Haruo Hattori

Genetic polymorphism of the CYP2C subfamily and its effect on the pharmacokinetics of phenytoin in Japanese patients with epilepsy

To examine the genetic polymorphism of CYP2C9 and CYP2C19 and its effect on the pharmacokinetics of phenytoin among 44 Japanese patients with epilepsy.

Inhibitor of Nitric Oxide Synthesis Reduces Hypoxic-Ischemic Brain Damage in the Neonatal Rat

ABSTRACT: We evaluated the neuroprotective effect of the nitric oxide synthesis inhibitor, NG-nitro-L-arginine in a neonatal hypoxic-ischemic rat model. Unilateral hypoxic-ischemic injury was produced in the brain of 7-d-old rats using a combination of a common carotid artery ligation and a hypoxic (8% oxygen) exposure for 2.5 h. In our experimental condition, rectal temperatures did not differ between NG-nitro-L-arginine-treated and saline-injected pups. We killed the animals 72 h later and assessed the hypoxic-ischemic brain damage histologically. NG-nitro-L-arginine (2 mg/kg) administered intraperitoneally 1.5 h before hypoxia resulted in 77% reduction of the infarcted hemispheric volume and 87% reduction of the infarcted striatal volume compared to saline injected controls. NG-nitro-L-arginine given 1.5 h before the insult also significantly prevented hypoxic-ischemic damage in the five hip-pocampal structures examined, dentate gyrus, CA4, CA3, CA1, and subiculum. NG-nitro-L-arginine administered immediately after hypoxia did not prevent hypoxic-ischemic brain damage. These results indicate that nitric oxide plays a key role in producing neonatal hypoxic-ischemic brain damage.

Excitatory amino acids in the developing brain: Ontogeny, plasticity, and excitotoxicity☆

Besides their role as neurotransmitters, excitatory amino acids (EAAs) in the developing brain are crucially involved in plasticity and excitotoxicity which are modified by their distinct ontogeny. Along with incomplete neuritogenesis and synaptogenesis, presynaptic markers of the EAA system are immature in the developing brain; however, postsynaptic EAA system activities, particularly of the N-methyl-D-aspartate and quisqualate receptors, are transiently enhanced early in life. This transient enhancement is presumably beneficial to the immature brain because physiologic activation of the EAA system plays a critical role in plasticity of early learning and morphogenesis. At the same time, this transient hypersensitivity renders the immature brain vulnerable to pathologic excitation of the EAA system (excitotoxicity) as observed during neonatal hypoxia-ischemia.

Protective effect of aminoguanidine on hypoxic-ischemic brain damage and temporal profile of brain nitric oxide in neonatal rat

Nitric oxide (NO) produced by inducible NO synthase contributes to ischemic brain damage. However, the role of inducible NO synthase-derived NO on neonatal hypoxic-ischemic encephalopathy has not been clarified. We demonstrate here that aminoguanidine, a relatively selective inhibitor of inducible NO synthase, ameliorated neonatal hypoxic-ischemic brain damage and that temporal profiles of NO correlated with the neuroprotective effect of aminoguanidine. Seven-day-old Wister rat pups were subjected to left carotid artery occlusion followed by 2.5 h of hypoxic exposure (8% oxygen). Infarct volumes (cortical and striatal) were assessed 72 h after the onset of hypoxia-ischemia by planimetric analysis of coronal brain slices stained with hematoxylin-eosin. Aminoguanidine (300 mg/kg i.p.), administered once before the onset of hypoxia-ischemia and then three times daily, significantly ameliorated infarct volume (89% reduction in the cerebral cortex and 90% in the striatum;p < 0.001). NO metabolites were measured by means of chemiluminescence using an NO analyzer. In controls, there was a significant biphasic increase in NO metabolites in the ligated side at 1 h (during hypoxia) and at 72 h after the onset of hypoxia (p < 0.05). Aminoguanidine did not suppress the first peak but significantly reduced the second one (p < 0.05), and markedly reduced infarct size in a neonatal ischemic rat model. Suppression of NO production after reperfusion is a likely mechanism of this neuroprotection.

Increase in nitric oxide in the hypoxic–ischemic neonatal rat brain and suppression by 7-nitroindazole and aminoguanidine

We measured the changes in nitric oxide (NO) metabolites in the brains of neonatal rats with hypoxic-ischemic damage. There were two peaks of NO metabolites in the lesioned side of the cortex without treatment: one during hypoxia and the other during the re-oxygenation period. Prehypoxic treatment with 7-nitroindazole, a selective neuronal NO synthase inhibitor, suppressed both peaks of NO metabolites, whereas prehypoxic treatment with aminoguanidine, a selective inducible NO synthase inhibitor, partially suppressed only the peak in the re-oxygenation period. These data suggest different roles of neuronal and inducible NO synthases in the pathogenesis of hypoxic-ischemic encephalopathy.

Increased neurons containing neuronal nitric oxide synthase in the brain of a hypoxic-ischemic neonatal rat model.

We evaluated the temporal profile of the number of neurons containing neuronal nitric oxide synthase (nNOS neurons) in the brain of a neonatal hypoxic-ischemic rat model. Hypoxic-ischemic insults were produced in the brains of 7-day-old rat pups using a combination of unilateral carotid artery ligation and hypoxic (8% oxygen) exposure. Sections of brain from rats killed at 0-24 h after the onset of hypoxia were stained immunohistochemically using a polyclonal anti-nNOS antibody. Histological changes of neuronal injury were evaluated in the adjacent Nissl stained sections. The number of nNOS neurons in the hemisphere ipsilateral to the carotid ligation was significantly increased (P < 0.05) at 3 h, when the neuronal injury consisted of clusters of degenerating hyperchromic neurons. Neuronal degeneration and an increased number of nNOS neurons were seen only in the ipsilateral hemisphere and the increase was most prominent in the dorsolateral area of the striatum. The increase in the number of nNOS neurons continued at 6 h, when the area of neuronal injury continued to expand. At 24 h, the neuronal injury was diffuse, and the number of nNOS neurons on the ipsilateral side significantly decreased. The increase of the number of nNOS neurons in the early phase of neonatal neuronal injury suggests its possible involvement in the hypoxic-ischemic injury. The delineation of its role in neuronal injury may lead to an improvement in managing neonatal hypoxic-ischemic brain injury.

Zonisamide reduces hypoxic-ischemic brain damage in neonatal rats irrespective of its anticonvulsive effect.

The neuroprotective effect of a novel anticonvulsant, zonisamide, was investigated in neonatal rats with hypoxic-ischemic brain damage. Rats underwent left carotid ligation followed by hypoxic exposure (8% O2) for 2.5 h. When zonisamide (75 mg/kg) was administered i.p. 1 h before hypoxia, it reduced the cortical infarction volume to 6 +/- 5% (mean +/- S.E.M.) from 68 +/- 7% in vehicle-treated controls and the striatal volume to 8 +/- 4% from 78 +/- 7%. Zonisamide also reduced neuronal necrosis in 5 hippocampal regions (the dentate gyrus, CA4, CA3, CA1, and the subiculum). The plasma zonisamide concentration before and after hypoxia was 47.9 +/- 2.0 microgram/ml and 42.3 +/- 3.9 microgram/ml, respectively. Epidural electrodes were implanted in 6 pups one day before hypoxia-ischemia. Electroencephalograms were recorded during hypoxia-ischemia in rats given zonisamide or vehicle before the insult. The intensity of seizure activities was similar in the zonisamide-treated pups and the vehicle-treated controls. These findings demonstrate that zonisamide reduces neonatal hypoxic-ischemic brain damage and that this protective effect does not depend on its anticonvulsant action.

LIVING-RELATED LIVER TRANSPLANTATION AND NEUROLOGICAL OUTCOME IN CHILDREN WITH FULMINANT HEPATIC FAILURE

BACKGROUND Fulminant hepatic failure (FHF) in children is associated with high mortality under medical management. Living-related liver transplantation (LRLT) is an accepted measure to treat the children with end-stage liver disease. Reversibility of hepatic encephalopathy is crucial for the quality of life among the survivors after transplantation. METHODS A retrospective review was made of the records of children undergoing LRLT at this hospital between May 1992 and November 1996. RESULTS Eleven children with FHF underwent emergency LRLT. The mean age was 5 years (range, 2 months to 15 years). The indication for transplantation was persistent or worsening hepatic encephalopathy and severe coagulopathy, despite repeated plasma exchanges or exchange transfusions. The cause of FHF was non-A, non-B hepatitis in seven children, hepatitis B in two children, herpes simplex virus hepatitis in one child, and fulminant Wilsons disease with intravascular hemolysis in one child. The grade of hepatic encephalopathy was II in four children, III in two, and IV in five. The actuarial survival rate was 73% after a mean follow-up of 28 months (range, 13-67 months). Short-term neurological morbidity was present in two children with grade IV encephalopathy who also showed brain edema on cranial computed tomography. Eight survivors exhibited no long-term neurological deficit; the mean intelligence or developmental quotient was 97 (range, 86-110) at the end of the follow-up period. CONCLUSIONS LRLT is an effective option for the treatment of FHF in children. The long-term neurological status is satisfactory among survivors.

Benign Familial Neonatal Convulsions Followed by Benign Epilepsy with Centrotemporal Spikes in Two Siblings

Summary: Purpose: To report on sibling cases with benign familial neonatal convulsions (BFNC) followed by benign epilepsy with centrotemporal spikes (BECT).

Spontaneous remission of spasms in West syndrome – implications of viral infection

On a database of the Japanese medical literature between 1970 and 2000, there were 29 patients with West syndrome showing spontaneous remission. In 25/29 (86%) of the patients, spontaneous remission was preceded by viral infections, among which exanthema subitum predominated. In 16/29 (55%), the spasms recurred a median of 2 months later. However, some of the remaining infants attained lasting remission of the spasms. This link between viral infections and spontaneous remission suggests immuno-inflammatory processes underlie West syndrome in certain patients. Better understanding of such mechanisms may lead to a new therapeutic approach to West syndrome.