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Fluoxetine protects against IL-1β-induced neuronal apoptosis via downregulation of p53

Han Shan1, Yaqi Bian1, Zhaoma Shu1

  • 1Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, China.

Neuropharmacology
|March 16, 2016
PubMed

Insights

Fluoxetine, a selective serotonin reuptake inhibitor, protects brain cells from stroke-related damage by reducing inflammation and apoptosis through a p38-p53 pathway. This finding offers new therapeutic possibilities for neurological diseases like stroke.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Selective serotonin reuptake inhibitors (SSRIs) like fluoxetine show neuroprotective potential in neurological diseases, but the mechanisms are not fully understood.
  • Ischemia/reperfusion injury and neuroinflammation are key factors in acute neuronal damage during stroke.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying fluoxetine's neuroprotective effects against ischemia/reperfusion-induced injury and inflammation-induced apoptosis.
  • To investigate the role of the p38-p53 signaling pathway in fluoxetine's action.

Main Methods:

  • Transient middle cerebral artery occlusion (tMCAO) model in mice to induce ischemic stroke.
  • Primary cultured cortical neurons treated with interleukin-1β (IL-1β) to mimic neuroinflammation.
  • N2a cell line with p53 overexpression to assess the role of p53.
  • Western blotting to analyze protein expression (Bax, Bcl-2, p53).
  • Pharmacological manipulation using p38 inhibitors (SB203580) and activators (anisomycin).

Main Results:

  • Fluoxetine treatment significantly alleviated neurological deficits and neuronal apoptosis in the tMCAO model.
  • Fluoxetine inhibited IL-1β, Bax, and p53 expression while upregulating Bcl-2.
  • In vitro, fluoxetine prevented IL-1β-induced neuronal apoptosis and p53 upregulation.
  • p53 overexpression abolished fluoxetine's anti-apoptotic effect, confirming p53 downregulation's necessity.
  • Fluoxetine's effect on p53 was mediated via the p38 signaling pathway.

Conclusions:

  • Fluoxetine exerts neuroprotection against IL-1β-induced neuronal apoptosis through a p38-p53 dependent pathway.
  • These findings highlight fluoxetine's potential as a therapeutic agent for stroke and other neurological diseases involving neuroinflammation and apoptosis.
Keywords:
ApoptosisFluoxetineInterleukin-1βNeuroinflammationStrokep53

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