title: Interleukin-1beta mediates sleep alteration in rats with rotenone-induced parkinsonism.
abstract: OBJECTIVE
  Recently, the pathogenesis of Parkinson disease (PD) has been focused on microglial activation, especially the subsequent increase of cytokines. A body of clinical evidence suggests that sleep is altered in patients with PD; however, there is a lack of understanding of the basic cellular mechanism. This study was designed to elucidate the influence of brain interleukin (IL)-1beta on sleep changes, in addition to the dopaminergic and gamma-aminobutyric acid (GABA)-ergic systems, in an animal PD model.
  
  
  METHODS
  We employed a long-term subcutaneous infusion of rotenone, a mitochondrial complex-I inhibitor, to induce a parkinsonism-like model in rats. Behavioral tests and tyrosine hydroxylase immunocytochemistry were used for confirmation of PD in this animal model. Pharmacologic agonist and antagonists were administered centrally to test the involvement of dopamine, GABA, and IL-1 in rotenone-induced sleep alteration. Protein expression of cytokines, ie, IL-1beta and tumor necrosis factor alpha (TNF-alpha), in 5 distinct brain regions was also determined by Western blot and enzyme-linked immunosorbent assay (ELISA).
  
  
  METHODS
  Sleep-recording equipment in the National Taiwan University and China Medical University. PARTICIPANT AND INTERVENTIONS: Male Sprague-Dawley rats were implanted with electroencephalogram electrodes, a thermistor, and an intracerebroventricular guide cannula. Chronic infusion of rotenone was given by an Alzet minipump implanted subcutaneously on the back of each rat.
  
  
  RESULTS
  We found that locomotion activity was reduced, slow-wave sleep (SWS) was increased during the dark (active) phase and decreased during the light (rest) period, and rapid eye movement sleep (REM) was enhanced in the dark period after rotenone treatment. This rotenone PD animal model successfully causes loss of tyrosine hydroxylase-immunopositive neurons in the substantia nigra; induces the events of sleep disturbance, such as excessive daytime sleepiness and insomnia during the nighttime, that are seen in patients with PD; and suppresses locomotion. Our results that intracerebroventricular administration of dopamine and blockade of GABA in the brain have less significant effect on rotenone-induced sleep alteration suggest that the sleep disturbance is not primarily mediated by the disruption of dopaminergic and GABAergic systems in the current PD rat model. The expression of TNF-alpha was not altered by rotenone. However, the results of enhanced expression of IL-1beta in the hypothalamus after rotenone and that of the blockade of sleep alteration, but not the locomotion activity, by intracerebroventricular administration of an IL-1 receptor antagonist implies that increased IL-1beta in the hypothalamus mediates sleep alteration, but not the locomotion, in rats with rotenone-induced parkinsonism.
  
  
  CONCLUSIONS
  These observations suggest that rotenone-induced sleep-wake alteration is dominated by central increase of somnogenic IL-1.
authors.affiliation: Department of Nursing, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan.
authors.forename: Pei-Lu
authors.initials: PL
authors.lastname: Yi
authors.forename: Chon-Haw
authors.initials: CH
authors.lastname: Tsai
authors.forename: Ming-Kuei
authors.initials: MK
authors.lastname: Lu
authors.forename: Hsu-Jan
authors.initials: HJ
authors.lastname: Liu
authors.forename: Ya-Chu
authors.initials: YC
authors.lastname: Chen
authors.forename: Fang-Chia
authors.initials: FC
authors.lastname: Chang
mesh_terms: D000818:Animals; D001143:Arousal / Q000502:physiology; D001921:Brain / Q000503:physiopathology; D001931:Brain Mapping; D004298:Dopamine / Q000378:metabolism; D053583:Interleukin-1beta / Q000502:physiology*; D008297:Male; D009043:Motor Activity / Q000502:physiology; D009048:Motor Skills / Q000502:physiology; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012894:Sleep Stages / Q000502:physiology*; D012895:Sleep, REM / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014851:Wakefulness / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D005680:gamma-Aminobutyric Acid; D004298:Dopamine