SVIBOR - Project code: 3-01-433

MINISTRY OF SCIENCE AND TECHNOLOGY

Strossmayerov trg 4, HR - 10000 ZAGREB
tel.: +385 1 459 44 44, fax: +385 1 459 44 69
E-mail: ured@znanost.hr

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Project code: 3-01-433


CHOLINOMIMETICS, CALCIUM CHANNEL BLOCKERS, NOOTROPICS AND LEARNING


Main researcher: ŽUPAN, GORDANA (142160)


Assistants
Type of research: basic
Duration from: 10/10/91. to 10/10/94.
Papers on project (total): 45
Papers on project quoted in Current Contents: 3
Institution name: Medicinski fakultet, Rijeka (62)
Department/Institute: DEPARTMENT OF PHARMACOLOGY
Address: Braće Branchetta 20/1
City: 51000 - Rijeka, Croatia
Communication
Phone: 385 (051) 514-391/227-444
Fax: 385 (051) 514-391
E-mail: Gordana.Zupan mamed.medri.hr
Summary: Cognitive disturbance caused by a variety of conditions, most frequently by normal aging or dementia disorders, has widespread social and economic implications. It increases in prevalence in all countries all over the world. Current pharmacotherapy of cognitive disturbances has been based mainly on symptomatic treatment and is not sufficiently effective. Therefore, this project is designed to examine 1.) some of the basic processes underlying learning and memory functions, and 2.) efficacy of variuos drugs in therapy of cognitive impairments caused by different experimental procedures in rats. The effects of the cholinomimetics with various mechanisms of action (lecithin,tetrahydroaminoacridine, physostigmine, arecoline), the calcium channel blockers (nimodipine, nifedipine, nitrendipine,amlodipine, nicardipine, felodipine) and the nootropics (piracetam, oxiracetam) in experimental animals whose cognitive deficit is caused by 1.) cerebral hypoxia, 2.) the lesions of the nucleus basalis magnocellularis (NBM), 3.) anticholinergic drug,scopolamine , and 4.) electroshock application have been investigated. In order to understand the biochemical basis of hypoxic brain injury the levels of the brain free fatty acids in intact rats or in hypoxic control animals or in hypoxic animals treated by various calcium channel blockers have been detected.The effects of the calcium channel blockers on penicillin- or kainic acid-induced epileptic discharge in rats have been examined, too. It has been found that cerebral hypoxia, the NBM lesions,scopolamine administration and electroshock application strongly impaired the retention of the passive avoidance response in the rat. The calcium channel blockers, cholinomimetics and nootropics tested did not influence the passive avoidance behavior in the intact animals,but significantly improved the retention deficits in animals exposed to hypoxia. The effects of mentioned substances were dose-dependent. Cerebral hypoxia induced progressive increase in the brain free fatty acids (particularly arachidonic acid) content. Nimodipine prevented the accumulation of the brain free arachidonic acid caused by hypoxia. Diffuse forebrain ischemia was induced by the four vessel occlusion procedure. It was manifested with disturbances of the neuronal density, structure and integrity of the CA1 pyramidal cells in the hippocampus. Nimodipine significantly reduced the neuronal damage caused by ischemia. The effects of the NBM lesions on central cholinergic system activity and behavior were examined in newborn, adult and aging rats. A marked loss of cortical choline acetyltransferase (ChAT) activity and behavioral impairment were found in all age groups of lesioned animals. Unoperated postnatal day 14 rats were unable to perform the passive avoidance conditioned responses.Acquisition began on postnatal day 17. No biochemical, but a partial behavioral recovery was observed 3 months after surgery in rats lesioned on postnatal day 14. On the contrary, despite a persistent decrease in cortical ChAT activity, rats lesioned on postnatal day 21 were unable to acquire and retain the passive avoidance conditioned response. In three months old rats GM1 ganglioside, 20 days beginning immediately after lesioning, reduced ChAT decrease and behavioral impairment.Significant improvement of passive avoidance behavior was noted in adult rats six months after bilateral NBM lesions. Cognitive activities in experimental animals have been examined also in scopolamine-induced amnesia model. It has been found that all tested doses of scopolamine significantly decreased retention of passive avoidance conditioned response. Cognitive deficit was antagonized by various doses of oxiracetam. The results of our experiments also demonstrated that pretreatment with the calcium channel blockers tested reversed the memory deficits in 8lectroshock-treated rats. It has also been found that application of penicillin into the left motorcortex or administration of kainic acid into the dorsal hippocampus induced focal seizure activity. Generalized seizures were induced by i.p.injection of picrotoxine.It has been found that the calcium channel blockers used posses certain anticonvulsant effects. Penicillin-induced seizures caused the increase of the brain free fatty acid level that could be prevent by nimodipine. Epileptic seizures induced by intracerebral application of penicillin or kainic acid caused statistically significant decrease in the number of the pyramidal neurons of the hippocampal CA1 region.

Keywords: brain, learning and memory,hypoxia,nucleus basalis lesions, scopolamine- or electroshock- induced amnesia,epilepsy, brain free fatty acids, cholinomimetics, calcium channel blockers, nootropics, rat

Research goals: The purpose of this project is to examine: 1.) some physiological aspects of memory processes,for example learning ability during the postnatal period of rapid development of the brain cholinergic system in physiological conditions and in the case of the nucleus basalis magnocellularis lesions; 2.) the influence of various cholinomimetics, calcium channel blockers, nootropics and vasodilatators on learning ability in rats whose cognitive deficit is caused by a) cerebral hypoxia, b)the nucleus basalis magnocellularis lesions, c) scopolamine administration, and d) electroshock application; 3.) the changes in the level of the brain free fatty acids caused by cerebral hypoxia or epileptic seizures in order to understand the biochemical basis underlying hypoxic and epileptic brain injury ,and 4.) to standardize some experimental models of epilepsy and to investigate antiepileptic efficacy of various calcium channel blockers. The results of this project could contribute to our knowledge of some basic aspects underlying the cognitive functions and epileptic discharge as well as to effective pharmacotherapy of cognitive disturbances and convulsive disorders.

COOPERATION - PROJECTS


  1. Name of project: 3-01-159 ANTAGONISTI KALCIJA I OŠTEĆENJE NEURONA SREDIŠNJEG ŽIVČEVLJA
    Name of institution: MEDICINSKI FAKULTET
    City: 51000 - Rijeka, Croatia

COOPERATION - INSTITUTIONS


  1. Name of institution: Ministarstvo znanosti i tehnologije RH
    City: 10000 - Zagreb, Croatia
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