SVIBOR - Project code: 3-01-159

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: 3-01-159


CALCIUM CHANNEL BLOCKERS AND CENTRAL NEURONS DAMAGE


Main researcher: SIMONIĆ, ANTE (43202)



Assistants
Type of research: basic
Duration from: 01/01/91. to 12/31/92.

Papers on project (total): 58
Papers on project quoted in Current Contents: 5
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: Ante.Simonic mamed.medri.hr

Summary: Trauma, ischemia and hypoxia of the central nervous system could provoke motor, sensory and cognitive deficit. These conditions are important medical and social problem and there is no effective drug therapy. Calcium overload in the nerve cells might lead to functional and morphological alterations even to death of neurons. We have investigated whether the voltage calcium channel blockers (nimodipine, nitrendipine, nifedipine, nicardipine, amlodipine and felodipine) and NMDA receptor blockers (ifenprodil and SL 820715) could reduce calcium overload in the nerve cell and already reduce neurological deficit provoked by the nerve tissue damage. The effects of various doses of mentioned drugs were examinated on: 1) the hind limbs motor activity of spinal cord contusioned rabbits, and 2) in the model of the passive avoidance behaviour in rats exposed to hypoxia, 3) in the model of the passive avoidance behaviour in rats exposed to brain ischemia, 4) in the models of partial and generalized epileptic seizures in rats. (EEG activity was measured). 5) Histological changes in the hippocampus, and the level of the total brain free fatty acids and arechodinic acid in the rat brain were also controled. 6) The influence of these drugs was examined through "in vitro" experiment on the isolated aorta rabbit strips and the bovine iris on various receptor systems. Calcium channel blockers (in tested doses) do not influence the motor, cognitive and EEG activities and free fatty acids level in the brain of the intact animals. On the contrary, they a) significantly (in dose dependent manner) improve cognitive activities to hypoxia and ischemia exposured rats and improve, also, b) motor activity of spinal cord contusioned rabbits. The effects of nifedipine, nitredipoine, nimodipine and nicardipine are more expressive than amlodipine and felodipine. Nimodipine reduces: a) the domage of CA1 pyramidal cells in the hippocampus of ischemia eposed rats, b) the inrease of the total free fatty acids and arechidonic acid levels in rats exposed to hypoxia and epileptic seizures. (The effect was dose dependent. Nicardipine, and amlodipine were inactive). c) seizures provoked with penicilin, kainic acid and picrotoxin. (The effect was dose dependent. Nifedipine, nicardipine and amlodipine suppress seizures provoked with penicillin, but not with cainic acid. Nifedipine only in the dose of 30 mg/kg decreases picrotoxine seizures).

Keywords: SPINAL CORD CONTUSION, MOTOR ACTIVITY, BRAIN HYPOXIA/ISHEMIA, COGNITION, HIPOCAMPAL NEURONS, MORPHOLOGY, FREE FATTY ACIDS, COPRTICAL EEG, Ca++ ANTAGONISTS

Research goals: The spinal cord injuries represent a significant medical andsocial problem. These injuries might cause a high level ofinvalidity , or often even death and they mainly occur intraffic, sports or labour accidents. The contusions of the spinal cord result mostly in paresis orparalysis of the limbs, in disfunction of the abdominal organs ortrophic damages of the skin. The above named injuries are oftenbeing present for many years, sometimes even for a lifetime, andan efficant therapy for such cases is lacking. The damages of the cognitive activities occur very often, theircause being: trauma, hypoxia, ageing, intoxication, etc. Theclinical changes following such conditions are extremely dramaticand almost irreversible. Since there is no efficient therapy forcognitive deficit, thus is the social and medical significanceeven more important. The purpose of this research is to improve thepharmacotherapeutical level in curing the patients with damagedbrain neurons and damaged spinal cord. The purpose ofpharmacotherapy is to quicken the recovery or reduce theneurological deficit of the patient. In this sense, the qualityof living for most patients would be raised to a hiher level. This research work serves to obtain new acknowledgementsregarding the central nervous system function and about thepathophysiological cause of the central nervous system damages,provoked by hypoxia or trauma. It is of a great interest to studythe significance of calcium overload into the nerve cells withinsuch processes. It is also important to obtain useful facts aboutcalcium L channel and NMDA - receptor blockers mechanisms. It isexpected that some calcium antagonists significantly reduce thedamages of the spinal cord and brain neurons, caused by trauma, hypoxia, ischemia and epilepsy.. Through "in vitro" experiment we wish to test the reactivity of the smooth muscle of blood vessels and the bovine iris to the mentioned substances, as well as to research their effect on adrenergic, serotonergic and cholinergicreceptors.


COOPERATION - PROJECTS


  1. Name of project: 3-01-433 KOLINOMIMETICI, ANTAGONISTI KALCIJA, NOOTROPICI I UČENJE
    Name of institution: Medicinski fakultet Rijeka
    City: 51000 - Rijeka, Croatia

  2. Name of project: -------- UTJECAJ BLOKATORA KALCIJSKIH KANALA DIHIDRIPIRIDINSKE GRUPE NA SPOZNAJU U INTAKTNIH I HIPOKSIJI IZLOŽENIH ŠTAKORA
    Name of institution: Tvornica lijekova "Lek"
    City: Ljubljana


COOPERATION - INSTITUTIONS


  1. Name of institution: "Lek" - tvornica lijekova
    Type of institution: Economical/Production
    City: Ljubljana

  2. Name of institution: "Krka - tvornica lijekova
    Type of institution: Economical/Production
    Type of cooperation: Joint project
    City: Novo Mesto

  3. Name of institution: "Synthelabo Recherche" (L.E.R.S.)
    Type of institution: Economical/Production
    Type of cooperation: Joint project
    City: Pariz

  4. Name of institution: Medicinski fakultet
    Type of institution: University/Faculty
    Type of cooperation: Joint project
    City: 51000 - Rijeka, Croatia

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Last update: 11/07/95
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