Dapoxetine induces neuroprotective effects against glutamate-induced neuronal cell death by inhibiting calcium signaling and mitochondrial depolarization in cultured rat hippocampal neurons.
Selective serotonin reuptake inhibitors (SSRIs) have an inhibitory effect on various ion channels including Ca2+channels. We used fluorescent dye-based digital imaging, whole-cell patch clamping and cytotoxicity assays to examine whether dapoxetine, a novel rapid-acting SSRI, affect glutamate-induced calcium signaling, mitochondrial depolarization and neuronal cell death in cultured rat hippocampal neurons. Pretreatment with dapoxetine for 10min inhibited glutamate-induced intracellular free Ca2+concentration ([Ca2+]i) increases in a concentration-dependent manner (Half maximal inhibitory concentration=4.79µM). Dapoxetine (5μM) markedly inhibited glutamate-induced [Ca2+]iincreases, whereas other SSRIs such as fluoxetine and citalopram only slightly inhibited them. Dapoxetine significantly inhibited the glutamate-induced [Ca2+]iresponses following depletion of intracellular Ca2+stores by treatment with thapsigargin. Dapoxetine markedly inhibited the metabotropic glutamate receptor agonist, (S)-3,5-dihydroxyphenylglycine-induced [Ca2+]iincreases. Dapoxetine significantly inhibited the glutamate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced [Ca2+]iresponses in either the presence or absence of nimodipine. Dapoxetine also significantly inhibited AMPA-evoked currents. However, dapoxetine slightly inhibited N-methyl-D-aspartate (NMDA)-induced [Ca2+]iincreases. Dapoxetine markedly inhibited 50mMK+-induced [Ca2+]iincreases. Dapoxetine significantly inhibited glutamate-induced mitochondrial depolarization. In addition, dapoxetine significantly inhibited glutamate-induced neuronal cell death and its neuroprotective effect was significantly greater than fluoxetine. These data suggest that dapoxetine reduces glutamate-induced [Ca2+]iincreases by inhibiting multiple pathways mainly through AMPA receptors, voltage-gated L-type Ca2+channels and metabotropic glutamate receptors, which are involved in neuroprotection against glutamate-induced cell death through mitochondrial depolarization.
Department of Physiology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero Seocho-gu, Seoul 06591, South Korea. Electronic address: imjujeong@gmail.com.
Imju
I
Jeong
Department of Physiology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero Seocho-gu, Seoul 06591, South Korea; Catholic Neuroscience Institute, The Catholic University of Korea, 222 Banpo-daero Seocho-gu, Seoul 06591, South Korea. Electronic address: jisoni83@naver.com.
Ji Seon
JS
Yang
Department of Physiology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero Seocho-gu, Seoul 06591, South Korea. Electronic address: yijaehong@gmail.com.
Yi Jae
YJ
Hong
Department of Physiology, College of Medicine, Dankook University, Dandae-ro, Dongnam-gu, Cheonan-si, Chungcheongnam-do 31116, South Korea. Electronic address: heejungkim@dankook.ac.kr.
Hee Jung
HJ
Kim
Department of Physiology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero Seocho-gu, Seoul 06591, South Korea; Catholic Neuroscience Institute, The Catholic University of Korea, 222 Banpo-daero Seocho-gu, Seoul 06591, South Korea. Electronic address: sjhahn@catholic.ac.kr.
Sang June
SJ
Hahn
Department of Physiology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero Seocho-gu, Seoul 06591, South Korea; Catholic Neuroscience Institute, The Catholic University of Korea, 222 Banpo-daero Seocho-gu, Seoul 06591, South Korea. Electronic address: s-hyoon@catholic.ac.kr.
Shin Hee
SH
Yoon
D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000633:toxicity*; D006624:Hippocampus / Q000166:cytology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D001596:Benzylamines; D018698:Glutamic Acid; D016202:N-Methylaspartate; D009281:Naphthalenes; D018696:Neuroprotective Agents; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D018091:Receptors, AMPA; D017367:Selective Serotonin Reuptake Inhibitors; C080598:dapoxetine
Ca(2+); Dapoxetine; Glutamate; Hippocampal neurons; Neuroprotection; Selective serotonin reuptake inhibitor