{"title":"情绪稳定剂(拉莫三嗪、锂和丙戊酸)通过抑制神经元细胞中的TRPM2通道减少双相情感障碍模型(瓦巴因)诱导的氧化应激和细胞凋亡。","authors":"Esra Nur Kaplan, İbrahim Eren, Mustafa Nazıroğlu","doi":"10.1111/bdi.70053","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Bipolar disease (BD) has been strongly associated with the etiologies of mitochondrial reactive oxygen species (mROS), apoptosis, and Ca<sup>2+</sup> influx. With the exception of BD, a number of neurological disorders have been linked to apoptosis and neuronal death mediated by mROS-dependent activated TRPM2 channel stimulation. Lamotrigine (LMT), lithium (Li), and valproic acid (VPA) are mood stabilizers in BD, and they have strong antioxidant roles. However, the molecular mechanisms underlying LMT, Li, and VPA neuroprotection through TRPM2 channel inhibiton remain elusive in BD.</p><p><strong>Aim: </strong>We evaluated the protective actions of LMT, Li, and VPA on BD (ouabain, OUA)-induced oxidative neurotoxicity in SH-SY5Y neuronal cells by modulating TRPM2.</p><p><strong>Methods: </strong>The SH-SY5Y cells were divided into nine groups as follows: control, Li, VPA, LMT, OUA, OUA + Li, OUA + VPA, LMT + VPA, and OUA + TRPM2 antagonists (N-(p-amylcinnamoyl)anthranilic acid or carvacrol).</p><p><strong>Results: </strong>OUA exposure and TRPM2 agonist (H<sub>2</sub>O<sub>2</sub> and ADP-ribose)-induced TRPM2 stimulation and TRPM2 current densities were downregulated by the treatments of TRPM2 antagonist, Li, VPA, and LMT. The OUA-induced upregulations of mROS, cytosolic ROS, lipid peroxidation, mitochondrial membrane dysfunction, apoptosis, Zn<sup>2+</sup>, cell death, and caspase-3, -8, and -9 values were also downregulated through the increases of cell viability, glutathione, and glutathione peroxidase by the treatments.</p><p><strong>Conclusions: </strong>The treatments of Li, VPA, and LMT modulate OUA-mediated mROS, apoptosis, Zn<sup>2+</sup>, glutathione, and TRPM2-mediated excess Ca<sup>2+</sup> influx. This could potentially offer protection against BD linked to elevated levels of mROS, Ca<sup>2+</sup>, and Zn<sup>2+</sup>.</p>","PeriodicalId":8959,"journal":{"name":"Bipolar Disorders","volume":" ","pages":""},"PeriodicalIF":4.5000,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Mood Stabilizers (Lamotrigine, Lithium, and Valproic Acid) Decrease Bipolar Disease Model (Ouabain)-Induced Oxidative Stress and Apoptosis Through the Inhibition of the TRPM2 Channel in Neuronal Cells.\",\"authors\":\"Esra Nur Kaplan, İbrahim Eren, Mustafa Nazıroğlu\",\"doi\":\"10.1111/bdi.70053\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Bipolar disease (BD) has been strongly associated with the etiologies of mitochondrial reactive oxygen species (mROS), apoptosis, and Ca<sup>2+</sup> influx. With the exception of BD, a number of neurological disorders have been linked to apoptosis and neuronal death mediated by mROS-dependent activated TRPM2 channel stimulation. Lamotrigine (LMT), lithium (Li), and valproic acid (VPA) are mood stabilizers in BD, and they have strong antioxidant roles. However, the molecular mechanisms underlying LMT, Li, and VPA neuroprotection through TRPM2 channel inhibiton remain elusive in BD.</p><p><strong>Aim: </strong>We evaluated the protective actions of LMT, Li, and VPA on BD (ouabain, OUA)-induced oxidative neurotoxicity in SH-SY5Y neuronal cells by modulating TRPM2.</p><p><strong>Methods: </strong>The SH-SY5Y cells were divided into nine groups as follows: control, Li, VPA, LMT, OUA, OUA + Li, OUA + VPA, LMT + VPA, and OUA + TRPM2 antagonists (N-(p-amylcinnamoyl)anthranilic acid or carvacrol).</p><p><strong>Results: </strong>OUA exposure and TRPM2 agonist (H<sub>2</sub>O<sub>2</sub> and ADP-ribose)-induced TRPM2 stimulation and TRPM2 current densities were downregulated by the treatments of TRPM2 antagonist, Li, VPA, and LMT. The OUA-induced upregulations of mROS, cytosolic ROS, lipid peroxidation, mitochondrial membrane dysfunction, apoptosis, Zn<sup>2+</sup>, cell death, and caspase-3, -8, and -9 values were also downregulated through the increases of cell viability, glutathione, and glutathione peroxidase by the treatments.</p><p><strong>Conclusions: </strong>The treatments of Li, VPA, and LMT modulate OUA-mediated mROS, apoptosis, Zn<sup>2+</sup>, glutathione, and TRPM2-mediated excess Ca<sup>2+</sup> influx. This could potentially offer protection against BD linked to elevated levels of mROS, Ca<sup>2+</sup>, and Zn<sup>2+</sup>.</p>\",\"PeriodicalId\":8959,\"journal\":{\"name\":\"Bipolar Disorders\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2025-09-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bipolar Disorders\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/bdi.70053\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bipolar Disorders","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/bdi.70053","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Mood Stabilizers (Lamotrigine, Lithium, and Valproic Acid) Decrease Bipolar Disease Model (Ouabain)-Induced Oxidative Stress and Apoptosis Through the Inhibition of the TRPM2 Channel in Neuronal Cells.
Background: Bipolar disease (BD) has been strongly associated with the etiologies of mitochondrial reactive oxygen species (mROS), apoptosis, and Ca2+ influx. With the exception of BD, a number of neurological disorders have been linked to apoptosis and neuronal death mediated by mROS-dependent activated TRPM2 channel stimulation. Lamotrigine (LMT), lithium (Li), and valproic acid (VPA) are mood stabilizers in BD, and they have strong antioxidant roles. However, the molecular mechanisms underlying LMT, Li, and VPA neuroprotection through TRPM2 channel inhibiton remain elusive in BD.
Aim: We evaluated the protective actions of LMT, Li, and VPA on BD (ouabain, OUA)-induced oxidative neurotoxicity in SH-SY5Y neuronal cells by modulating TRPM2.
Methods: The SH-SY5Y cells were divided into nine groups as follows: control, Li, VPA, LMT, OUA, OUA + Li, OUA + VPA, LMT + VPA, and OUA + TRPM2 antagonists (N-(p-amylcinnamoyl)anthranilic acid or carvacrol).
Results: OUA exposure and TRPM2 agonist (H2O2 and ADP-ribose)-induced TRPM2 stimulation and TRPM2 current densities were downregulated by the treatments of TRPM2 antagonist, Li, VPA, and LMT. The OUA-induced upregulations of mROS, cytosolic ROS, lipid peroxidation, mitochondrial membrane dysfunction, apoptosis, Zn2+, cell death, and caspase-3, -8, and -9 values were also downregulated through the increases of cell viability, glutathione, and glutathione peroxidase by the treatments.
Conclusions: The treatments of Li, VPA, and LMT modulate OUA-mediated mROS, apoptosis, Zn2+, glutathione, and TRPM2-mediated excess Ca2+ influx. This could potentially offer protection against BD linked to elevated levels of mROS, Ca2+, and Zn2+.
期刊介绍:
Bipolar Disorders is an international journal that publishes all research of relevance for the basic mechanisms, clinical aspects, or treatment of bipolar disorders and related illnesses. It intends to provide a single international outlet for new research in this area and covers research in the following areas:
biochemistry
physiology
neuropsychopharmacology
neuroanatomy
neuropathology
genetics
brain imaging
epidemiology
phenomenology
clinical aspects
and therapeutics of bipolar disorders
Bipolar Disorders also contains papers that form the development of new therapeutic strategies for these disorders as well as papers on the topics of schizoaffective disorders, and depressive disorders as these can be cyclic disorders with areas of overlap with bipolar disorders.
The journal will consider for publication submissions within the domain of: Perspectives, Research Articles, Correspondence, Clinical Corner, and Reflections. Within these there are a number of types of articles: invited editorials, debates, review articles, original articles, commentaries, letters to the editors, clinical conundrums, clinical curiosities, clinical care, and musings.