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. Graphical Abstract Possible molecular pathways of involvement of DEX in cerebral ischemia-induced apoptosis, oxidative stress, and calcium accumulation through TRPA1, TRPM2 and TRPV1 in the hippocampus and DRG neurons of rats. The N domain of the TRPM2 contains ADP-ribose (ADPR) pyrophosphate enzyme, which is separately activated by ADPR and oxidative stress, although the channel is reversibly inhibited by N-(p-amylcinnamoyl) anthranilic acid (ACA). The TRPV1 is also activated by mitochondrial oxidative stress and capsaicin, and it is blocked by capsazepine (CPZ). TRPA1 is also activated by oxidative stress it is inhibited by AP18. Increased cytosolic Ca2+concentration through TRPA1, TRPM2 and TRPV1 in ovariectomized (OVX) rats may lead to neuronal toxicity, reactive oxygen species (ROS) processes, and eventual cell death. 17β-Estradiol (E2), tamoxifen (TMX), and raloxifene (RLX) reduced oxidative stress, apoptosis (including caspase-3 and caspase-9), mitochondrial membrane depolarization, and Ca2+influx through the inhibition of TRPA1, TRPM2 and TRPV1 activation.
Department of Biophysics, Institute of Health Science, Suleyman Demirel University, Isparta, Turkey.
Yener
Y
Yazğan
Department of Biophysics, Institute of Health Science, Suleyman Demirel University, Isparta, Turkey. mustafanaziroglu@sdu.edu.tr.|Neuroscience Research Center, University of Suleyman Demirel, Isparta, Turkey. mustafanaziroglu@sdu.edu.tr.|Nörolojik Bilimler Uygulama ve Araştırma Merkezi Müdürü, Süleyman Demirel Üniversitesi, TR 32260, Isparta, Turkey. mustafanaziroglu@sdu.edu.tr.
Mustafa
M
Nazıroğlu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D004958:Estradiol / Q000008:administration & dosage*; D004965:Estrogen Antagonists / Q000008:administration & dosage*; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010052:Ovariectomy / Q000639:trends; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D020849:Raloxifene Hydrochloride / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D000074025:TRPA1 Cation Channel / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013629:Tamoxifen / Q000008:administration & dosage
D004965:Estrogen Antagonists; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels; D050916:TRPV Cation Channels; C480976:Trpa1 protein, rat; C557080:Trpm2 protein, rat; C493922:Trpv1 protein, rat; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D002118:Calcium
Hippocampus; Ovariectomy; Raloxifene; TRPM2; TRPV1; Tamoxifen