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LPS also increases adenosine triphosphate (ATP) release from immune and dying cells, activating microglia through the purinergic P2X7R receptor. However, the effects of P2X7 inhibitor on microglial hyperactivation, brain inflammation, neurogenesis, and depression\u2010like behavior in obese models challenged with LPS remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Sixty\u2010four male Wistar rats were fed either normal diet or HFD for 12\u2009weeks and subsequently received an intraperitoneal (IP) injection of normal saline or LPS (500\u2009\u03bcg\/kg). LPS\u2010treated rats\u00a0were then given saline, minocycline (45\u2009mg\/kg, twice, IP), or the P2X7R inhibitor JNJ\u201055308942 (30\u2009mg\/kg, single dose, orally). Depression\u2010 and anxiety\u2010like behaviors were assessed 24\u2009h later.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>LPS alone induced pronounced peripheral and brain inflammation, elevated circulating LPS, microglial hyperactivation, increased ATP\/P2X7\u2010mediated neuroinflammation, excessive C1q\u2010mediated synaptic pruning, and mood\u2010related behavioral deficits. Chronic HFD additionally induced metabolic disturbances, oxidative stress, blood\u2013brain barrier disruption, and reduced neurogenesis. Combined HFD and LPS exposures further amplified brain pathologies and the severity of mood\u2010related deficits. P2X7R inhibitor effectively reduced oxidative stress, suppressed ATP\/P2X7\u2010mediated neuroinflammation, limited aberrant synaptic pruning, restored neurogenesis, and improved behaviors. Minocycline improved behavioral outcomes primarily by reducing endotoxemia and inflammation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The comparable neuroprotection produced by JNJ\u201055308942 and minocycline suggests that ATP\/P2X7\u2010mediated neuroinflammation plays a major role in regulating brain pathologies in HFD\u2010fed rats, followed by LPS challenge. These findings suggest P2X7 signaling as a promising therapeutic target for depression and inflammation\u2010associated neuropsychiatric disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/apha.70241","type":"journal-article","created":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T12:24:26Z","timestamp":1778415866000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Inhibiting Purinergic Receptor (\n                    <scp>P2X7R<\/scp>\n                    ) Alleviates Depression\u2010 and Anxiety\u2010Like Behaviors in Obese Rats With Immune Challenge"],"prefix":"10.1111","volume":"242","author":[{"given":"Titikorn","family":"Chunchai","sequence":"first","affiliation":[{"name":"Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine Chiang Mai University  Chiang Mai Thailand"},{"name":"Center of Excellence in Cardiac Electrophysiology Research 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