Abstract
Neurodegeneration associated with acute central nervous system injuries and diseases such as spinal cord injury and traumatic brain injury (TBI) are reported to be mediated by the regulation of apoptosis and oxidative stress through Ca2+ influx. The thiol redox system antioxidants, such as N-acetylcysteine (NAC) and selenium (Se), display neuroprotective activities mediated at least in part by their antioxidant and anti-inflammatory properties. However, there are no reports on hippocampal apoptosis, cytosolic reactive oxygen species (ROS), or Ca2+ values in rats with an induced TBI. Therefore, we tested the effects of Se and NAC administration on apoptosis, oxidative stress, and Ca2+ influx through TRPV1 channel activations in the hippocampus of TBI-induced rats. The 32 rats were divided into four groups: control, TBI, TBI + NAC, and TBI + Se groups. Intraperitoneal administrations of NAC and Se were performed at 1, 24, 48, and 72 h after TBI induction. After 3 days, the hippocampal neurons were freshly isolated from the rats. In cytosolic-free Ca2+ analyses, the neurons were stimulated with the TRPV1 channel agonist capsaicin, a pungent compound found in hot chili peppers. Cytosolic-free Ca2+, apoptosis, cytosolic ROS levels, and caspase-3 and -9 activities were higher in the TBI group than control. The values in the hippocampus were decreased by Se and NAC administrations. In conclusion, we observed that NAC and Se have protective effects on oxidative stress, apoptosis, and Ca2+ entry via TRPV1 channel activation in the hippocampus of this TBI model, but the effect of NAC appears to be much greater than that of Se. They are both interesting candidates for studying the amelioration of TBIs.
Graphical Abstract
Possible molecular pathways of TBI on oxidative stress, apoptosis and Ca2+ entry through TRPV1 cation channels in hippocampus and DRG neurons. It is likely that TRPV1-mediated Ca2+ entry in the hippocampus of epileptic rats involves accumulation of ROS and opening of mitochondrial membrane pores that consequently leads to mitochondrial dysfunction, substantial swelling of the mitochondria with rupture of the outer membrane and release of apoptosis-inducing factors such as caspase-3 and -9.
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Abbreviations
- [Ca2+]i :
-
Intracellular Ca2+
- CAP:
-
Capsaicin
- DMSO:
-
Dimethyl sulfoxide
- ROS:
-
Reactive oxygen species
- PBS:
-
Phosphate-buffered saline
- Se:
-
Selenium
- TBI:
-
Traumatic brain injury
- TRP:
-
Transient receptor potential
- TRPV1:
-
Transient receptor potential vanilloid 1
- NAC:
-
N-acetylcysteine
References
Al-Samsam RH, Alessandri B, Bullock R (2000) Extracellular N-acetyl-aspartate as a biochemical marker of the severity of neuronal damage following experimental acute traumatic brain injury. J Neurotrauma 17:31–39
Arakawa M, Ito Y (2007) N-acetylcysteine and neurodegenerative diseases: basic and clinical pharmacology. Cerebellum 6:308–314
Celik O, Nazıroğlu M (2012) Melatonin modulates apoptosis and TRPM2 channels in transfected cells activated by oxidative stress. Physiol Behav 107:458–465
Chen G, Shi J, Hu Z, Hang C (2008) Inhibitory effect on cerebral inflammatory response following traumatic brain injury in rats: a potential neuroprotective mechanism of N-acetylcysteine. Mediat Inflamm 2008:716458
Daiber A, Mader M, Stamm P, Zinßius E, Kröller-Schön S, Oelze M, Münzel T (2013) Oxidative stress and vascular function. Cell Membr Free Radic Res 5:221–231
Dalla Puppa L, Savaskan NE, Bräuer AU, Behne D, Kyriakopoulos A (2007) The role of selenite on microglial migration. Ann NY Acad Sci 1096:179–183
Elphick LM, Hawat M, Toms NJ, Meinander A, Mikhailov A, Eriksson JE, Kass GE (2008) Opposing roles for caspase and calpain death proteases in l-glutamate-induced oxidative neurotoxicity. Toxicol Appl Pharmacol 232(2):258–267
Englezou PC, Esposti MD, Wiberg M, Reid AJ, Terenghi G (2012) Mitochondrial involvement in sensory neuronal cell death and survival. Exp Brain Res 221(4):357–367
Espino J, Bejarano I, Paredes SD, Barriga C, Rodríguez AB, Pariente JA (2011) Protective effect of melatonin against human leukocyte apoptosis induced by intracellular calcium overload: relation with its antioxidant actions. J Pineal Res 51:195–206
González A, Pariente JA, Salido GM (2007) Ethanol stimulates ROS generation by mitochondria through Ca2+ mobilization and increases GFAP content in rat hippocampal astrocytes. Brain Res 1178:28–37
Grynkiewicz C, Poenie M, Tsien RY (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260:3440–3450
Hallak M, Vazana L, Shpilberg O, Levy I, Mazar J, Nathan I (2008) A molecular mechanism for mimosine-induced apoptosis involving oxidative stress and mitochondrial activation. Apoptosis 13:147–155
Hoffer ME, Balaban C, Slade MD, Tsao JW, Hoffer B (2013) Amelioration of acute sequelae of blast induced mild traumatic brain injury by N-acetyl cysteine: a double-blind, placebo controlled study. PLoS One 8:e54163
Jeo JE, Kang SK (2007) Selenium effectively inhibits ROS-mediated apoptotic neural precursor cell death in vitro and in vivo in traumatic brain injury. Biochim Biophys Acta 1772:1199–1210
Junn E, Mouradian MM (2001) Apoptotic signaling in dopamine-induced cell death: the role of oxidative stress, p38 mitogen-activated protein kinase, cytochrome c and caspases. J Neurochem 78:374–383
Karalija A, Novikova LN, Kingham PJ, Wiberg M, Novikov LN (2012) Neuroprotective effects of N-acetyl-cysteine and acetyl-l-carnitine after spinal cord injury in adult rats. PLoS One 7:e41086
Kim TS, Jeong DW, Yun BY, Kim IY (2002) Dysfunction of rat liver mitochondria by selenite: induction of mitochondrial permeability transition through thiol-oxidation. Biochem Biophys Res Commun 294:1130–1137
Limbrick DD Jr, Sombati S, DeLorenzo RJ (2003) Calcium influx constitutes the ionic basis for the maintenance of glutamate-induced extended neuronal depolarization associated with hippocampal neuronal death. Cell Calcium 33:69–81
Liu Y, Liu XJ, Sun D (2009) Ion transporters and ischemic mitochondrial dysfunction. Cell Adhes Migr 3:94–98
Marmarou A, Foda MA, van den Brink W, Campbell J, Kita H, Demetriadou K (1994) A new model of diffuse brain injury in rats. Part I: pathophysiology and biomechanics. J Neurosurg 80:291–300
Nazıroğlu M (2007) New molecular mechanisms on the activation of TRPM2 channels by oxidative stress and ADP-ribose. Neurochem Res 32:1990–2001
Nazıroğlu M (2009) Role of selenium on calcium signaling and oxidative stress-induced molecular pathways in epilepsy. Neurochem Res 34:2181–2191
Nazıroğlu M (2011) TRPM2 cation channels, oxidative stress and neurological diseases: where are we now? Neurochem Res 36:355–366
Nazıroğlu M, Yürekli VA (2013) Effects of antiepileptic drugs on antioxidant and oxidant molecular pathways: focus on trace elements. Cell Mol Neurobiol 33:589–599
Nazıroğlu M, Kutluhan S, Yilmaz M (2008) Selenium and topiramate modulates brain microsomal oxidative stress values, Ca2+-ATPase activity, and EEG records in pentylentetrazol-induced seizures in rats. J Membr Biol 225:39–49
Nazıroğlu M, Dikici DM, Dursun S (2012) Role of oxidative stress and Ca(2+) signaling on molecular pathways of neuropathic pain in diabetes: focus on TRP channels. Neurochem Res 37:2065–2075
Nazıroğlu M, Ciğ B, Ozgül C (2013a) Neuroprotection induced by N-acetylcysteine against cytosolic glutathione depletion-induced Ca2+ influx in dorsal root ganglion neurons of mice: role of TRPV1 channels. Neuroscience 242:151–160
Nazıroğlu M, Uğuz AC, Ismailoğlu O, Ciğ B, Ozgül C, Borcak M (2013b) Role of TRPM2 cation channels in dorsal root ganglion of rats after experimental spinal cord injury. Muscle Nerve 48:945–950
Nazıroğlu M, Kutluhan S, Ovey IS, Aykur M, Yurekli VA (2013c) Modulation of oxidative stress, apoptosis, and calcium entry in leukocytes of patients with multiple sclerosis by Hypericum perforatum. Nutr Neurosci (in press)
Oksay T, Nazıroğlu M, Ergün O, Doğan S, Özatik O, Armağan A, Özorak A, Çelik Ö (2013) N-acetyl cysteine attenuates diazinon exposure-induced oxidative stress in rat testis. Andrologia 45:171–177
Özgül C, Nazıroğlu M (2012) TRPM2 channel protective properties of N-acetylcysteine on cytosolic glutathione depletion dependent oxidative stress and Ca2+ influx in rat dorsal root ganglion. Physiol Behav 106:122–128
Piao CS, Loane DJ, Stoica BA, Li S, Hanscom M, Cabatbat R, Blomgren K, Faden AI (2012) Combined inhibition of cell death induced by apoptosis inducing factor and caspases provides additive neuroprotection in experimental traumatic brain injury. Neurobiol Dis 46:745–758
Raghupathi R (2004) Cell death mechanisms following traumatic brain injury. Brain Pathol 14:215–222
Rothe G, Oser A, Valet G (1988) Dihydrorhodamine 123: a new flow cytometric indicator for respiratory burst activity in neutrophil granulocytes. Naturwissenschaften 75:354–355
Senol N, Nazıroğlu M, Yürüker V (2014) N-Acetylcysteine and selenium modulate oxidative stress, antioxidant vitamin and cytokine values in traumatic brain injury-induced rats. Neurochem Res 39:685–692
Shang D, Li Y, Wang C, Wang X, Yu Z, Fu X (2011) A novel polysaccharide from Se-enriched Ganoderma lucidum induces apoptosis of human breast cancer cells. Oncol Rep 25:267–272
Sierra A, Abiega O, Shahraz A, Neumann H (2013) Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis. Front Cell Neurosci 7:6
Uğuz AC, Nazıroğlu M (2012) Effects of selenium on calcium signaling and apoptosis in rat dorsal root ganglion neurons induced by oxidative stress. Neurochem Res 37:1631–1638
Uğuz AC, Cig B, Espino J, Bejarano I, Naziroglu M, Rodríguez AB, Pariente JA (2012) Melatonin potentiates chemotherapy-induced cytotoxicity and apoptosis in rat pancreatic tumor cells. J Pineal Res 53:91–98
Weber JT (2012) Altered calcium signaling following traumatic brain injury. Front Pharmacol 3:60
Woodcock T, Morganti-Kossmann MC (2013) The role of markers of inflammation in traumatic brain injury. Front Neurol 4:18
Xiong Y, Shie FS, Zhang J, Lee CP, Ho YS (2004) The protective role of cellular glutathione peroxidase against trauma-induced mitochondrial dysfunction in the mouse brain. J Stroke Cerebrovasc Dis 13:129–137
Yeo JE, Kang SK (2007) Selenium effectively inhibits ROS-mediated apoptotic neural precursor cell death in vitro and in vivo in traumatic brain injury. Biochim Biophys Acta 1772:1199–1210
Yeo JE, Kim JH, Kang SK (2008) Selenium attenuates ROS-mediated apoptotic cell death of injured spinal cord through prevention of mitochondria dysfunction; in vitro and in vivo study. Cell Physiol Biochem 21:225–238
Zhang Y, Liu H, Jin J, Zhu X, Lu L, Jiang H (2010) The role of endogenous reactive oxygen species in oxymatrine-induced caspase-3-dependent apoptosis in human melanoma A375 cells. Anticancer Drugs 21:494–501
Zhao X, Gorin FA, Berman RF, Lyeth BG (2008) Differential hippocampal protection when blocking intracellular sodium and calcium entry during traumatic brain injury in rats. J Neurotrauma 25:1195–1205
Acknowledgments
Dr.Vahid Ghazizadeh was partially supported for the project by Free Oxygen Radical Society, Isparta, Turkey. MN formulated the present hypothesis and was responsible for writing the report. NŞ, VG, and VY were responsible for the analyses. The authors wish to thank the Research Assistant, Ahmi Öz (Department of Biophysics, Medical Faculty, Suleyman Demirel University, Isparta, Turkey) for preparation of graphical abstract.
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The authors declare that they have no conflict of interest.
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Nazıroğlu, M., Şenol, N., Ghazizadeh, V. et al. Neuroprotection Induced by N-acetylcysteine and Selenium Against Traumatic Brain Injury-Induced Apoptosis and Calcium Entry in Hippocampus of Rat. Cell Mol Neurobiol 34, 895–903 (2014). https://doi.org/10.1007/s10571-014-0069-2
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DOI: https://doi.org/10.1007/s10571-014-0069-2