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TNF-NF-kappaB signaling mediates excessive somnolence in hemiparkinsonian rats

Chin-Yu Lu1, Pei-Lu Yi, Chon-Haw Tsai

  • 1Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan.

Behavioural Brain Research
|January 2, 2010
PubMed

Insights

Excessive daytime sleepiness in Parkinson's disease (PD) may involve microglial activation. Tumor necrosis factor-alpha (TNF-alpha), not IL-1beta, increased and mediated sleep changes via the TNF-NF-kappaB pathway in a rat model.

Area of Science:

  • Neuroscience
  • Immunology
  • Sleep Medicine

Background:

  • Daytime somnolence is a prevalent symptom in Parkinson's disease (PD).
  • The underlying cellular mechanisms, particularly the role of neuroinflammation, remain poorly understood.
  • Microglial activation and pro-inflammatory cytokines are implicated in PD pathogenesis and may influence sleep regulation.

Purpose of the Study:

  • To investigate the role of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in mediating daytime somnolence in a rat model of Parkinson's disease.
  • To explore the involvement of the TNF-NF-kappaB signaling pathway in sleep alterations associated with Parkinson's disease.

Main Methods:

  • Induction of hemiparkinsonism in rats using the proteasome inhibitor MG-132.
  • Assessment of microglial activation, dopaminergic neuron loss, and cytokine expression (TNF-alpha, IL-1beta) in the midbrain and hypothalamus.
  • Monitoring of sleep patterns, specifically slow-wave sleep (SWS) and rapid eye movement (REM) sleep.
  • Pharmacological interventions using TNF receptor fragment (TNFRF), IL-1 receptor antagonist (IL-1ra), and an NF-kappaB inhibitor.

Main Results:

  • MG-132 induced microglial activation and dopaminergic neuron loss, consistent with Parkinson's disease pathology.
  • Expression of TNF-alpha, but not IL-1beta, was elevated in the midbrain and hypothalamus.
  • Hemiparkinsonian rats exhibited increased SWS, while REM sleep remained largely unchanged.
  • Administration of TNFRF reversed the SWS alterations, whereas IL-1ra had no effect.
  • Increased nuclear translocation of NF-kappaB was observed, and NF-kappaB inhibition blocked the SWS enhancement.

Conclusions:

  • The TNF-alpha, not IL-1beta, plays a critical role in mediating sleep alterations, specifically increased SWS, in the MG-132-induced hemiparkinsonian rat model.
  • The TNF-NF-kappaB signaling cascade is a key mediator of these sleep disturbances.
  • Targeting the TNF-NF-kappaB pathway presents a potential therapeutic strategy for managing excessive daytime somnolence in Parkinson's disease patients.

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