Masataka Ueno

Perampanel: A novel, orally active, noncompetitive AMPA‐receptor antagonist that reduces seizure activity in rodent models of epilepsy

Purpose:  To assess the pharmacology of perampanel and its antiseizure activity in preclinical models. Perampanel [2‐(2‐oxo‐1‐phenyl‐5‐pyridin‐2‐yl‐1,2‐dihydropyridin‐3‐yl) benzonitrile] is a novel, orally active, prospective antiepileptic agent currently in development for refractory partial‐onset seizures.

Altered expression of glutamate transporters in experimental autoimmune encephalomyelitis.

Amelioration of experimental autoimmune encephalomyelitis (EAE) by blockade of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), has been recently demonstrated [Nat. Med. 6 (2000) 67; Nat. Med. 6 (2000) 62]. However, the mechanisms underlying regulation of the extracellular glutamate concentration in EAE are unclear. To address this, we examined the expression of three distinct Na(+)-dependent glutamate transporters (GLT-1, GLAST and EAAC1) in the spinal cord of the Lewis rat EAE. EAE induced a dramatic increase in EAAC1 protein and mRNA levels, which corresponded closely with the course of neurological symptoms. In contrast, the levels of GLT-1 and GLAST protein were down-regulated in the spinal cord at the peak of disease symptoms, and no recovery was observed after remission. Furthermore, these changes in GLT-1, GLAST and EAAC1 expression were suppressed by treatment with NBQX. These results suggest that AMPA receptor activation precedes the altered expression of glutamate transporters, and that the dysregulation of extracellular glutamate concentration might play a critical role in pathological changes and neuronal dysfunction in EAE.

Regulation by Androgen of Levels of the β Subunit of Nerve Growth Factor and Its mRNA in Selected Regions of the Mouse Brain

Abstract: Our previous studies showed that the concentration of the β subunit of nerve growth factor (β‐NGF) in nervous tissues is higher in male than in female mice. To identify the brain regions that are affected by androgens, the amounts of β‐NGF protein and its mRNAs were measured in male, female, and castrated male CD‐1 mice and testicular feminization mice at 3–4 months of age. Among tissues examined, the hypophysis of males contained the highest average concentration of β‐NGF protein. In most regions of the brain, individual levels were more variable in males than in females. However, after the castration, such variations in β‐NGF levels disappeared. Average levels of β‐NGF protein in males were higher in the cerebellum (eightfold higher), olfactory bulb (12‐fold higher), hypothalamus (sixfold higher), and hypophysis (72‐fold higher) than thope in corresponding regions of females. No significant differences were observed in levels of β‐NGF protein in the hippocampus, cerebral cortex, striatum, septum, and brainstem. The castration of male mice caused a reduction in levels of β‐NGF protein in the hypothalamus and hypophysis, but not in the cerebellum and olfactory bulb, to the femgle levels. The concentrations of β‐NGF protein in testicular feminization mice were similar to those in female CD‐1 mice in all regions. The concentrations of mRNA for β‐NGF in the olfactory bulb and hypophysis from males were higher than those from females. By contrast, northern blots showed no remarkable differences in the amounts of brain‐derived neurotrophic factor and neurotrophin‐3 between the two sexes. Thus, in some regions of the brain, the production of β‐NGF appears to be regulated by testosterone, but the regulatory mechanisms do not appear to be simple. Our present results indicate that the binding of testosterone to its receptor is an important step in the regulation of the level of β‐NGF in these region.

Delayed functional recovery by vincristine after sciatic nerve crush injury: a mouse model of vincristine neurotoxicity

Neuropathy is the dose-limiting side effect of vincristine (VCR) in cancer therapy. However, no simple experimental model has yet been reported. Here, we present a simple experimental model of VCR neurotoxicity using a mouse sciatic nerve crush model, which allows evaluation within a few weeks. VCR administered intravenously once on the day after the crush lesion caused a dose-dependent delay of the recovery of motor and sensory functions. The minimal dose required to cause the delay was 0.25 mg/kg, which corresponded to five times the usual clinical dose for man and was far less than the reported doses required to cause functional impairment in intact animals. The model would be useful not only for the development of new drugs but also for the estimation of the drug interactions in combination cancer therapy.

Basic research for Alzheimer's disease drugs.

アルツハイマー病（AD）はかつてnon-treatableと言われてきた．しかし近年，コリン仮説に基づいた創薬研究からコリンエステラーゼ阻害薬が開発され，薬物治療の対象となった．現在ではタクリン，ドネペジル，リバスチグミン，ガランタミンが上市されている．さらにNMDA受容体拮抗薬のメマンチンが承認されている．一方，ADの根本治療の研究開発も進められており，ADの原因および発症に密接に関与しているとされるアミロイド・βタンパク（Aβ）に関する研究から，Aβの産生・代謝に関与する酵素阻害薬および免疫療法などが開発されてきている．将来これらの研究成果が実を結び実際の治療に寄与していくことを期待したい．