UWANO Teruko Toyama Medical and Pharmaceutical University, Department of Physiology, Assistan, 医学部, 助手 (80242486)
FUKUDA Masaji Toyama Medical and Pharmaceutical University, Department of Behavioral Sciences,, 医学部, 教授 (60126547)
ONO Taketoshi Toyama Medical and Pharmaceutical University, Department of Physiology, Professo, 医学部, 教授 (50019577)
|Budget Amount *help
¥2,100,000 (Direct Cost : ¥2,100,000)
Fiscal Year 1993 : ¥500,000 (Direct Cost : ¥500,000)
Fiscal Year 1992 : ¥1,600,000 (Direct Cost : ¥1,600,000)
Mechanisms and pharmacological therapy of memory disorders due to hippocampal(HF)lesions were investigated. First, techniques to produce ischemic neuronal death confined to CA1 subfield of the HF in monkeys was developed. Ischemia for 10 to 15 min by occluding 8 vessels(the bilateral vertebral, common, internal and external carotid arteries)produced cell death limited to the deeper portion of the pyramidal cell layr of the CA1 subfield in the HF.Treatment with (+)-1-(3, 4-dimethoxyphenyl)-2-(4-diphenylmethylpiperazinyl) ethanol dihydrochloride (NC-1100, Nippon Chemiphar Co., Ltd)markedly reduced both ischemic neuronal damage in the CA1 subfield of the HF and memory disorder. It is suggested that post-ischemic treatment with the calcium entry blocker, NC-1100, might protect the brain from the ischemic damage that is produced in patients suffering from trransient ischemia.
Second, rats were also subjected to 15 min brain ischemia to produce same HF lesions as in monkeys. In a spatial navigation task in which rats were required to memorize specific areas in the field, the acquisition performance of ischemic-rats was significantly inferior to that of control-rats. Repeated administrations of (-)R-1-(Benzo[b]thiophen-5-yl)-2-[2(N, N-diethylamino)ehoxy]ethanol hydrochloride (T-588, Toyama Cheminal Co.Ltd.)siginificantly ameliorate impaired performance of ischemic-rats in a spatial navigation task, without causing any behavioral abnormalities. The intracellular recording from HF pyramidal cells indicated that T-588 has a direct excitatory effects on hippocampal CA1 pyramidal cells. The functional MRI detected increment in signal intensity, which reflects increment in blood flow, in various brain areas such as HF, parietal cortex, amygdala, and striatum. T-588 may be, at least in part, attributable to its ability to improve the cognitive dysfunction in patients with senile dementia or other organic brain syndrome.