Background: SKF83959 stimulates the phospholipase Cβ/inositol phosphate 3 pathway, resulting in the activation of Ca(2+)/calmodulin-dependent kinase IIα, which affects the synthesis of brain-derived neurotrophic factor, a neurotrophic factor critical for the pathophysiology of depression. Previous reports showed that SKF83959 elicited antidepressant activity in the forced swim test and tail suspension test as a novel triple reuptake inhibitor. However, there are no studies showing the effects of SKF83959 in a chronic stress model of depression and the role of phospholipase C/inositol phosphate 3/calmodulin-dependent kinase IIα/brain-derived neurotrophic factor pathway in SKF83959-mediated antidepressant effects.
Methods: In this study, SKF83959 was firstly investigated in the chronic social defeat stress model of depression. The changes in hippocampal neurogenesis, dendrite spine density, and brain-derived neurotrophic factor signaling pathway after chronic social defeat stress and SKF83959 treatment were then investigated. Pharmacological inhibitors and small interfering RNA/short hairpin RNA methods were further used to explore the antidepressive mechanisms of SKF83959.
Results: We found that SKF83959 produced antidepressant effects in the chronic social defeat stress model and also restored the chronic social defeat stress-induced decrease in hippocampal brain-derived neurotrophic factor signaling pathway, dendritic spine density, and neurogenesis. By using various inhibitors and siRNA/shRNA methods, we further demonstrated that the hippocampal dopamine D5 receptor, phospholipase C/inositol phosphate 3/ calmodulin-dependent kinase IIα pathway, and brain-derived neurotrophic factor system are all necessary for the SKF83959 effects.
Conclusion: These results suggest that SKF83959 can be developed as a novel antidepressant and produces antidepressant effects via the hippocampal D5/ phospholipase C/inositol phosphate 3/calmodulin-dependent kinase IIα/brain-derived neurotrophic factor pathway.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438541 | PMC |
| http://dx.doi.org/10.1093/ijnp/pyu096 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Therapeutic Potential of Saffron Extract in Mild Depression: A Study of Its Role on Anhedonia in Rats and Humans.
Phytother Res
January 2025
Department of Molecular and Developmental Medicine, School of Medicine, University of Siena, Polo Universitario San Miniato, Siena, Italy.
Drugs generally used in major depressive disorder are considered inappropriate for the more common milder forms. The efficacy of saffron extracts has been demonstrated in mild to moderate depression and in preclinical models of depression. However, evidence of saffron activity on reduced hedonic responsiveness and motivational anhedonia is limited.
View Article and Find Full Text PDFBiotin Mitigates Alcohol Withdrawal-Induced Anxiety and Depression by Regulating Serotonin Metabolism, BDNF, Inflammation, and Oxidative Stress in Rats.
Neuropsychopharmacol Rep
March 2025
Department of Biology and Microbiology, Faculty of Medical Laboratory Technology, Khatam Al-Nabieen University, Kabul, Afghanistan.
Introduction: Substance use disorders, particularly alcohol use disorders, represent a significant public health problem, with adolescents particularly vulnerable to their adverse effects. This study examined the possible anxiolytic and antidepressant effects of biotin, a crucial vitamin for brain function, in attenuating the behavioral and neurobiological changes associated with alcohol withdrawal in adolescent rats.
Materials And Methods: Sixty male Sprague-Dawley rats were exposed to a 20% ethanol solution for 21 days, followed by a 21-day drug-free period to assess long-term behavioral and physiological changes.
Indole and Coumarin Derivatives Targeting EEF2K in Aβ Folding Reporter Cells.
J Neurochem
January 2025
Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
Misfolding and accumulation of amyloid-β (Aβ) in the brains of patients with Alzheimer's disease (AD) lead to neuronal loss through various mechanisms, including the downregulation of eukaryotic elongation factor 2 (EEF2) protein synthesis signaling. This study investigated the neuroprotective effects of indole and coumarin derivatives on Aβ folding and EEF2 signaling using SH-SY5Y cells expressing Aβ-green fluorescent protein (GFP) folding reporter. Among the tested compounds, two indole (NC009-1, -6) and two coumarin (LM-021, -036) derivatives effectively reduced Aβ misfolding and associated reactive oxygen species (ROS) production.
View Article and Find Full Text PDFTrkB Agonist (7,8-DHF)-Induced Responses in Dorsal Root Ganglia Neurons Are Decreased after Spinal Cord Injury: Implication for Peripheral Pain Mechanisms.
eNeuro
January 2025
Department of Cell Biology, School of Medicine, Emory University, Atlanta, Georgia 30322
Brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) are known to contribute to both protective and pronociceptive processes. However, their contribution to neuropathic pain after spinal cord injury (SCI) needs further investigation. In a recent study utilizing TrkB mice, it was shown that systemic pharmacogenetic inhibition of TrkB signaling with 1NM-PP1 (1NMP) immediately after SCI delayed the onset of pain hypersensitivity, implicating maladaptive TrkB signaling in pain after SCI.
View Article and Find Full Text PDFChitosan lactate improves repeated closed head injury-generated motor and neurological dysfunctions in mice by impacting microbiota gut-brain axis.
Metab Brain Dis
January 2025
Department of Biological Sciences (Pharmacology and Toxicology), National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Balanagar, Hyderabad, 500037, Telangana, India.
The negative impact of repeated-mild traumatic brain injury (rmTBI) is profoundly seen in circadian-disrupted individuals. The unrelenting inflammation, glial activation, and gut dysbiosis are key neuropathological aberrations in the aftermath of rmTBI. In this study, we examined the impact of chitosan lactate (CL) on circadian disturbance (CD) + rmTBI-generated neurological dysfunctions and its prebiotic response on the gut-brain axis.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!