Fingolimod suppressed the chronic unpredictable mild stress-induced depressive-like behaviors via affecting microglial and NLRP3 inflammasome activation
| Autor: | Yuanxin Guo, Hongmei Tang, Houfeng Zhou, Xia Long, Tao Feng, Xiaohong Gan, Shiyun Pu, Changyu Ren, Hongjing Zhou |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Sphingosine 1 Phosphate Receptor Modulators Inflammasomes Hippocampus Morris water navigation task Pharmacology medicine.disease_cause 030226 pharmacology & pharmacy Neuroprotection General Biochemistry Genetics and Molecular Biology Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine NLR Family Pyrin Domain-Containing 3 Protein Medicine Animals General Pharmacology Toxicology and Pharmaceutics Maze Learning Neuroinflammation Behavior Animal business.industry Depression Fingolimod Hydrochloride Multiple sclerosis Inflammasome General Medicine medicine.disease Fingolimod Antidepressive Agents Rats Disease Models Animal Oxidative Stress 030104 developmental biology Microglia business Oxidative stress Stress Psychological medicine.drug |
| Zdroj: | Life sciences. 263 |
| ISSN: | 1879-0631 |
| Popis: | Depression is a common aspect of the modern lifestyle, and most patients are recalcitrant to the current antidepressants. Fingolimod (FTY720), a sphingosine analogue approved for the treatment of multiple sclerosis, has a significant neuroprotective effect on the central nervous system. The aim of this study was to determine the potential therapeutic effect of FTY720 on the behavior and cognitive function of rats exposed daily to chronic unpredictable mild stress (CUMS), and elucidate the underlying mechanisms. The 42-day CUMS modeling induced depression-like behavior as indicated by the scores of sugar water preference, forced swimming, open field and Morris water maze tests. Mechanistically, CUMS caused significant damage to the hippocampal neurons, increased inflammation and oxidative stress, activated the NF-κB/NLRP3 axis, and skewed microglial polarization to the M1 phenotype. FTY720 not only alleviated neuronal damage and oxidative stress, but also improved the depression-like behavior and cognitive function of the rats. It also inhibited NF-κB activation and blocked NLRP3 inflammasome assembly by down-regulating NLRP3, ACS and caspase-1. Furthermore, FTY720 inhibited the microglial M1 polarization markers iNOS and CD16, and promoted the M2 markers Arg-1 and CD206. This in turn reduced the levels of TNF-α, IL-6 and IL-1β, and increased that of IL-10 in the hippocampus. In conclusion, FTY720 protects hippocampal neurons from stress-induced damage and alleviates depressive symptoms by inhibiting neuroinflammation. Our study provides a theoretical basis for S1P receptor modulation in treating depression. |
| Databáze: | OpenAIRE |
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