Takashi Ogino

Detection of hypothalamic activation by manganese ion contrasted T1-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.

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.

Quinoline-3-carbothioamides and related compounds as novel immunomodulating agents.

A series of quinoline-3-carbothioamides and their analogues was prepared via four synthetic routes and evaluated for their antinephritic and immunomodulating activities. The optimal compound 9g strongly inhibited the T-cell independent antibody production in mice immunized with TNP-LPS and was highly effective in two nephritis models, namely chronic graft-versus-host disease and autoimmune MRL/l mice.

Water permeability of capillaries in the subfornical organ of rats determined by Gd-DTPA2- enhanced 1H magnetic resonance imaging

The water permeability of capillaries in the subfornical organ (SFO) of rat was measured by a 1H nuclear magnetic resonance method in combination with a venous injection of a relaxation reagent, gadolinium‐diethylene triamine‐N,N,N′,N″,N″‐pentaacetic acid (Gd‐DTPA2‐), which could not pass through the blood‐brain barrier (BBB). Judging from results of Gd‐DTPA2‐ dose dependency in the intact brain and the BBB‐permeabilized brain, Gd‐DTPA2‐ could not have leaked out from the capillaries in the cortex, thalamus or SFO, but it could have been extravasated in the posterior lobe of the pituitary gland. The longitudinal (T1) relaxation time of water in the SFO region was measured by inversion‐recovery magnetic resonance imaging at 4.7 T. The T1 relaxation rates (1/T1) before and after Gd‐DTPA2‐ infusion were 0.70 ± 0.02 s−1 (mean ±s.e.m., n= 9) and 1.53 ± 0.11 s−1 (n= 9), respectively. The rate constant for water influx to the capillaries was estimated to be 0.84 ± 0.11 s−1 (n= 9) which corresponds with a diffusive membrane permeability (Pd) of 3.7 × 10−3 cm s−1. Compared with values found in the literature available on this subject, this Pd value for the capillaries in the SFO was the same order of magnitude as that for transmembrane permeability of water for the vasa recta, and it may be 10–100 times larger than that of the blood‐brain barrier in the cortex. Areas of the cortex and thalamus showed minimal changes in the T1 relaxation rate (ca 0.09 s−1), but these values were not statistically significant and they corresponded to Pd values much smaller than those found in the SFO. From these results, we conclude that the capillaries in the SFO have one of the highest water permeability values among all of the capillaries in the brain. It is also suggested that this magnetic resonance imaging, based on T1 relaxation rate, is a useful method to detect local water permeability in situ.

Discovery of FR115092 : A novel antinephritic agent

A series of dapsone-related 4-aminopheynl and 2-aminothiazolyl derivatives was prepared, and their antinephritic activity and blood toxicity were evaluated. 5-(2-Pyridylsulfonyl)-2-thiazolamine (FR115092, 26) was effective against two nephritis models, namely graft-versus-host disease (GVHD) and autoimmune W/BF1 mice, and showed none of the blood toxicity observed with dapsone.

Mn‐bicine: A low affinity chelate for manganese ion enhanced MRI

The toxicity of free Mn2+ is a bottleneck for the in vivo application of manganese ion enhanced MRI. To reduce free Mn2+ concentration ([Mn2+]), a low affinity chelate reagent: N,N‐bis(2‐hydroxyethyl)glycine (bicine) was used. Considering the conditional association constant of Mn‐bicine at pH 7.4 (102.9 M−1), (i) a 100 mM Mn‐bicine solution should contain about 10 mM of free manganese ion, but (ii) free manganese will make up 3/4 of the final plasma concentration (0.5 mM) with an intravenous infusion of 100 mM Mn‐bicine. The T1 relaxivity of Mn‐bicine in a 5 mM Mn‐bicine solution was estimated as 5 mM−1 sec−1 at 24°C, 7 T in a pH range of 6.8–7.5. Mn‐bicine demonstrated a tendency for better contractility when employed with an isolated perfused frog heart, compared with MnCl2. A venous infusion of 100 mM Mn‐bicine (8.3 μmol kg−1 min−1) showed a minimal decrease and maintained a constant heart rate level and arterial pressure in rats, while rats infused with 100 mM of MnCl2 showed a significant suppression of the hemodynamic functions. Thus, Mn‐bicine appears to be a better choice for maintaining the vital conditions of experimental animals, and may improve the reproducibility of manganese ion enhanced MRI. Magn Reson Med, 2010.

The First Synthesis of N-Alkyl-N-Arylthiocarbamoylacetates and Acetic Acids

Abstract N-Alkyl-N-arylthiocarbamoylacetates, the key intermediates for the synthesis of novel antinephritic agents, have been prepared for the first time. Some of the esters were in turn hydrolyzed to the corresponding acids. An alternative, indirect synthetic route was also developed to prepare some unusual acids.

Synthesis and effects of novel thiazole derivatives against thrombocytopenia

5-(2-Pyridylsulfonyl)-2-thiazolamine (2) was effective both in mitomycin C (MMC)-induced thrombocytopenia and in an animal model of idiopathic thrombocytopenic purpura (ITP). It also suppressed the increase of autoantibodies against platelets in the ITP model and showed no blood toxicity. Chemical modification of 2 led to the discovery of more potent compounds against MMC-induced thrombocytopenia.

Development of an animal model and a social behavior assessment scoring method for developmental disorders

Background Autism is recognized as a spectrum including Asperger syndrome and the disorder of social interaction is as central. Various behavioral and cognitive approaches to support autistic children and adults have been developed since the mid-1960s, for example, ABA (Applied Behavior Analysis), TEACCH (Trains and Education of Autistic and related Communication handicapped Children), and more recently RDI (Relationship Development Intervention) programs. These educational and therapeutic approaches, however, have been poorly shaded by the light of brain science on development of social empathy mainly because of lacking good animal model. Here we have introduced an animal model which allows us to investigate the correlation of social behavior and brain development.

Mn-citrate and Mn-HIDA: intermediate-affinity chelates for manganese-enhanced MRI.

In this study we investigated two manganese chelates in order to improve the image enhancement of manganese-enhanced MRI and decrease the toxicity of free manganese ions. Since both MnCl₂ and a low-affinity chelate were associated with a slow continuous decrease of cardiac functions, we investigated intermediate-affinity chelates: manganese N-(2-hydroxyethyl)iminodiacetic acid (Mn-HIDA) and Mn-citrate. The T₁ relaxivity values for Mn-citrate (4.4 m m⁻¹ s⁻¹) and Mn-HIDA (3.3 m m⁻¹ s⁻¹) in artificial cerebrospinal fluid (CSF) were almost constant in a concentration range from 0.5 to 5 m m at 37 °C and 4.7 T. In human plasma, the relaxivity values increased when the concentrations of these Mn chelates were decreased, suggesting the presence of free Mn²⁺ bound with serum albumin. Mn-HIDA and Mn-citrate demonstrated a tendency for better contractility when employed with an isolated perfused frog heart, compared with MnCl₂. Only minimal changes were demonstrated after a venous infusion of 100 m m Mn-citrate or Mn-HIDA (8.3 µmol kg⁻¹ min⁻¹) in rats and a constant heart rate, arterial pressure and sympathetic nerve activity were maintained, even after breaking the blood-brain barrier (BBB). Mn-citrate and Mn-HIDA could not cross the intact BBB and appeared in the CSF, and then diffused into the brain parenchyma through the ependymal layer. The responses in the supraoptic nucleus induced by the hypertonic stimulation were detectable. Therefore, Mn-citrate and Mn-HIDA appear to be better choices for maintaining the vital conditions of experimental animals, and they may improve the reproducibility of manganese-enhanced MRI of the small nuclei in the hypothalamus and thalamus.