Ovariectomy-Induced Mitochondrial Oxidative Stress, Apoptosis, and Calcium Ion Influx Through TRPA1, TRPM2, and TRPV1 Are Prevented by 17β-Estradiol, Tamoxifen, and Raloxifene in the Hippocampus and Dorsal Root Ganglion of Rats
Relative 17β-estradiol (E2) deprivation and excessive production of mitochondrial oxygen free radicals (OFRs) with a high amount of Ca2+ influx TRPA1, TRPM2, and TRPV1 activity is one of the main causes of neurodegenerative disease in postmenopausal women. In addition to the roles of tamoxifen (TMX) and raloxifene (RLX) in cancer and bone loss treatments, regulator roles in Ca2+ influx and mitochondrial oxidative stress in neurons have not been reported. The aim of this study was to evaluate whether TMX and RLX interactions with TRPA1, TRPM2, and TRPV1 in primary hippocampal (HPC) and dorsal root ganglion (DRG) neuron cultures of ovariectomized (OVX) rats. Forty female rats were divided into five groups: a control group, an OVX group, an OVX+E2 group, an OVX+TMX group, and an OVX+RLX group. The OVX+E2, OVX+TMX, and OVX+RLX groups received E2, TMX, and RLX, respectively, for 14 days after the ovariectomy. E2, ovariectomy-induced TRPA1, TRPM2, and TRPV1 current densities, as well as accumulation of cytosolic free Ca2+ in the neurons, were returned to the control levels by E2, TMX, and RLX treatments. In addition, E2, TMX, and RLX via modulation of TRPM2 and TRPV1 activity reduced ovariectomy-induced mitochondrial membrane depolarization, apoptosis, and cytosolic OFR production. TRPM2, TRPV1, PARP, and caspase-3 and caspase-9 expressions were also decreased in the neurons by the E2, TMX, and RLX treatments. In conclusion, we first reported the molecular effects of E2, TMX, and RLX on TRPA1, TRPM2, and TRPV1 channel activation in the OVX rats. In addition, we observed neuroprotective effects of E2, RLX, and TMX on oxidative and apoptotic injuries of the hippocampus and peripheral pain sensory neurons (DRGs) in the OVX rats.
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The abstracts of the study were presented at the 6th World Congress of Oxidative Stress, Calcium Signaling and TRP Channels, held on 24 and 27 May 2016 in Isparta, Turkey (www.cmos.org.tr). The authors wish to thank the researcher technicians İshak Suat Övey and Muhammet Şahin (Neuroscience Research Center, SDU, Isparta, Turkey) for helping with the Western blot and plate reader analyses.
MN formulated the hypothesis and was responsible for writing the report. Ovariectomy of rats was performed by MN. The analyses were performed by YY.
Compliance with Ethical Standards
Unit of Scientific Research Project (BAP) of Suleyman Demirel University.
This study was partially supported by the Unit of Scientific Research Project (BAP) of Suleyman Demirel University in Isparta, Turkey (Project Number BAP: 4135-YL2-14). There is no financial disclosure for the current study.
Conflict of Interest
The authors declare that they have no conflict of interest.
Nazıroğlu M (2007) New molecular mechanisms on the activation of TRPM2 channels by oxidative stress and ADP-ribose. Neurochem Res 32:1990–2001CrossRefPubMedGoogle Scholar
Espino J, Bejarano I, Redondo PC, Rosado JA, Barriga C, Reiter RJ, Pariente JA, Rodríguez AB (2010) Melatonin reduces apoptosis induced by calcium signaling in human leukocytes: evidence for the involvement of mitochondria and Bax activation. J Membr Biol 233:105–118CrossRefPubMedGoogle Scholar
Hara Y, Wakamori M, Ishii M, Maeno E, Nishida M, Yoshida T, Yamada H, Shimizu S et al (2002) LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death. Mol Cell 9:163–173CrossRefPubMedGoogle Scholar
Nazıroğlu M, Lückhoff A (2008) A calcium influx pathway regulated separately by oxidative stress and ADP-ribose in TRPM2 channels: single channel events. Neurochem Res 33:1256–1262CrossRefPubMedGoogle Scholar
Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997(389):816–824Google Scholar
Pecze L, Jósvay K, Blum W, Petrovics G, Vizler C, Oláh Z, Schwaller B (2016) Activation of endogenous TRPV1 fails to induce overstimulation-based cytotoxicity in breast and prostate cancer cells but not in pain-sensing neurons. Biochim Biophys Acta 1863:2054–2064CrossRefPubMedGoogle Scholar
Takahashi N, Kuwaki T, Kiyonaka S, Numata T, Kozai D, Mizuno Y, Yamamoto S, Naito S et al (2011) TRPA1 underlies a sensing mechanism for O2. Nat Chem Biol 7(10):701–711CrossRefPubMedGoogle Scholar
Toda T, Yamamoto S, Yonezawa R, Mori Y, Shimizu S (2016) Inhibitory effects of Tyrphostin AG-related compounds on oxidative stress-sensitive transient receptor potential channel activation. Eur J Pharmacol 786:19–28CrossRefPubMedGoogle Scholar
Wu YW, Bi YP, Kou XX, Xu W, Ma LQ, Wang KW, Gan YH, Ma XC (2010) 17-Beta-estradiol enhanced allodynia of inflammatory temporomandibular joint through upregulation of hippocampal TRPV1 in ovariectomized rats. J Neurosci 30:8710–8719CrossRefPubMedGoogle Scholar
Kahya MC, Nazıroğlu M, Çiğ B. (2016) Modulation of diabetes-induced oxidative stress, apoptosis, and Ca2+ entry through TRPM2 and TRPV1 channels in dorsal root ganglion and hippocampus of diabetic rats by melatonin and selenium. Mol Neurobiol. 2016 [Epub ahead of print]. doi:10.1007/s12035-016-9727-3.
Özdemir ÜS, Nazıroğlu M, Şenol N, Ghazizadeh V (2016) Hypericum perforatum attenuates spinal cord injury-induced oxidative stress and apoptosis in the dorsal root ganglion of rats: involvement of TRPM2 and TRPV1 channels. Mol Neurobiol 53:3540–3551CrossRefPubMedGoogle Scholar
Obata K, Katsura H, Mizushima T, Yamanaka H, Kobayashi K, Dai Y, Fukuoka T, Tokunaga A et al (2005) TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury. J Clin Invest 115:2393–2401CrossRefPubMedPubMedCentralGoogle Scholar
Cristino L, de Petrocellis L, Pryce G, Baker D, Guglielmotti V, Di Marzo V (2006) Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain. Neuroscience 139:1405–1415CrossRefPubMedGoogle Scholar
Fonfria E, Murdock PR, Cusdin FS, Benham CD, Kelsell RE, McNulty S (2006) Tissue distribution profiles of the human TRPM cation channel family. J Recept Signal Transduct Res 26:159–178CrossRefPubMedGoogle Scholar
Bai JZ, Lipski J (2010) Differential expression of TRPM2 and TRPV4 channels and their potential role in oxidative stress-induced cell death in organotypic hippocampal culture. Neurotoxicology 31:204–214CrossRefPubMedGoogle Scholar
Nativi C, Gualdani R, Dragoni E, Di Cesare ML, Sostegni S, Norcini M, Gabrielli G, la Marca G et al (2013) A TRPA1 antagonist reverts oxaliplatin-induced neuropathic pain. Sci Rep 3:2005CrossRefPubMedPubMedCentralGoogle Scholar
Cho T, Chaban VV (2012) Expression of P2X3 and TRPV1 receptors in primary sensory neurons from estrogen receptors-α and estrogen receptor-β knockout mice. Neuroreport 23:530–534CrossRefPubMedPubMedCentralGoogle Scholar
Kimelberg HK, Jin Y, Charniga C, Feustel PJ (2003) Neuroprotective activity of tamoxifen in permanent focal ischemia. J Neurosurg 99:138–142CrossRefPubMedGoogle Scholar
Moreira PI, Custodio JB, Oliveira CR, Santos MS (2005) Brain mitochondrial injury induced by oxidative stress-related events is prevented by tamoxifen. Neuropharmacology 48:435–447CrossRefPubMedGoogle Scholar
Osmanova S, Sezer E, Turan V, Zeybek B, Terek MC, Kanıt L (2011) The effects of raloxifene treatment on oxidative status in brain tissues and learning process of ovariectomized rats. Iran J Reprod Med 9:295–300PubMedPubMedCentralGoogle Scholar
Ozgocmen S, Kaya H, Fadillioglu E, Yilmaz Z (2007) Effects of calcitonin, risedronate, and raloxifene on erythrocyte antioxidant enzyme activity, lipid peroxidation, and nitric oxide in postmenopausal osteoporosis. Arch Med Res 38:196e205CrossRefGoogle Scholar
O’Neill K, Chen S, Brinton RD (2004) Impact of the selective estrogen receptor modulator, raloxifene, on neuronal survival and outgrowth following toxic insults associated with aging and Alzheimer’s disease. Exp Neurol 185:63–80CrossRefPubMedGoogle Scholar
Moreira PI, Custódio JB, Nunes E, Oliveira PJ, Moreno A, Seiça R, Oliveira CR, Santos MS (2011) Mitochondria from distinct tissues are differently affected by 17β-estradiol and tamoxifen. J Steroid Biochem Mol Biol 123:8–16CrossRefPubMedGoogle Scholar
Huang Y, Lai B, Zheng P, Zhua YC, Yaoa T (2007) Raloxifene acutely reduces glutamate-induced intracellular calcium increase in cultured rat cortical neurons via inhibition of high-voltage-actıvated calcium current. Neuroscience 147:334–341CrossRefPubMedGoogle Scholar
Dilek M, Nazıroğlu M, Oral BH, Övey İS, Küçükyaz M, Mungan MT, Kara HY, Sütçü R (2010) Melatonin modulates hippocampus NMDA receptors, blood and brain oxidative stress levels in ovariectomized rats. J Membr Biol 233:135–142CrossRefPubMedGoogle Scholar
Kramer PR, Bellinger LL (2013) Modulation of temporomandibular joint nociception and inflammation in male rats after administering a physiological concentration of 17beta-oestradiol. Eur J Pain 17:174–184CrossRefPubMedGoogle Scholar
Yazgan B, Yazgan Y, Övey İS (2016) Nazıroğlu M. Raloxifene and tamoxifen reduce PARP activity, cytokine and oxidative stress levels in the brain and blood of ovariectomized rats. J Mol Neurosci 60:214–222CrossRefPubMedGoogle Scholar
Olah ME, Jackson MF, Li H, Perez Y, Sun HS, Kiyonaka S, Mori Y, Tymianski M et al (2009) Ca2+-dependent induction of TRPM2 currents in hippocampal neurons. J Physiol 587(Pt 5):965–979CrossRefPubMedPubMedCentralGoogle Scholar
Grynkiewicz C, Poenie M, Tsien RY (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260:3440–3450PubMedGoogle Scholar
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 51:195–206CrossRefPubMedGoogle Scholar
Nazıroğlu M, Dikici DM, Dursun Ş (2012) Role of oxidative stress and Ca2+ signaling on molecular pathways of neuropathic pain in diabetes: focus on TRP channels. Neurochem Res 37:2065–2075CrossRefPubMedGoogle Scholar
Nazıroğlu M (2015) Role of melatonin on calcium signaling and mitochondrial oxidative stress in epilepsy: focus on TRP channels. Tr J Biol 39:813–821Google Scholar
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489CrossRefPubMedGoogle Scholar
Phillips SM, Sherwin BB (1992) Effects on estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology 17:485–495CrossRefPubMedGoogle Scholar
Vega-Vela NE, Osorio D, Avila-Rodriguez M, Gonzalez J, García-Segura LM, Echeverria V, Barreto GE (2016) L-type calcium channels modulation by estradiol. Mol Neurobiol [Epub ahead of print]. doi:10.1007/s12035-016-0045-6Google Scholar
Malagarie-Cazenave S, Olea-Herrero N, Vara D, Díaz-Laviada I (2009) Capsaicin, a component of red peppers, induces expression of androgen receptor via PI3K and MAPK pathways in prostate LNCaP cells. FEBS Lett 583:141–147CrossRefPubMedGoogle Scholar
Zheng G, Hong S, Hayes JM, Wiley JW (2015) Chronic stress and peripheral pain: evidence for distinct, region-specific changes in visceral and somatosensory pain regulatory pathways. Exp Neurol 273:301–311CrossRefPubMedPubMedCentralGoogle Scholar
Scotland PE, Patil M, Belugin S, Henry MA, Goffin V, Hargreaves KM, Akopian AN (2011) Endogenous prolactin generated during peripheral inflammation contributes to thermal hyperalgesia. Eur J Neurosci 34:745–754CrossRefPubMedPubMedCentralGoogle Scholar
Pan Y, Huang S, Cai Z, Lan H, Tong Y, Yu X, Zhao G, Chen F (2016) TRPA1 and TRPM8 receptors may promote local vasodilation that aggravates oxaliplatin-induced peripheral neuropathy amenable to 17β-estradiol treatment. Curr Neurovasc Res 13:309-317Google Scholar
Lee DY, Chai YG, Lee EB, Kim KW, Nah SY, Oh TH, Rhim H (2002) 17β-estradiol inhibits high-voltage-activated calcium channel currents in rat sensory neurons via a non-genomic mechanism. Life Sci 70:2047–2059CrossRefPubMedGoogle Scholar
Xu S, Cheng Y, Keast JR, Osborne PB (2008) 17beta-estradiol activates estrogen receptor beta-signalling and inhibits transient receptor potential vanilloid receptor 1 activation by capsaicin in adult rat nociceptor neurons. Endocrinology 149:5540–5548CrossRefPubMedPubMedCentralGoogle Scholar
Cardoso CM, Almeida LM, Custódio JB (2004) Protection of tamoxifen against oxidation of mitochondrial thiols and NAD(P)H underlying the permeability transition induced by prooxidants. Chem Biol Interact 148:149–161CrossRefPubMedGoogle Scholar
Kumar VS, Gopalakrishnan A, Nazıroğlu M, Rajanikant GK (2014) Calcium ion-the key player in cerebral ischemia. Curr Med Chem 21:2065–2075CrossRefPubMedGoogle Scholar
Yu X, Rajala RV, McGinnis JF, Li F, Anderson RE, Yan X, Li S, Elias RV et al (2004) Involvement of insulin/phosphoinositide 3-kinase/Akt signal pathway in 17 beta-estradiol-mediated neuroprotection. J Biol Chem 26(279):13086–13094CrossRefGoogle Scholar
Feng Y, Wang B, Du F, Li H, Wang S, Hu C, Zhu C, Yu X (2013) The involvement of PI3K-mediated and L-VGCC-gated transient Ca2+ influx in 17β-estradiol-mediated protection of retinal cells from H2O2-induced apoptosis with Ca2+ overload. PLoS One 8:e77218CrossRefPubMedPubMedCentralGoogle Scholar
Irnaten M, Blanchard-Gutton N, Praetorius J, Harvey BJ (2009) Rapid effects of 17 beta-estradiol on TRPV5 epithelial Ca2+ channels in rat renal cells. Steroids 74:642–649CrossRefPubMedGoogle Scholar