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Agomelatine Exerts an Anti-inflammatory Effect by Inhibiting Microglial Activation Through TLR4/NLRP3 Pathway in
Wijitra Chumboatong1,2, Satchakorn Khamchai1, Chainarong Tocharus3
1Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
Abstract:
Cerebral ischemic stroke is one of the main causes of death and long-term disability worldwide. However, the mechanism is unclear, and treatments are limited. In this study, we aimed to investigate the anti-inflammatory effect of agomelatine in a permanent middle cerebral artery occlusion (pMCAO) model. Forty-eight male Wistar rats were randomly divided into four groups: sham, pMCAO + vehicle, pMCAO + agomelatine (40 mg/kg, i.p.), and pMCAO + melatonin (10 mg/kg, i.p.) groups. On day 1 after permanent cerebral ischemia, the animals were sacrificed, and brain tissues were collected for western blot analysis, and immunohistochemistry. Agomelatine treatment ameliorated inflammatory responses by decreasing the protein levels of trigger Toll-like receptor (TLR4)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway components together with nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome components. In addition, agomelatine suppressed microglial activation and pyroptotic cell death after cerebral ischemic injury. These results suggest that agomelatine exerts an anti-inflammatory effect and attenuates brain damage by inhibiting microglial activation through the TLR4/NLRP3 signaling pathway.
Insights
Agomelatine reduces inflammation and brain damage after ischemic stroke by inhibiting microglial activation. This study investigated its anti-inflammatory effects in a rat model of cerebral ischemia.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Cerebral ischemic stroke is a leading cause of death and disability globally.
- Current treatment options for stroke are limited, and underlying mechanisms require further elucidation.
- Inflammation plays a critical role in the pathophysiology of ischemic stroke.
Purpose of the Study:
- To investigate the anti-inflammatory effects of agomelatine in a rat model of permanent middle cerebral artery occlusion (pMCAO).
- To explore the potential mechanisms underlying agomelatine's neuroprotective effects, focusing on inflammatory pathways.
Main Methods:
- A permanent middle cerebral artery occlusion (pMCAO) model was established in male Wistar rats.
- Rats were randomly assigned to sham, pMCAO + vehicle, pMCAO + agomelatine, or pMCAO + melatonin treatment groups.
- Brain tissues were analyzed using Western blot and immunohistochemistry to assess inflammatory markers and cellular changes.
Main Results:
- Agomelatine treatment significantly reduced inflammatory responses in the pMCAO model.
- Agomelatine decreased the protein levels of Toll-like receptor 4 (TLR4)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway components and NLRP3 inflammasome.
- Agomelatine suppressed microglial activation and pyroptotic cell death following cerebral ischemic injury.
Conclusions:
- Agomelatine exerts significant anti-inflammatory effects in the context of cerebral ischemic stroke.
- Agomelatine attenuates brain damage by inhibiting microglial activation, likely through modulation of the TLR4/NLRP3 signaling pathway.
- These findings suggest agomelatine as a potential therapeutic agent for ischemic stroke.
