| Narcolepsy is a disabling, incurable sleep disorder that affects 0.2–1.6 per thousand in European countries, Japan and the US. Its daytime excessive somnolence is currently treated with CNS stimulants such as modafinil. But the adverse reactions of CNS stimulants limit their usage in controlling narcolepsy. Neuroanatomical, neurochemical and neuropharmacological evidence support a role for histamine in the control of the sleep/wake cycle. Histamine H3 receptor antagonists are getting attention in the treatment of narcolepsy for the fact that H3 receptor antagonists can induce wakefulness. Ciproxifan is a new, highly potent, selective and brain-penetrating and orally active H3 receptor antagonist, designed in 1996. In this research, we monitored extracellular histamine level in the frontal cortex by in vivo microdialysis coupled with electroencephalogram (EEG) and electromyogram (EMG) recordings in freely moving rats. We observed the effect of ciproxifan on sleep-wake cycle in wild-type (WT) and H1 receptor gene knockout (H1RKO) mice by EEG/EMG recordings in WT and H1RKO mice. By using microdialysis and high performance liquid chromatography (HPLC), we observed the effect of ciproxifan on histamine release from the frontal cortex of WT and H1RKO mice. We also observed the effect of ciproxifan on the histidine decarboxylase (HDC) activity in the hypothalamus, thalamus and cortex, and on the histamine content in the hypothalamus, thalamus, cortex, striatum, hippocampus, midbrain and medulla oblongata of WT mice. Results:Part 1: Correlation extracellular histamine level in the frontal cortex with the amount of wakefulness in rats.The average histamine release during night period (0.19±0.01pmol/20 min, n=34) was 3.8 times as high as that during day period (0.05 ±0.002 pmol/20 min, n=38, P < 0.01), being positively correlated (r=0.845) with the time spent in wakefulness by regression analysis. During day period (8:00-20:00), the total histamine release was 2.93±0.11 pmol/12 hr and the time spent in wakefulness was 239±11.16 min/12 hr. During night period (20:00-8:00), the total histamine release was 6.71±0.92 pmol/12 hr and the time spent in wakefulness was 485.79±20.95 min/12 hr. Part 2: Effect and mechanism of ciproxifan on sleep-wake cycle in WT and H1R KO mice. At the first and the second hour after ciproxifan administration at 3 mg/kg i.p.( ciproxifan i.p. at 8 a.m. on the second experimental day ), ciproxifan rapidly increased the wake time by 50% and 81%, respectively, and the arousal effect was maintained for nearly 3 hr, when the wakefulness was compared with that of the baseline day (saline 0.1ml/10g i.p. at 8 a.m. on the first experimental day). This enhancement of wakefulness was concomitant with decreases in non-rapid movement (NREM) and rapid movement (REM) sleep. The total amounts of wakefulness within the first 2 hr after ciproxifan administration at 0.3, 1 and 3 mg/kg were 1.4-, 1.6- and 2-fold of baseline day, respectively.No statistical difference by paired t test was observed in H1RKO mice in the amounts of wakefulness per hour between baseline day and ciproxifan given at 3 mg/kg i.p.. Part 3: Effect of ciproxifan on histamine release from the frontal cortex of WT and H1RKO mice.Within 4 hr after ciproxifan administration at 0.3, 1 and 3 mg/kg, ciproxifan increased histamine release from the frontal cortex of WT mice, the maximum level being 1.7-, 1.9- and 2.6-fold of the baseline level respectively. And the total amounts of histamine release within 2 hr are 2.1-, 2.5- and 2.7-fold of the vehicle level respectively.Within 4 hr after ciproxifan administration at 0.3, 1 and 3 mg/kg, ciproxifan increased histamine release from the frontal cortex of H1RKO mice, the maximum level being 1.7-, 2.3- and 3.2-fold of the baseline level, respectively. Total amounts of histamine release within 2 hr after ciproxifan administration at 1 and 3 mg/kg are 2.3- and 3.3-fold of the vehicle level respectively.Part 4: Effect of ciproxifan on the HDC activity and the histamine content in sev... |
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