Pharmacological evaluation methods of drugs for treatment of patients in the chronic phase of organic brain syndrome - Effects of calcium channel blockers on impairment of brain function in senescence-accelerated mice

This report reviews methods of pharmacological evaluation of drugs for the treatment of patients in the chronic phase of organic brain syndrome includ ing stroke, head injury and senile dementia. The models were developed from the aspects of both species and parameter. In the approach based on specie s, using middle cerebral artery occluded rats, repeated carotid artery occl uded gerbils, internal capsule-lesioned rabbits and rats, head injured rats and senescence accelerated mice (SAM-P/8), impairments of passive learning behavior and EEG, neurological deficits, and/or neuronal degeneration, whi ch are frequently used as parameters in preclinical study, were observed fo r a long period after surgical operation or aging. Same cerebral activators such as indeloxazine, Ca-hopantenate, dihydroergotoxine, thyrotropin-relea sing hormone (TRH), azetireline (TRH analogue) and cytidine diphosphate (CD P)choline ameliorated these brain dysfunctions. Thus, it was found that bra in dysfunction could be observed for a long period in some animal models. H owever, additional parameters corresponding well to clinical events should be observed for evaluating drugs for treatment in the chronic phase. In app roach based on parameters, motor (rota rod and traction test) and emotional functions (swimming tests), which have not yet been examined in organic br ain syndrome models, were examined in SAM-P/8 mice. Disturbance of brain fu nction in passive avoidance response, forced swimming, rota-rod and tractio n tests was observed for a long period in SAM-P/8 mice of 8 months of age, compared with senescence-accelerated-resistant mouse (SAM-R/1). The daily o ral administration of calcium channel blockers such as nicardipine and nimo dipine once a day for 3 weeks ameliorated brain dysfunction in passive avoi dance response and rota-rod tests, while amlodipine showed little pharmacol ogical effect in any of the four tests in SAM-P/8. The study suggests that SAM-P/8 is an appropriate model for evaluating the pharmacological effects of calcium channel blockers on brain dysfunction. A number of above reports about the approach from both species and parameter showed the possibility of animal models of drugs far treatment of the patients in the chronic phas e of organic brain syndrome.