Lilla Lenart1,2, Judit Hodrea1, Adam Hosszu1, Sandor Koszegi1,3, Dora Zelena4, Dora Balogh1,2, Edgar Szkibinszkij1,5, Apor Veres-Szekely3, Laszlo Wagner5, Adam Vannay3, Attila J Szabo2,3, Andrea Fekete6,7. 1. MTA-SE "Lendület" Diabetes Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary. 2. 1st Department of Pediatrics, Semmelweis University, Bókay János u. 53-54, 1083, Budapest, Hungary. 3. MTA-SE Pediatrics and Nephrology Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary. 4. Institute of Experimental Medicine, Budapest, Hungary. 5. Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary. 6. MTA-SE "Lendület" Diabetes Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary. fekete.andrea@med.semmelweis-univ.hu. 7. 1st Department of Pediatrics, Semmelweis University, Bókay János u. 53-54, 1083, Budapest, Hungary. fekete.andrea@med.semmelweis-univ.hu.
Abstract
RATIONALE: Depression is highly prevalent in diabetes (DM). Brain-derived neurotrophic factor (BDNF) which is mainly regulated by the endoplasmic reticulum chaperon sigma-1 receptor (S1R) plays a relevant role in the development of depression. OBJECTIVES: We studied the dose-dependent efficacy of S1R agonist fluvoxamine (FLU) in the prevention of DM-induced depression and investigated the significance of the S1R-BDNF pathway. METHODS: We used streptozotocin to induce DM in adult male rats that were treated for 2 weeks p.o. with either different doses of FLU (2 or 20 mg/bwkg) or FLU + S1R antagonist NE100 (1 mg/bwkg) or vehicle. Healthy controls were also enrolled. Metabolic, behaviour, and neuroendocrine changes were determined, and S1R and BDNF levels were measured in the different brain regions. RESULTS: In DM rats, immobility time was increased, adrenal glands were enlarged, and thymuses were involuted. FLU in 20 mg/bwkg, but not in 2 mg/bwkg dosage, ameliorated depression-like behaviour. S1R and BDNF protein levels were decreased in DM, while FLU induced SIR-BDNF production. NE100 suspended all effects of FLU. CONCLUSIONS: We suggest that disturbed S1R-BDNF signaling in the brain plays a relevant role in DM-induced depression. The activation of this cascade serves as an additional target in the prevention of DM-associated depression.
RATIONALE: Depression is highly prevalent in diabetes (DM). Brain-derived neurotrophic factor (BDNF) which is mainly regulated by the endoplasmic reticulum chaperon sigma-1 receptor (S1R) plays a relevant role in the development of depression. OBJECTIVES: We studied the dose-dependent efficacy of S1R agonist fluvoxamine (FLU) in the prevention of DM-induced depression and investigated the significance of the S1R-BDNF pathway. METHODS: We used streptozotocin to induce DM in adult male rats that were treated for 2 weeks p.o. with either different doses of FLU (2 or 20 mg/bwkg) or FLU + S1R antagonist NE100 (1 mg/bwkg) or vehicle. Healthy controls were also enrolled. Metabolic, behaviour, and neuroendocrine changes were determined, and S1R and BDNF levels were measured in the different brain regions. RESULTS: In DMrats, immobility time was increased, adrenal glands were enlarged, and thymuses were involuted. FLU in 20 mg/bwkg, but not in 2 mg/bwkg dosage, ameliorated depression-like behaviour. S1R and BDNF protein levels were decreased in DM, while FLU induced SIR-BDNF production. NE100 suspended all effects of FLU. CONCLUSIONS: We suggest that disturbed S1R-BDNF signaling in the brain plays a relevant role in DM-induced depression. The activation of this cascade serves as an additional target in the prevention of DM-associated depression.
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