Yasuaki Akasaki

Gender of demented patients and specific family relationship of caregiver to patients influence mental fatigue and burdens on relatives as caregivers.

To survey the burden and psychological problems of family caregivers of demented people.

Relationships between convulsive seizures and serum and brain concentrations of phenobarbital and zonisamide in mutant inbred strain EL mouse

We evaluated the anticonvulsive effects of phenobarbital (PB) and zonisamide (ZNS) in the EL mouse, a strain that is highly susceptible to seizures. The concentration of each agent was analyzed in the serum and brain. PB suppressed the seizures dose-dependently, whereas even the higher dose of ZNS was ineffective in achieving a complete suppression. Serum and brain concentrations of these two drugs increased in proportion to the higher dose injected intraperitoneally. Brain concentration of PB was lower than the serum concentration, while the brain concentration of ZNS exceeded that in serum. Although serum concentration of ZNS was essential unchanged after the combined administration of PB and ZNS, the concentration of ZNS in brain tended to rise in proportion to the highly dose of PB. Combined administration was more effective than other treatment alone. Results indicated that brain concentration of ZNS especially after concomitant PB administration, were higher than that would be expected from the concentration of ZNS in serum.

In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin decreases serotonin-immunoreactive neurons in raphe nuclei of male mouse offspring

Female ddY mice were administered 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by gavage for 8 weeks prior to pregnancy. In the male breast-fed offspring born to the TCDD-exposed mice, serotonergic neurons in the brainstem were examined using an immunocytochemical method at 42 days of age. In all offspring, a marked decrease in the intensity of immunostaining occurred in all raphe nuclei compared with the control offspring. The number of serotonin-immunoreactive neurons in each raphe nucleus was measured by computer-assisted analysis. Approximately a quarter to half of immunoreactive neurons were detected in the TCDD-exposed offspring raphe nuclei compared with the control offspring. The present findings suggest that in utero and/or lactational TCDD exposure cause a long-lasting change in the serotonergic system in the raphe nuclei of offspring.

Effects of MK-801, dantrolene, and FK506 on convulsive seizures and brain nitric oxide production in seizure-susceptible EL mice.

To clarify the role of nitric oxide (NO) in the pathogenesis of seizures in susceptible EL mice, we investigated effects of three drugs potentially related to NO production, MK-801, dantrolene, and FK506, on convulsive seizures and brain NO metabolites (NOx). MK-801 or dantrolene, but not FK506, suppressed convulsive seizures in EL mice; only MK-801 reduced NOx in the brain. Our results suggested involvement of the N-methyl-D-aspartate receptor-channel complex and intracellular calcium mobilization, but not calcineurin, in the convulsions of EL mice.

Effects of combined administration of zonisamide and valproic acid or phenytoin to nitric oxide production, monoamines and zonisamide concentrations in the brain of seizure-susceptible EL mice.

This study was undertaken to elucidate the anticonvulsive effects of zonisamide (ZNS: 25, 50, and 75 mg/kg, intraperitoneal [i.p.]), which was coadministered with valproic acid (VPA: 25, 50, and 100 mg/kg, i.p.), or phenytoin (PHT: 10, 25, and 50 mg/kg, i.p.) to ZNS concentration, nitric oxide metabolites (NOx levels), and monoamines in the brain of the EL mouse, a strain highly susceptible to seizures. NOx levels were obtained from measuring of combined level of nitrite plus nitrate. Coadministration of ZNS with VPA or PHT suppressed convulsive seizures more effectively than with treatment of ZNS alone. Both serum and brain concentrations of ZNS tended to increase as the dose of VPA or PHT was increased. While coadministrations of ZNS (75 mg/kg) and VPA or PHT at any dose did not change brain and serum NOx levels, those altered brain monoamine contents. These results suggested that anticonvulsive effect of coadministrations of ZNS and VPA or PHT were caused by changes of monoamines rather than changes of NO metabolites.

Sparse distribution of NADPH diaphorase neurons in the hippocampal formation of the inbred mutant strain EL mouse

The number of NADPH diaphorase-positive cells in the CA1/CA2 and CA3 regions of Ammons horn and the subiculum of the hippocampal formation of EL mice, an inbred mutant strain of the ddY mouse susceptible to convulsive seizures, was fewer than that of ddY mice. These findings suggest that smaller numbers of nitric oxide producing cells in the hippocampal formations of EL mice is related to their susceptibility to convulsive seizures.

Nitric oxide production is decreased in the brain of the seizure susceptible EL mouse.

To investigate nitric oxide production in the brain of the EL mouse, an inbred mutant strain of the ddY mouse that is susceptible to convulsive seizures, we measured whole brain nitric oxide metabolites, and counted the number of nitric oxide-producing cells in the parietal cortex and striatum. Nitric oxide metabolites in the brain and serum were determined by measuring levels of nitrite plus nitrate. Nitric oxide-producing cells were demonstrated histochemically by staining for nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase. Levels of nitrite plus nitrate in the whole brain were significantly lower than those of the control mice, although levels of nitrite plus nitrate in the serum did not differ between groups. There were significantly fewer NADPH-diaphorase-positive cells in the parietal cortex and striatum of the EL mouse compared to the ddY controls. These results suggest that lower nitric oxide production in the brain may be related to the susceptibility of the EL mouse to convulsive seizures.

Influences of caffeine to nitric oxide production and zonisamide concentration in the brain of seizure‐susceptible EL mice

Abstract To investigate changes of nitric oxide (NO) productions and zonisamide (ZNS) concentrations in the brain of seizure‐susceptible EL mice given caffeine orally, mice were given caffeine (600 μg/mL) solution ad libitum as a drinking fluid for 1–3 weeks. Nitric oxide production in the brain was determined by measuring levels of nitrite plus nitrate (NOx). The brain NOx levels of mice treated with caffeine for 3 weeks were significantly higher than the control. Seizures in mice treated with caffeine for 2 and 3 weeks were not suppressed by ZNS at a dose of 75 mg/kg. Serum ZNS concentrations of mice with caffeine intake for 1–3 weeks were higher than in untreated mice. Conversely, brain ZNS concentrations of mice with caffeine intake for the same periods were significantly lower than in untreated mice. These results suggested that caffeine influenced brain NO production and ZNS concentrations in the seizure susceptibility of EL mice.

Kainic and domoic acids differentially affect NADPH-diaphorase neurons in the mouse hippocampal formation.

We investigated changes in numbers of nitric-oxide-producing cells in the hippocampal formation, striatum, and temporal cortex of mice 24 h after intraperitoneal administration of kainic acid (5, 10, 15, and 20 mg/kg) or domoic acid (1, 2, and 4 mg/kg). Nitric-oxide-producing cells were demonstrated histochemically by staining for nicotinamide adenine dinucleotide phosphate diaphorase. Nicotinamide adenine dinucleotide phosphate-diaphorase-positive neurons in the dentate gyrus and the subiculum did not change in number following administration of kainic acid or domoic acid at any dose. Positive neurons in the CA3 region of mice treated with kainic acid or domoic acid at any dose were significantly fewer than in controls. Although the numbers of positive neurons in the CA1/CA2 regions did not differ from those of controls at any of the four doses of kainic acid, positive cells in the CA1/CA2 were significantly more numerous than in controls at any dose of domoic acid. Although no significant differences in the numbers of positive neurons in the striatum were apparent between controls and any of the four doses of kainic acid, domoic acid significantly decreased the numbers of such cells. These results suggest that systemically administered kainic acid and domoic acid affect differentially nitric-oxide-producing cells in the hippocampal formation.

Alcohol intake decreases brain zonisamide concentration in inbred EL mice

THIS study was undertaken to evaluate the effect of ethanol intake on the anticonvulsive effects of Zonisamide (ZNS), a sulfonamide derivative. EL mice, a strain highly susceptible to seizures, were given a 10% ethanol solution ad lib for 1–4 weeks. Seizures in mice treated with ethanol for 1–3 weeks were decreased by ZNS at a dose of 75 mg kg−1, i.p., but those in mice treated with ethanol for 4 weeks were not suppressed. Serum ZNS concentrations following ethanol consumption for 1–4 weeks were higher than in untreated mice; however, brain ZNS concentrations following ethanol consumption were lower than those in untreated mice. These results suggest that alcohol intake decreases the brain concentration, but not the serum concentration.