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Inhibiting Purinergic Receptor (P2X7R) Alleviates Depression- and Anxiety-Like Behaviors in Obese Rats With Immune
Titikorn Chunchai1,2, Hiranya Pintana1,2, Patcharapong Pantiya1,2,3
1Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
Acta Physiologica (Oxford, England)
|May 10, 2026
Summary
A P2X7 receptor inhibitor reduced brain inflammation, restored neurogenesis, and improved mood in obese rats challenged with LPS. This highlights P2X7 signaling as a potential therapeutic target for depression and inflammation-related disorders.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Chronic high-fat diet (HFD) and lipopolysaccharide (LPS) induce microglial hyperactivation, neuroinflammation, and depression-like behaviors.
- LPS triggers P2X7 receptor (P2X7R)-mediated microglial activation via adenosine triphosphate (ATP) release.
- The therapeutic potential of P2X7R inhibition in HFD-induced obesity and LPS challenge models is not well understood.
Purpose of the Study:
- To investigate the effects of a P2X7R inhibitor on neuroinflammation, neurogenesis, and mood disorders in rats subjected to chronic HFD and LPS challenge.
- To explore the role of ATP/P2X7R signaling in HFD-induced obesity and LPS-induced brain pathologies.
Main Methods:
- Rats were fed either a normal diet or HFD for 12 weeks, followed by an LPS challenge.
- LPS-treated rats received saline, minocycline, or the P2X7R inhibitor JNJ-55308942.
- Behavioral tests, assessment of brain inflammation, oxidative stress, neurogenesis, and synaptic pruning were performed.
Main Results:
- LPS induced peripheral and brain inflammation, microglial hyperactivation, and mood deficits, which were exacerbated by HFD.
- HFD led to metabolic disturbances, oxidative stress, blood-brain barrier disruption, and reduced neurogenesis.
- P2X7R inhibition significantly reduced oxidative stress, neuroinflammation, synaptic pruning, restored neurogenesis, and improved mood-related behaviors.
Conclusions:
- ATP/P2X7-mediated neuroinflammation is a critical factor in HFD-induced obesity and LPS challenge-related brain pathologies.
- P2X7R signaling represents a promising therapeutic target for treating depression and inflammation-associated neuropsychiatric disorders.
- Both JNJ-55308942 and minocycline demonstrated neuroprotective effects, underscoring the importance of targeting neuroinflammation.
