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Mouse Footpad Inoculation Model to Study Viral-Induced Neuroinflammatory Responses
Published on: June 14, 2020
Basic Science and Pathogenesis
Titikorn Chunchai1,2, Hiranya Pintana1,2, Patcharapong Pantiya1,2
1Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
Background:
Chronic high-fat diet (HFD) consumption and lipopolysaccharide (LPS) injection prime microglia, enhance inflammatory responses, decrease neurogenesis, resulting in depressive-like behavior. It has been reported that LPS stimulates adenosine triphosphate production from immune cells and dead cells, activating microglia via the purinergic receptor P2X7. However, the effects of P2X7 inhibitors on body weight, visceral fat, spleen weight, neurogenesis, and depressive-like behavior in obese and lean rats under immune challenge remain unclear.
Method:
Thirty-six male Wistar rats were fed either a normal diet (ND) or HFD (59.28% energy from fat) for 12 weeks. Each group was divided into three subgroups receiving either normal saline solution, minocycline (45 mg/kg, two doses, every 12 hours, intraperitoneal (i.p.) injection), or P2X7 inhibitor (JNJ-55308942, 30 mg/kg, a single dose, orally). To induce immune challenge, all rats received LPS (500 µg/kg, a single dose, i.p.) after their assigned tretments for an hour. Depressive-like behavior was assessed 24 hours after immune challenge, followed by euthanasia.
Result:
All HFD-fed rats equally increased body and visceral fat weights (p <0.05, Figure 1A-B). Spleen weight decreased in ND-fed rats treated with minocycline, when compared to ND-fed rats treated with vehicle, suggesting suppression of inflammatory responses by minocycline in lean rats. In addition, HFD-fed rats receiving vehicle also increased spleen weight, which was decreased by both treatments, indicating the anti-inflammatory effect of both treatments in obese rats receiving an immune challenge (p <0.05, Figure 1C). Moreover, SOX2-positive cells in the subgranular zone of the dentate gyrus was reduced in HFD-fed rats treated with vehicle, suggesting a decrease in neurogenesis. Interestingly, the number of neurogenesis was restored in HFD-fed rats treated with minocycline or a P2X7 inhibitor (p <0.05, Figure 1D). In addition, the number and latency of freezing time in the forced swim test increased in HFD-fed rats treated with vehicle, which were attenuated in HFD-fed rats treated with minocycline or P2X7 inhibitor (p <0.05, Figure 1E-F).
Conclusion:
In addition, HFD-fed rats receiving vehicle also increased spleen weight, which were decreased by both treatments, indicating anti-inflammatory effect of both treatments in obese rats receiving immune challenge (p <0.05, Figure 1C).
Insights
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.
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.
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