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abstract:
Experimental research

Minocycline impedes mitochondrial-dependent cell death and stabilizes expression of hypoxia inducible factor-1α in spinal cord injury

Guolei Zhang, Junpu Zha, Junchuan Liu, Jun Di

Arch Med Sci
Online publish date: 2018/02/15
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Introduction: One of the crucial mechanisms following spinal cord injury is mitochondria-associated cell death. Minocycline, an anti-inflammatory drug, is well known to impede mitochondrial cell death. However, there has been no study on the effect of minocycline linking Fas cell surface death receptor (FAS)-mediated cell death and hypoxia inducible factor (HIF-1α), the targets involved in mitochondrial cell death.

Material and methods: Male Sprague Dawley rats (N = 15, divided into three groups) were subjected to traumatic spinal cord injury and were injected with minocycline (n = 5) (90 mg/kg and later a 45 mg/kg dose twice a day (every 12 h)). Injection with sterile PBS in injured animals served as the vehicle (n = 5) and another group comprised healthy animals (n = 5). TUNEL assay was used to quantify cell death. The release of Smac/Diablo, cytochrome-c (cyt-c), HIF-1α, FAS ligand (FASL) and tumour necrosis factor-α (TNF-α) was measured using ELISA. Expression of HIF-1α, FASL and other cell death associated factors was quantified at the mRNA and protein level and confirmed with immunohistochemistry.

Results: There was a marked reduction in the HIF-1α and FASL expression levels in the minocycline-treated group compared to the vehicle. The reduction of HIF-1α and FASL was associated with other factors linked to cell death (Smac/Diablo, cyt-c, TNF-α, p53, caspase-8 and BH3 interacting domain death agonist (BID)) (p < 0.5; *p < 0.05 vs. vehicle group, **p < 0.01 vs. vehicle group).

Conclusions: The present study focuses on the investigation of minocycline in inhibiting mitochondria-associated cell death by modulating FASL and HIF-1α expression, which are seemingly interlinked mechanisms contributing to cell death.
keywords:

minocycline, mitochondrial proteins, apoptosis, HIF-1α, spinal cord injury

references:
Yrjänheikki J, Keinänen R, Pellika M, Hökfelt T, Koistinaho J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci U S A 1998; 95: 15769-74.
Fagan SC, Edwards DJ, Borlongan CV, et al. Optimal delivery of minocycline to the brain: implication for human studies of acute neuroprotection. Exp Neurol 2004; 186: 248-51.
Brundula V, Rewcastle NB, Metz LM, Bernard CC, Yong VW. Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 2002; 125: 1297-308.
Lee SM, Yune TY, Kim SJ, et al. Minocycline reduces cell death and improves functional recovery after traumatic spinal cord injury in the rat. J Neurotrauma 2003; 20: 1017-27.
Anderson DK, Hall ED. Pathophysiology of spinal cord trauma. Ann Emerg Med 1993; 22: 987-92.
Wang X, Zhu S, Drozda M, et al. Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington’s disease. Proc Natl Acad Sci USA 2003; 100: 10483-7.
Zhu S, Stavrovskaya IG, Drozda M, et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 2002; 417: 74-8.
Maier K, Merkler D, Gerber J, et al. Multiple neuroprotective mechanisms of minocycline in autoimmune CNS inflammation. Neurobiol Dis 2007; 25: 514-25.
Redin GS. Antibacterial activity in mice of minocycline, a new tetracycline. Antimicrob Agents Chemother (Beth­esda) 1966; 6: 371-6.
Sanchez Mejia RO, Ona VO, Li M, Friedlander RM. Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction. Neurosurgery 2001; 48: 1393-401.
Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM. The promise of minocycline in neurology. Lancet Neurol 2004; 3: 744-51.
Xue M, Mikliaeva EI, Casha S, Zygun D, Demchuk A, Yong VW. Improving outcomes of neuroprotection by minocycline: guides from cell culture and intracerebral hemorrhage in mice. Am J Pathol 2010; 176: 1193-202.
Yu WR, Liu T, Fehlings TK, Fehlings MG. Involvement of mitochondrial signaling pathways in the mechanism of Fas-mediated apoptosis after spinal cord injury. Eur J Neurosci 2009; 29: 114-31.
Ke Q, Costa M. Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol 2006; 70: 1469-80.
Zhu T, Zhan L, Liang D, et al. Hypoxia-inducible factor 1alpha mediates neuroprotection of hypoxic postconditioning against global cerebral ischemia. J Neuropathol Exp Neurol 2014; 73: 975-86.
López-Hernández B, Posadas I, Podlesniy P, Abad MA, Trullas R, Ceña V. HIF-1 is neuroprotective during the early phases of mild hypoxia in rat cortical neurons. Exp Neurol 2012; 233: 543-54.
Volm M, Koomägi R. Hypoxia-inducible factor (HIF-1) and its relationship to apoptosis and proliferation in lung cancer. Anticancer Res 2000; 20: 1527-33.
Gruner JA. A monitored contusion model of spinal cord injury in the rat. J Neurotrauma 1992; 9: 123-8.
Basso DM, Beattie MS, Bresnahan JC. A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 1995; 12: 1-21.
Morota S, Hansson MJ, Ishii N, Kudo Y, Elmer E, Uchino H. Spinal cord mitochondria display lower calcium retention capacity compared with brain mitochondria without inherent differences in sensitivity to cyclophilin D inhibition. J Neurochem 2007; 103: 2066-76.
Kim HS, Suh YH. Minocycline and neurodegenerative diseases. Behav Brain Res 2009; 196: 168-79.
Nikolic I, Andjelkovic M, Zaric M, et al. Induction of mitochondrial apoptotic pathway by raloxifene and estrogen in human endometrial stromal ThESC cell line. Arch Med Sci 2017; 13: 293-301.
Fernandez-Gomez FJ, Galindo MF, Gomez-Lazaro M, et al. Involvement of mitochondrial potential and calcium buffering capacity in minocycline cytoprotective actions. Neuroscience 2005; 133: 959-67.
Sugawara T, Fujimura M, Noshita N, et al. Neuronal death/survival signaling pathways in cerebral ischemia. NeuroRx 2004; 1: 17-25.
Jia L, Yu Z, Hui L, et al. Fas and FasL expression in the spinal cord following cord hemisection in the monkey. Neurochem Res 2011; 36: 419-25.
Yu WR, Fehlings MG. Fas/FasL-mediated apoptosis and inflammation are key features of acute human spinal cord injury: implications for translational, clinical application. Acta Neuropathologica 2011; 122: 747-61.
McEwen ML, Sullivan PG, Rabchevsky AG, Springer JE. Targeting mitochondrial fnction for the treatment of acute spinal cord injury. Neurotherapeutics 2011; 8: 168-79.
Teng YD, Choi H, Onario RC, et al. Minocycline inhibits contusion-triggered mitochondrial cytochrome c release and mitigates functional deficits after spinal cord injury. Proc Natl Acad Sci U S A 2004; 101: 3071-6.
Elzey BD, Griffith TS, Herndon JM, Barreiro R, Tschopp J, Ferguson TA. Regulation of Fas ligand-induced apoptosis by TNF. J Immunol 2001; 167: 3049-56.
Xiaowei H, Ninghui Z, Wei X, Yiping T, Linfeng X. The experimental study of hypoxia-inducible factor-1alpha and its target genes in spinal cord injury. Spinal Cord 2006; 44: 35-43.
Wang L, Duan D, Zhao Z, et al. Repair of spinal cord injury by hypoxia-inducible factor-1a-expressing neural stem cells. J Med Hyp Ideas 2014; 8: 27-9.
Schmid T, Zhou J, Brüne B. HIF-1 and p53: communication of transcription factors under hypoxia. J Cell Mol Med 2004; 8: 423-31.
Waring P, Müllbacher A. Cell death induced by the Fas/Fas ligand pathway and its role in pathology. Immunol Cell Biol 1999; 77: 312-7.
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