Loss of Melanopsin Photoreception and Antagonism of the Histamine H3 Receptor by Ciproxifan Inhibit Light-Induced Sleep in Mice

Light has direct effects on sleep and wakefulness causing arousal in diurnal animals and sleep in nocturnal animals. In the present study, we assessed the modulation of light-induced sleep by melanopsin and the histaminergic system by exposing mice to millisecond light flashes and continuous light respectively. First, we show that the induction of sleep by millisecond light flashes is dose dependent as a function of light flash number. We found that exposure to 60 flashes of light occurring once every 60 seconds for 1-h (120-ms of total light over an hour) induced a similar amount of sleep as a continuous bright light pulse. Secondly, the induction of sleep by millisecond light flashes was attenuated in the absence of melanopsin when animals were presented with flashes occurring every 60 seconds over a 3-h period beginning at ZT13. Lastly, the acute administration of a histamine H3 autoreceptor antagonist, ciproxifan, blocked the induction of sleep by a 1-h continuous light pulse during the dark period. Ciproxifan caused a decrease in NREMS delta power and an increase in theta activity during both sleep and wake periods respectively. The data suggest that some form of temporal integration occurs in response to millisecond light flashes, and that this process requires melanopsin photoreception. Furthermore, the pharmacological data suggest that the increase of histaminergic neurotransmission is sufficient to attenuate the light-induced sleep response during the dark period.Down Syndrome Research and Treatment FoundationResearch Down Syndrome Organizatio

Melanopsin required for millisecond light flash induced sleep early in the dark period.

<p>(A,B) Total sleep (NREMS +REMS) during flash stimulation delivered once every 60 seconds for 3 hours between ZT13-15 is shown in WT (n = 8) and MKO (n = 6) mice. Baseline period is shown by the black bars (NO FLASH) and the stimulation period is shown by the white bars (Flash ON). **p = 0.009, paired <i>t</i> test. (C,D) Hourly total sleep between ZT12-16 is shown for WT and MKO mice during baseline (top graph) and stimulation (bottom graph). During baseline, no effect of genotype was detected. However, an effect of time (*) was detected. During the flash stimulation (ZT13-15), two-way repeated measures ANOVA reveals an effect of genotype but no time effect. No interaction was detected (see text for details). *p < 0.05 by Bonferroni’s <i>post hoc t</i> test versus WT mice. Data are expressed as mean ± SD.</p

Effects of ciproxifan administration on light-induced sleep and cortical EEG early in the dark period.

<p>(A) An illustration of the protocol used to assess the effect of ciproxifan administration on light-induced sleep is shown. Twenty minutes before exposure no light or continuous light at ZT13, mice (n = 7) were administered with saline (SAL) or ciproxifan (CIP) (12mg/kg, i.p). The light exposure lasted one hour. (B) Total sleep in response to saline or ciproxifan during the no pulse (NP) condition and the light pulse (LP) condition is shown. *p<0.05; by Tukey’s <i>post hoc t</i> test after one-way repeated measures ANOVA. (C) Representative EEG and EMG traces are shown after saline and ciproxifan administration in the light condition. (D, E) Power in the 0.8–40 Hz range for artifact-free recordings was averaged, and the mean values plotted as previously described [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0128175#pone.0128175.ref003" target="_blank">3</a>]. (<i>Insets</i>) Delta/theta ratios during NREMS and wake were calculated and plotted. Data represent mean ± SD (n = 5). *p<0.05, **p<0.001 by paired <i>t</i> test.</p

Effects of ciproxifan administration on locomotor activity.

<p>(A) Representative actograms from mice exposed to light with saline or ciproxifan. Days are indicated on the left and time during the day is indicated on the top. Light period was between 0700–1900 hrs and the dark period was between 1900–0700 hrs. The asterisk (day 4) indicates the period when the light pulse was given (2000–2100 hrs) after saline or ciproxifan administration 20 min before the pulse. (B) Quantification of locomotor activity (total count between 2000–2100 hrs) during no light pulse (black bars) and light pulse condition (white bars) after saline and ciproxifan administration is shown. Note that baseline refers to no light pulse or administration of either saline or ciproxifan. Data represent mean ± SD (n = 3–7). *p<0.05 by Tukey’s <i>post hoc t</i> test after one-way ANOVA for saline and ciproxifan treatments.</p

Sleep induction in response to different number of light flashes.

<p>(A) Wildtype mice (n = 8) received equally distributed light flashes (0, 1, 3, 15 and 60) across a 60 minute period beginning at ZT13. (B) Total sleep (NREMS+REMS), (C) NREMS, and (D) REMS are shown. *p < 0.05, **p < 0.01 ****p < 0.0001; versus baseline (0 pulses) by one-way repeated measures ANOVA followed by Bonferroni's <i>post-hoc</i> test. The continuous pulse data (white bar) are from Muindi et al. (2013). Data expressed as mean ± SD.</p

Functional health and white matter hyperintensities as effect modifiers of blood pressure-lowering on cognitive function and vascular events in older Secondary Prevention of Small Subcortical Strokes trial participants.

OBJECTIVE To determine whether cerebral small vessel disease or disability modify the effect of SBP treatment on cognitive and vascular outcomes in older patients with recent lacunar stroke. METHODS Participants aged at least 65 years of the Secondary Prevention of Small Subcortical Strokes Trial were randomized to a higher (130-149 mmHg) or lower (<130 mmHg) SBP target. The primary outcome was change in cognitive function (Cognitive Abilities Screening Instrument); secondary outcomes were incident mild cognitive impairment, stroke, major vascular events (all-stroke, myocardial infarction), and all-cause death. Results were stratified by severity of white matter hyperintensities (WMH; none/mild, moderate, severe) on baseline MRI, and by disability (no vs. at least one limitation in activities of daily living). RESULTS One thousand, two hundred and sixty-three participants (mean age 73.8 ± 5.9 years, 40% women) were included. Participants with severe WMH or disability had worse cognitive function at baseline and after a mean follow-up of 3.9 years. No significant interactions existed between treatment group and effect modifiers (WMH, disability) for change in cognitive function (P for interaction 0.42 and 0.66, respectively). A lower SBP target appeared more beneficial among those with worse WMH burden for vascular outcomes (P for interaction = 0.01 for stroke and 0.03 for major vascular events). CONCLUSION There was no difference in the effect of lowering SBP to less than 130 mmHg on cognitive function by cerebral small vessel disease or disability among older adults with a history of lacunar stroke. Those with evidence of small vessel disease may derive greater benefit from lower SBP on prevention of subsequent vascular events. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT00059306

Clinical Risk Factors For Kidney Tubule Biomarker Abnormalities Among Hypertensive Adults With Reduced eGFR in the SPRINT Trial.

BACKGROUND: Urine biomarkers of kidney tubule health may distinguish aspects of kidney damage that cannot be captured by current glomerular measures. Associations of clinical risk factors with specific kidney tubule biomarkers have not been evaluated in detail. METHODS: We performed a cross-sectional study in the Systolic Blood Pressure Intervention Trial among 2,436 participants with a baseline estimated glomerular filtration rate (eGFR) &lt;60 ml/min/1.73 m2. Associations between demographic and clinical characteristics with urine biomarkers of kidney tubule health were evaluated using simultaneous multivariable linear regression of selected variables. RESULTS: Each standard deviation higher age (9 years) was associated with 13% higher levels of chitinase-3-like protein-1 (YKL-40), indicating higher levels of tubulointerstitial inflammation and repair. Men had 31% higher levels of alpha-1 microglobulin and 16% higher levels of beta-2 microglobulin, reflecting worse tubule resorptive function. Black race was associated with significantly higher levels of neutrophil gelatinase-associated lipocalin (12%) and lower kidney injury molecule-1 (26%) and uromodulin (22%). Each standard deviation (SD) higher systolic blood pressure (SBP) (16 mmHg) was associated with 10% higher beta-2 microglobulin and 10% higher alpha-1 microglobulin, reflecting lower tubule resorptive function. CONCLUSIONS: Clinical and demographic characteristics, such as race, sex, and elevated SBP, are associated with unique profiles of tubular damage, which could reflect under-recognized patterns of kidney tubule disease among persons with decreased eGFR

Cerebral White Matter Hyperintensities, Kidney Function Decline, and Recurrent Stroke After Intensive Blood Pressure Lowering: Results From the Secondary Prevention of Small Subcortical Strokes ( SPS 3) Trial.

Background We aimed to determine whether cerebral white matter hyperintensities ( WMHs ) can distinguish stroke survivors susceptible to rapid kidney function decline from intensive blood pressure ( BP ) lowering. Methods and Results The SPS3 (Secondary Prevention of Small Subcortical Strokes) trial randomized participants with recent lacunar stroke to systolic BP targets of 130 to 149 and &lt;130 mm Hg. We included 2454 participants with WMH measured by clinical magnetic resonance imaging at baseline and serum creatinine measured during follow-up. We tested interactions between BP target and WMH burden on the incidence of rapid kidney function decline (≥30% decrease from baseline estimated glomerular filtration rate at 1-year follow-up) and recurrent stroke. Rapid kidney function decline incidence was 11.0% in the lower- BP -target arm and 8.1% in the higher-target arm (odds ratio=1.40; 95% CI=1.07-1.84). Odds ratio for rapid kidney function decline between lower- and higher-target groups ranged from 1.26 in the lowest WMH tertile (95% CI , 0.80-1.98) to 1.71 in the highest tertile (95% CI , 1.05-2.80; P for interaction=0.65). Overall incidence of recurrent stroke was 7.9% in the lower-target arm and 9.6% in the higher-target arm (hazard ratio=0.80; 95% CI , 0.63-1.03). Hazard ratio for recurrent stroke in the lower-target group was 1.13 (95% CI , 0.73-1.75) within the lowest WMH tertile compared with 0.73 (95% CI , 0.49-1.09) within the highest WMH tertile ( P for interaction=0.04). Conclusions Participants with higher WMH burden appeared to experience greater benefit from intensive BP lowering in prevention of recurrent stroke. By contrast, intensive BP lowering increased the odds of kidney function decline, but WMH burden did not significantly distinguish this risk. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00059306