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Titikorn Chunchai1,2, Hiranya Pintana1,2, Patcharapong Pantiya1,2

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Chronic high-fat diet and LPS induce depressive-like behavior by impairing neurogenesis. P2X7 inhibitors and minocycline restored neurogenesis and attenuated depressive behaviors in obese rats, suggesting therapeutic potential.

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Area of Science:

  • Neuroscience
  • Immunology
  • Metabolism

Background:

  • Chronic high-fat diet (HFD) and lipopolysaccharide (LPS) administration promote neuroinflammation and depressive-like behaviors.
  • Microglia activation via purinergic receptor P2X7 is implicated in LPS-induced inflammation and ATP production.
  • The impact of P2X7 inhibitors on neurogenesis and behavior in diet-induced obesity under immune challenge is not well understood.

Purpose of the Study:

  • To investigate the effects of P2X7 inhibition on body weight, visceral fat, spleen weight, neurogenesis, and depressive-like behavior.
  • To evaluate the therapeutic potential of P2X7 inhibitors in obese rats challenged with LPS.

Main Methods:

  • Wistar rats were fed a normal diet (ND) or HFD for 12 weeks.
  • Rats received saline, minocycline, or a P2X7 inhibitor (JNJ-55308942) before LPS injection.
  • Depressive-like behavior was assessed using the forced swim test, and neurogenesis was evaluated in the dentate gyrus.

Main Results:

  • HFD increased body and visceral fat weight. Both minocycline and P2X7 inhibitor reduced spleen weight in HFD-fed rats, indicating anti-inflammatory effects.
  • Neurogenesis, assessed by SOX2-positive cells, was reduced in HFD-fed rats but restored by minocycline or P2X7 inhibitor.
  • Depressive-like behaviors, indicated by increased freezing time and latency, were attenuated by both treatments in HFD-fed rats.

Conclusions:

  • P2X7 inhibition and minocycline demonstrate anti-inflammatory effects in obese rats subjected to immune challenge.
  • Both treatments effectively restored neurogenesis and ameliorated depressive-like behaviors in HFD-fed rats.
  • Targeting P2X7 offers a potential therapeutic strategy for diet-induced obesity-related depression.