PubMed Health⌕ Search

Biomedical subjects

Nobuhiro Fujiki

Publications and source records attributed to Nobuhiro Fujiki.

15 recordsLinked to original sources
PubMed2007

Neuropeptides as possible targets in sleep disorders.

Insomnia and hypersomnia are frequent sleep disorders, and they are most often treated pharmacologically with hypnotics and wake-promoting compounds. These compounds act on classical neurotransmitter systems, such as benzodiazepines on GABA-A receptors, and amfetamine-like stimulants on monoaminergic terminals to modulate neurotransmission. In addition, acetylcholine, amino acids, lipids and proteins (cytokines) and peptides, are known to significantly modulate sleep and are, therefore, possibly involved in the pathophysiology of some sleep disorders. Due to the recent developments of molecular biological techniques, many neuropeptides have been newly identified, and some are found to significantly modulate sleep. It was also discovered that the impairment of the hypocretin/orexin neurotransmission (a recently isolated hypothalamic neuropeptide system) is the major pathophysiology of narcolepsy, and hypocretin replacement therapy is anticipated to treat the disease in humans. In this article, the authors briefly review the history of neuropeptide research, followed by the sleep modulatory effects of various neuropeptides. Finally, general strategies for the pharmacological therapeutics targeting the peptidergic systems for sleep disorders are discussed.

Animals↗
PubMed2006

Sex difference in body weight gain and leptin signaling in hypocretin/orexin deficient mouse models.

Recent studies in human and animal models of narcolepsy have suggested that obesity in narcolepsy may be due to deficiency of hypocretin signaling, and is also under the influence of environmental factors and the genetic background. In the current study, using two hypocretin/orexin deficient narcoleptic mouse models (i.e. preproorexin knockout (KO) and orexin/ataxin-3 transgenic (TG) mice) with cross-sectional assessments, we have further analyzed factors affecting obesity. We found that both KO and TG narcoleptic mice with mixed genetic backgrounds (N4-5, 93.75-96.88% genetic composition of C57BL/6) tended to be heavier than wild type (WT) mice of 100-200 days old. The body weight of heterozygous mice was intermediate between those of KO and WT mice. Obesity was more prominent in females in both KO and TG narcoleptic mice and was associated with higher serum leptin levels, suggesting a partial leptin resistance. Obesity is less prominent in the congenic TG narcoleptic mice, but is still evident in females. Our results confirmed that hypocretin/orexin ligand deficiency is one of the critical factors for the obese tendency in narcolepsy. However, multiple factors are also likely to affect this phenotype, and a sex difference specific alteration of leptin-hypocretin signaling may be involved.

Animals↗
PubMed2005

Change in intrathoracic pressure in rats with spontaneous and controlled ventilation during microgravity by parabolic flight.

We previously reported that the intrathoracic pressure (ITP) decreases and the transmural pressure of the aortic wall (TMP) increases during 4.5 s of microgravity (muG) induced by free drop. To examine the ITP response to a longer period of muG in the absence of the respiratory rate (RR) decrease, i.e., bradypnea, which occurs at the onset of muG, we measured the aortic blood pressure at the diaphragma level (AP) and ITP. We then calculated the TMP at the aortic arch level during 20 s of muG induced by parabolic flight in anesthetized rats (n = 7) with either spontaneous ventilation (SPN-V) or controlled ventilation (CONT-V). In the SPN-V group, the bradypnea was observed in all rats after the onset of the muG (RR change -13.9 +/- 2.9/min). The ITP during muG (-9.3 +/- 0.9 mmHg) was significantly lower than that during 1 G (-7.7 +/- 0.9 mmHg), and the TMP was significantly increased during muG (112 +/- 6 mmHg) compared to 1 G (103 +/- 5 mmHg). Similar changes in ITP and TMP were observed in the CONT-V group: During muG and 1G, respectively, the ITP was -8.4 +/- 0.6 mmHg and -5.9 +/- 0.7 mmHg, and the TMP was 112 +/- 6 mmHg and 101 +/- 6 mmHg, whereas no change in RR was observed because of the controlled ventilation. These results show that the ITP decreases and the TMP increases during muG, and they are not affected by a disturbance of respiratory rhythm.

Anesthesia↗
PubMed2004

Sequence of forebrain activation induced by intraventricular injection of hypertonic NaCl detected by Mn2+ contrasted T1-weighted MRI.

In order to define the sequence of forebrain activation involved in osmoregulation, central activation in response to intracerebroventricular injection of NaCl solution (10 microl of 0.15, 0.5, or 1.5 M) was detected using manganese-contrasted magnetic resonance imaging (MRI) in anesthetized rats. Changes in renal sympathetic nerve activity (RNA) were also measured, and the time courses of forebrain activation and RNA changes compared. NaCl injection resulted in rapid activation of the subfornical organ (SFO), organum vasculosum lamina terminalis (OVLT), and periventricular regions and the lateral hypothalamic area (LHA), then of the paraventricular hypothalamic nucleus (PVN) and supraoptic nucleus (SON). The delay in activation in the PVN and SON showed a wide variation from 0 to 5.78 min, and the average delay in the PVN (2.88+/-0.34 min) and SON (2.90+/-0.39 min) was significantly greater than that in the SFO (0.40+/-0.10 min) and OVLT (0.74+/-0.13 min). NaCl (1.5 M) injection elicited a rapid, large increase in RNA, which consisted of two components, an early rapid increase at 99 s after injection (160+/-27%) and a slower increase at 9 min after injection (209+/-34%). These results suggest that the PVN and SON are activated not only by the afferent input from the SFO and OVLT but also by diffusion of the hypertonic stimulus to these regions and probably by their intrinsic osmosensitivity. The PVN might be responsible for the second slower component of the RNA response, but cannot be responsible for the first component.

Animals↗
PubMed2004

Acute hemodynamic responses in the head during microgravity induced by free drop in anesthetized rats.

To examine acute hemodynamic responses to microgravity (microG) in the head, we measured carotid artery pressure (CAP) and jugular vein pressure (JVP) to calculate cephalic perfusion pressure (CPP = CAP - JVP) and recorded images of microvessels in the iris to evaluate capillary blood flow velocity (CBFV) and capillary diameter (CD) in anesthetized rats during 4.5 s of microG induced by free drop. Rats were placed in 30 degrees head-up whole body-tilted (HU, n = 7) or horizontal (flat, n = 6) position. In the flat group, none of the measured variables was significantly affected by microG, whereas in the HU group, CAP, JVP, and CPP increased, respectively, by 23.4 +/- 2.6, 1.3 +/- 0.2, and 22.9 +/- 3.1 mmHg, and CBFV and CD increased, respectively, by 33 +/- 8 and 9 +/- 3%, showing an increase in capillary blood flow. To further examine the mechanisms underlying these CAP and JVP increases, another experiment was performed in which CAP and JVP were measured in anesthetized rats (n = 6) during a postural change from HU to flat. In these animals, the change in JVP was similar to that observed during actual microG, but no change in CAP was seen, indicating that the JVP increase during actual microG is caused by disappearance of the gravitational pressure gradient in the head-to-foot axis, whereas the CAP increase is not. In conclusion, actual microG elicits an increase in CPP due to a greater increase in CAP than JVP, resulting in increased capillary blood flow. Although the increase in JVP is explained by the disappearance of gravitational pressure gradient in the head-to-foot axis as a result of microG, the larger increase in CAP is not.

Anesthesia↗
PubMed2004

The roles of midbrain and diencephalic dopamine cell groups in the regulation of cataplexy in narcoleptic Dobermans.

Cataplexy, an emotion-triggered sudden loss of muscle tone specific to narcolepsy, is tightly associated with hypocretin deficiency. Using hypocretin receptor 2 gene (hcrtr 2)-mutated narcoleptic Dobermans, we have previously demonstrated that altered dopamine (DA) D(2/3) receptor mechanisms in mesencephalic DA nuclei are important for the induction of cataplexy. In the current study, we also found that the administration of D(2/3) agonists into diencephalic dopaminergic cell groups, including the area dorsal to the ventral tegmental area (DRVTA) and the periventricular gray (PVG) matter of the caudal thalamus (corresponding to area A11), significantly aggravated cataplexy in hcrtr 2-mutated narcoleptic Dobermans. A D(1) agonist and antagonist and a DA uptake inhibitor perfused into the DRVTA had no effect on cataplexy, suggesting an involvement of D(2/3) receptors located on DA cell bodies (i.e., autoreceptors) for the regulation of cataplexy. Because the A11 cell group projects to the spinal ventral horn, the A11 D(2/3) receptive mechanisms may directly modulate the activity of spinal motoneurons and modulate cataplexy.

Animals↗
PubMed2003

Effects of IV and ICV hypocretin-1 (orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin-ligand-deficient narcoleptic dog.

STUDY OBJECTIVES: Using two different canine models of narcolepsy, we evaluated the therapeutic effects of hypocretin-1 on cataplexy and sleep. MEASUREMENTS AND RESULTS: Intracerebroventricular administration of hypocretin-1 (10 and 30 nmol per dog) but not intravenous administration (up to 6 microg/kg) induced significant wakefulness in control dogs. However, hypocretin-1 had no effect on cataplexy or wakefulness in hypocretin receptor-2 gene (Hcrtr2) mutated narcoleptic Dobermans. Only very high intravenously doses of hypocretin-1 (96-384 microg/kg) penetrated the brain, to produce a short-lasting anticataplectic effect in a hypocretin-ligand-deficient animal. CONCLUSIONS: Hypocretin-1 administration, by central and systemic routes, does not improve narcoleptic symptoms in Hcrtr2 mutated Dobermans. Systemic hypocretin-1 hardly crosses the blood-brain barrier to produce therapeutic effects. The development of more centrally penetrable and longer lasting hypocretin analogs will be needed to further explore this therapeutic pathway in humans.

Animals↗
PubMed2003

Roles of baroreflex and vestibulosympathetic reflex in controlling arterial blood pressure during gravitational stress in conscious rats.

Gravity acts on the circulatory system to decrease arterial blood pressure (AP) by causing blood redistribution and reduced venous return. To evaluate roles of the baroreflex and vestibulosympathetic reflex (VSR) in maintaining AP during gravitational stress, we measured AP, heart rate (HR), and renal sympathetic nerve activity (RSNA) in four groups of conscious rats, which were either intact or had vestibular lesions (VL), sinoaortic denervation (SAD), or VL plus SAD (VL + SAD). The rats were exposed to 3 G in dorsoventral axis by centrifugation for 3 min. In rats in which neither reflex was functional (VL + SAD group), RSNA did not change, but the AP showed a significant decrease (-8 +/- 1 mmHg vs. baseline). In rats with a functional baroreflex, but no VSR (VL group), the AP did not change and there was a slight increase in RSNA (25 +/- 10% vs. baseline). In rats with a functional VSR, but no baroreflex (SAD group), marked increases in both AP and RSNA were observed (AP 31 +/- 6 mmHg and RSNA 87 +/- 10% vs. baseline), showing that the VSR causes an increase in AP in response to gravitational stress; these marked increases were significantly attenuated by the baroreflex in the intact group (AP 9 +/- 2 mmHg and RSNA 38 +/- 7% vs. baseline). In conclusion, AP is controlled by the combination of the baroreflex and VSR. The VSR elicits a huge pressor response during gravitational stress, preventing hypotension due to blood redistribution. In intact rats, this AP increase is compensated by the baroreflex, resulting in only a slight increase in AP.

Animals↗
PubMed2003

Differential kinetics of hypocretins in the cerebrospinal fluid after intracerebroventricular administration in rats.

Different potencies for hypocretin-1 and -2 in sleep-wake regulation and feeding after intracerebroventricular (ICV) administration have been reported. These differences were often explained by the selectivity of the two hypocretins for hypocretin receptor-1 and -2, but little attention has been paid to kinetics of hypocretin peptides. We investigated the kinetics of the ICV hypocretin-1 and -2 in rats. ICV hypocretin-1 (10 nmol) increased hypocretin-1 peptide level in the CSF by 800-fold from baseline with the elevation lasting over 4 h. In contrast, after ICV hypocretin-2 (10 nmol), no significant rise in the CSF was found. CSF hypocretin levels were significantly correlated with the biological activities of CSF hypocretin-1 and -2 using the Ca(2+) mobilization assay. Difference in the kinetics of hypocretins should be considered for interpreting ICV effects of hypocretins.

Animals↗
PubMed2003

Relationship between transmural pressure and aortic diameter during free drop-induced microgravity in anesthetized rats.

To test the hypothesis that the aortic wall is stretched without increasing aortic pressure (AP) during microgravity (microG), the AP, intrathoracic pressure (ITP), and aortic diameter (AD) were measured in anesthetized Sprague-Dawley rats during 4.5 s of microG produced by freefall. A smooth and immediate reduction in gravity (G) occurred during freefall, microG being achieved 100 ms after the start of the drop. Acute microG elicited an immediate increase in AD, which was not accompanied by an increase in AP. However, the ITP decreased during microG resulted in an increase in the calculated transmural pressure (TP = AP-ITP) of the aortic wall. A simple linear regression analysis showed that the slopes of the plot of AP vs. AD differed at 1 G and microG, whereas those for the plot of TP vs. AD did not. Thus, the increase in AD during microG was accounted for by the increase in TP. These results suggest that a decrease in ITP, resulting in an increase in TP of the aorta, is a key issue in understanding cardiovascular responses to microG.

Anesthesia↗
PubMed2003

Cerebral circulation during acute microgravity induced by free drop in anesthetized rats.

To evaluate changes in the cerebral circulation during acute microgravity (microG), we measured intracranial pressure (ICP), aortic pressure at the diaphragm level, and cerebral flow velocity (CFV) in anesthetized rats (n = 5) during 4.5 s of microG induced by free drop, then calculated arterial pressure at the eye level (AP(eye)) and cerebral perfusion pressure (CPP = AP(eye)-ICP), and estimated CPP-CFV relationship. The rats were placed in the flat and the 30 degrees head-up positions. In the head-up position, ICP, AP(eye), and CPP were significantly increased by 2.2 +/- 0.4, 12.3 +/- 2.0, and 10.1 +/- 1.7 mmHg respectively during microG, whereas the CFV did not change significantly. In the flat position, none of these variables were significantly affected by microG. The slope of the CPP-CFV relationship was decreased only in the head-up position, suggesting that the cerebrovascular resistance was increased by microG. These findings indicate that the change in gravitational (hydrostatic) pressure is a key factor in understanding the changes in cerebral circulation during acute microG.

Animals↗
PubMed2003

Cerebral hemodynamics during microgravity.

As one of the causes of the space adaptation syndrome, an increased intracranial pressure due to the cephalad fluid shift is suggested. In the present study, we measured intracranial pressure (ICP), aortic pressure and cerebral flow velocity (CFV) in anesthetized rats (n=5) during 4.5 sec of microgravity induced by free drop. The rats were set at horizontal prone (Flat) and 30-degree head-up whole body tilting (HU) positions to examine the effect of gravitational pressure gradient. Then, arterial pressure at the eye level (APeye), cerebral perfusion pressure (CPP; CPP=APeye-ICP), and CPP-CFV relationship was calculated. In HU position, ICP, APeye, and CPP increased by 2.2 +/- 0.4, 12.3 +/- 2.0, and 10.1 +/- 1.7 mmHg respectively. However, CFV did not change significantly. In Flat position, none of these variables did not change significantly. In HU position the slope of CPP-CFV relationship decreased, suggesting the increased cerebral flow resistance. However, it did not change in Flat position. These results can be understood by the disappearance of gravitational pressure gradient by microgravity and the cerebral autoregulation.

Animals↗
PubMed2002

Detection of hypothalamic activation by manganese ion contrasted T(1)-weighted magnetic resonance imaging in rats.

To examine the usefulness of Mn(2+) contrasted magnetic resonance imaging (MRI) in hypothalamic imaging, images obtained using T(1)-weighted MRI were compared with Fos expression, which is known to increase after activation of voltage-dependent Ca(2+) channels. Intravenous infusion of MnCl(2) elicited a rapid increase in the T(1)-weighted MRI signal intensity in the vessels and ventricles, but not in the brain parenchyma, suggesting that Mn(2+) did not diffuse freely across the blood-brain barrier. When the blood-brain barrier was broken by right intracarotid arterial injection of 25% D-mannitol, an increased signal intensity was seen in the right brain. Intracarotid arterial injection of hypertonic NaCl elicited rapid and striking increases in signal intensity in the paraventricular hypothalamic nucleus, supraoptic nucleus, and preoptic area, which are thought to be involved in central osmotic regulation. These observations were consistent with the Fos expression results. These results indicate that Mn(2+) contrasted MRI is a useful technique for investigating the autonomic center in the hypothalamus.

Animals↗
PubMed2002

Analysis of onset location, laterality and propagation of cataplexy in canine narcolepsy.

Hypocretin deficiency is involved in most cases of human narcolepsy. Although cataplexy is pathognomonic of narcolepsy, mechanisms of induction of cataplexy are largely unknown. Patterns of occurrence of cataplectic attacks (i.e. onset location, laterality, and propagation of attacks) in hypocretin receptor 2-mutated narcoleptic Dobermans were characterized in order to understand the basic mechanism of this abnormal sleep-related atonia. Most cataplexy attacks were bilateral (98%) and were initiated in the hind legs (80%). Progression of attacks was also seen (49%) and atonia during propagation was most often bilateral (94%). Involvement of abnormal inactivation of bilateral pathways to the spinal motoneurones due to a deficiency in hypocretin neurotransmission is suggested in the occurrence of cataplexy.

Animals↗