SYK-623, a δ Opioid Receptor Inverse Agonist, Mitigates Chronic Stress-Induced Behavioral Abnormalities and Disrupted Neurogenesis
The δ opioid receptor (DOR) inverse agonist has been demonstrated to improve learning and memory impairment in mice subjected to restraint stress. Here, we investigated the effects of SYK-623, a new DOR inverse agonist, on behavioral, immunohistochemical, and biochemical abnormalities in a mouse mod...
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| Format: | Article |
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MDPI AG
2024-01-01
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| Series: | Journal of Clinical Medicine |
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| Online Access: | https://www.mdpi.com/2077-0383/13/2/608 |
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| author | Takashi Iwai Rei Mishima Shigeto Hirayama Honoka Nakajima Misa Oyama Shun Watanabe Hideaki Fujii Mitsuo Tanabe |
| author_facet | Takashi Iwai Rei Mishima Shigeto Hirayama Honoka Nakajima Misa Oyama Shun Watanabe Hideaki Fujii Mitsuo Tanabe |
| author_sort | Takashi Iwai |
| collection | DOAJ |
| description | The δ opioid receptor (DOR) inverse agonist has been demonstrated to improve learning and memory impairment in mice subjected to restraint stress. Here, we investigated the effects of SYK-623, a new DOR inverse agonist, on behavioral, immunohistochemical, and biochemical abnormalities in a mouse model of imipramine treatment-resistant depression. Male ddY mice received daily treatment of adrenocorticotropic hormone (ACTH) combined with chronic mild stress exposure (ACMS). SYK-623, imipramine, or the vehicle was administered once daily before ACMS. After three weeks, ACMS mice showed impaired learning and memory in the Y-maze test and increased immobility time in the forced swim test. SYK-623, but not imipramine, significantly suppressed behavioral abnormalities caused by ACMS. Based on the fluorescent immunohistochemical analysis of the hippocampus, ACMS induced a reduction in astrocytes and newborn neurons, similar to the reported findings observed in the postmortem brains of depressed patients. In addition, the number of parvalbumin-positive GABA neurons, which play a crucial role in neurogenesis, was reduced in the hippocampus, and western blot analysis showed decreased glutamic acid decarboxylase protein levels. These changes, except for the decrease in astrocytes, were suppressed by SYK-623. Thus, SYK-623 mitigates behavioral abnormalities and disturbed neurogenesis caused by chronic stress. |
| first_indexed | 2024-03-08T09:51:15Z |
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| issn | 2077-0383 |
| language | English |
| last_indexed | 2024-03-08T09:51:15Z |
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| series | Journal of Clinical Medicine |
| spelling | doaj.art-bf18e283273845b2be2c8b0094966c572024-01-29T14:03:41ZengMDPI AGJournal of Clinical Medicine2077-03832024-01-0113260810.3390/jcm13020608SYK-623, a δ Opioid Receptor Inverse Agonist, Mitigates Chronic Stress-Induced Behavioral Abnormalities and Disrupted NeurogenesisTakashi Iwai0Rei Mishima1Shigeto Hirayama2Honoka Nakajima3Misa Oyama4Shun Watanabe5Hideaki Fujii6Mitsuo Tanabe7Laboratory of Pharmacology, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, JapanLaboratory of Pharmacology, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, JapanMedicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, JapanLaboratory of Pharmacology, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, JapanLaboratory of Pharmacology, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, JapanLaboratory of Pharmacology, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, JapanMedicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, JapanLaboratory of Pharmacology, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, JapanThe δ opioid receptor (DOR) inverse agonist has been demonstrated to improve learning and memory impairment in mice subjected to restraint stress. Here, we investigated the effects of SYK-623, a new DOR inverse agonist, on behavioral, immunohistochemical, and biochemical abnormalities in a mouse model of imipramine treatment-resistant depression. Male ddY mice received daily treatment of adrenocorticotropic hormone (ACTH) combined with chronic mild stress exposure (ACMS). SYK-623, imipramine, or the vehicle was administered once daily before ACMS. After three weeks, ACMS mice showed impaired learning and memory in the Y-maze test and increased immobility time in the forced swim test. SYK-623, but not imipramine, significantly suppressed behavioral abnormalities caused by ACMS. Based on the fluorescent immunohistochemical analysis of the hippocampus, ACMS induced a reduction in astrocytes and newborn neurons, similar to the reported findings observed in the postmortem brains of depressed patients. In addition, the number of parvalbumin-positive GABA neurons, which play a crucial role in neurogenesis, was reduced in the hippocampus, and western blot analysis showed decreased glutamic acid decarboxylase protein levels. These changes, except for the decrease in astrocytes, were suppressed by SYK-623. Thus, SYK-623 mitigates behavioral abnormalities and disturbed neurogenesis caused by chronic stress.https://www.mdpi.com/2077-0383/13/2/608delta opioidstresslearning and memorydepressionneurogenesisGABA |
| spellingShingle | Takashi Iwai Rei Mishima Shigeto Hirayama Honoka Nakajima Misa Oyama Shun Watanabe Hideaki Fujii Mitsuo Tanabe SYK-623, a δ Opioid Receptor Inverse Agonist, Mitigates Chronic Stress-Induced Behavioral Abnormalities and Disrupted Neurogenesis Journal of Clinical Medicine delta opioid stress learning and memory depression neurogenesis GABA |
| title | SYK-623, a δ Opioid Receptor Inverse Agonist, Mitigates Chronic Stress-Induced Behavioral Abnormalities and Disrupted Neurogenesis |
| title_full | SYK-623, a δ Opioid Receptor Inverse Agonist, Mitigates Chronic Stress-Induced Behavioral Abnormalities and Disrupted Neurogenesis |
| title_fullStr | SYK-623, a δ Opioid Receptor Inverse Agonist, Mitigates Chronic Stress-Induced Behavioral Abnormalities and Disrupted Neurogenesis |
| title_full_unstemmed | SYK-623, a δ Opioid Receptor Inverse Agonist, Mitigates Chronic Stress-Induced Behavioral Abnormalities and Disrupted Neurogenesis |
| title_short | SYK-623, a δ Opioid Receptor Inverse Agonist, Mitigates Chronic Stress-Induced Behavioral Abnormalities and Disrupted Neurogenesis |
| title_sort | syk 623 a δ opioid receptor inverse agonist mitigates chronic stress induced behavioral abnormalities and disrupted neurogenesis |
| topic | delta opioid stress learning and memory depression neurogenesis GABA |
| url | https://www.mdpi.com/2077-0383/13/2/608 |
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