrnes G (2010) Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 375: 1695–1703.
7. Wardlaw JM, Murray V, Berge E, del Zoppo G, Sandercock P, Lindley RL, Cohen G (2012) Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet 379: 2364–2372.
8. Pei Z, Ho HT, Cheung RT (2002) Pre-treatment with melatonin reduces volume of cerebral infarction in a permanent middle cerebral artery occlusion stroke model in the rat. Neurosci. Lett. 318: 141–144.
9. Pei Z, Pang SF, Cheung RT (2003) Administration of melatonin after onset of ischemia reduces the volume of cerebral infarction in a rat middle cerebral artery occlusion stroke model. Stroke 34: 770–775.
10. Peng S, Kuang Z, Zhang Y, Xu H, Cheng Q (2011) The protective effects and potential mechanism of calpain inhibitor calpeptin against focal cerebral ischemia-reperfusion injury in rats. Mol. Biol. Rep. 38: 905–912.
11. Ma Z, Xin Z, Di W, Yan X, Li X, Reiter RJ, Yang Y (2017) Melatonin and mitochondrial function during ischemia/reperfusion injury. Cell. Mol. Life Sci. 74: 3989–3998.
12. Kato H, Kogure K (1999) Biochemical and molecular characteristics of the brain with developing cerebral infarction. Cell. Mol. Neurobiol. 19: 93–108.
13. Bartus RT, Dean RL, Mennerick S, Eveleth D, Lynch G (1998) Temporal ordering of pathogenic events following transient global ischemia. Brain Res. 790: 1–13.
14. Inserte J, Hernando V, Garcia-Dorado D (2012) Contribution of calpains to myocardial ischaemia/reperfusion injury. Cardiovasc. Res. 96: 23–31.
15. Cheng S-Y, Wang S-C, Lei M, Wang Z, Xiong K (2018) Regulatory role of calpain in neuronal death. Neural Regen. Res. 13: 556–562.
16. Wang KK (2000) Calpain and caspase: can you tell the difference? Trends Neurosci. 23: 20–26.
17. Takaoka M, Itoh M, Kohyama S, Shibata A, Ohkita M, Matsumura Y (2000) Proteasome inhibition attenuates renal endothelin-1 production and the development of ischemic acute renal failure in rats. J. Cardiovasc. Pharmacol. 36: S225–S227.
18. Feng J, Schaus BJ, Fallavollita JA, Lee TC, Canty JM (2001) Preload induces troponin I degradation independently of myocardial ischemia. Circulation 103: 2035–2037.
19. Das A, Sribnick EA, Wingrave JM, Del Re AM, Woodward JJ, Appel SH, Banik NL, Ray SK (2005) Calpain activation in apoptosis of ventral spinal cord 4.1 (VSC4.1) motoneurons exposed to glutamate: calpain inhibition provides functional neuroprotection. J. Neurosci. Res. 81: 551–562.
20. Bartus RT, Baker KL, Heiser AD, Sawyer SD, Dean RL, Elliott PJ, Straub JA (1994) Postischemic administration of AK275, a calpain inhibitor, provides substantial protection against focal ischemic brain damage. J. Cereb. Blood Flow Metab. 14: 537–544.
21. Hong SC, Goto Y, Lanzino G, Soleau S, Kassell NF, Lee KS (1994) Neuroprotection with a calpain inhibitor in a model of focal cerebral ischemia. Stroke 25: 663–669.
22. Tan DX, Manchester LC, Liu X, Rosales-Corral SA, Acuna-Castroviejo D, Reiter RJ (2013) Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin’s primary function and evolution in eukaryotes. J. Pineal Res. 54: 127–138.
23. Suofu Y, Li W, Jean-Alphonse FG, Jia J, Khattar NK, Li J, Baranov SV, Leronni D, Mihalik AC, He Y, Cecon E, Wehbi VL, Kim J, Heath BE, Baranova OV, Wang X, Gable MJ, Kretz ES, Di Benedetto G, Lezon TR, Ferrando LM, Larkin TM, Sullivan M, Yablonska S, Wang J, Minnigh MB, Guillaumet G, Suzenet F, Richardson RM, Poloyac SM, Stolz DB, Jockers R, Witt-Enderby PA, Carlisle DL, Vilardaga JP, Friedlander RM (2017) Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release. Proc. Natl. Acad. Sci. USA 114: E7997–E8006.
24. Manchester LC, Poeggeler B, Alvares FL, Ogden GB, Reiter RJ (1995) Melatonin immunoreactivity in the photosynthetic prokaryote Rhodospirillum rubrum: implications for an ancient antioxidant system. Cell. Mol. Biol. Res. 41: 391–395.
25. Zhang HM, Zhang Y (2014) Melatonin: a well-documented antioxidant with conditional pro-oxidant actions. J. Pineal Res. 57: 131–146.
26. García JJ, López-Pingarrón L, Almeida-Souza P, Tres A, Escudero P, García-Gil FA, Tan DX, Reiter RJ, Ramírez JM, Bernal-Pérez M (2014) Protective effects of melatonin in reducing oxidative stress and in preserving the fluidity of biological membranes: a review. J. Pineal Res. 56: 225–237.
27. Galano A, Tan DX, Reiter RJ (2011) Melatonin as a natural ally against oxidative stress: a physicochemical examination. J. Pineal Res. 51: 1–16.
28. Sarkar S, Chattopadhyay A, Bandyopadhyay D (2021) Multiple strategies of melatonin protecting against cardiovascular injury related to inflammation: A comprehensive overview. Melatonin Res. 4, 1: 1–29.
29. Burkhardt S, Reiter RJ, Tan DX, Hardeland R, Cabrera J, Karbownik M (2001) DNA oxidatively damaged by chromium(III) and H(2)O(2) is protected by the antioxidants melatonin, N(1)-acetyl-N(2)-formyl-5-methoxykynuramine, resveratrol and uric acid. Int. J. Biochem. Cell. Biol. 33: 775–783.
30. Ressmeyer AR, Mayo JC, Zelosko V, Sáinz RM, Tan DX, Poeggeler B, Antolín I, Zsizsik BK, Reiter RJ, Hardeland R (2003) Antioxidant properties of the melatonin metabolite N1-acetyl-5-methoxykynuramine (AMK): scavenging of free radicals and prevention of protein destruction. Redox Rep. 8: 205–213.
31. Reiter RJ, Tan DX, Leon J, Kilic U, Kilic E (2005) When melatonin gets on your nerves: its beneficial actions in experimental models of stroke. Exp. Biol. Med. 230: 104–117.
32. Pundik S, Xu K, Sundararajan S (2012) Reperfusion brain injury: focus on cellular bioenergetics. Neurology 79: S44–S51.
33. Wang X, Figueroa BE, Stavrovskaya IG, Zhang Y, Sirianni AC, Zhu S, Day AL, Kristal BS, Friedlander RM (2009) Methazolamide and melatonin inhibit mitochondrial cytochrome C release and are neuroprotective in experimental models of ischemic injury. Stroke 40: 1877–1885.
34. Joo JY, Uz T, Manev H (1998) Opposite effects of pinealectomy and melatonin administration on brain damage following cerebral focal ischemia in rat. Restor. Neurol. Neurosci. 13: 185–191.
35. Zhang J, Guo JD, Xing SH, Gu SL, Dai TJ (2002) The protective effects of melatonin on global cerebral ischemia-reperfusion injury in gerbils]. Acta Pharm. Sin. 37: 329–333.
36. Letechipía-Vallejo G, González-Burgos I, Cervantes M (2001) Neuroprotective effect of melatonin on brain damage induced by acute global cerebral ischemia in cats. Arch. Med. Res. 32: 186–192.
37. Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jimenez M, Qin L (2016) Melatonin as an antioxidant: under promises but over delivers. J. Pineal Res. 61: 253–278.
38. Liu L, Chen H, Jin J, Tang Z, Yin P, Zhong D, Li G (2019) Melatonin ameliorates cerebral ischemia/reperfusion injury through SIRT3 activation. Life Sci. 239: 117036.
39. Feng D, Wang B, Wang L, Abraham N, Tao K, Huang L, Shi W, Dong Y, Qu Y (2017) Pre-ischemia melatonin treatment alleviated acute neuronal injury after ischemic stroke by inhibiting endoplasmic reticulum stress-dependent autophagy via PERK and IRE1 signalings. J. Pineal Res. 62: 12395.
40. Wakatsuki A, Okatani Y, Shinohara K, Ikenoue N, Fukaya T (2001) Melatonin protects against ischemia/reperfusion-induced oxidative damage to mitochondria in fetal rat brain. J. Pineal Res. 31: 167–172.
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Published
2021-12-31
How to Cite
[1]
Feng, Y., Xu, Q. and Cheung, R. 2021. Melatonin and calpeptin synergistically protect against post-reperfusion injury in a rat middle cerebral artery occlusion stroke model. Melatonin Research. 4, 4 (Dec. 2021), 592-612. DOI:https://doi.org/https://doi.org/10.32794/mr112500114.
Section
Research Articles
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