CALCIUM CHANNEL BLOCKERS AND CENTRAL NEURONS DAMAGE
Main researcher
: SIMONIĆ, ANTE (43202) Assistants
ŽIVKOVIĆ, BRANIMIR (55736)
ŽUPAN, GORDANA (142160)
DRAGANIĆ, PERO (145152)
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).
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
Name of project
: 3-01-433 KOLINOMIMETICI, ANTAGONISTI KALCIJA,
NOOTROPICI I UČENJE Name of institution: Medicinski fakultet Rijeka City: 51000 - Rijeka, Croatia
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
Name of institution
: "Lek" - tvornica lijekova Type of institution: Economical/Production City: Ljubljana
Name of institution
: "Krka - tvornica lijekova Type of institution: Economical/Production Type of cooperation: Joint project City: Novo Mesto
Name of institution
: "Synthelabo Recherche" (L.E.R.S.) Type of institution: Economical/Production Type of cooperation: Joint project City: Pariz
Name of institution
: Medicinski fakultet Type of institution: University/Faculty Type of cooperation: Joint project City: 51000 - Rijeka, Croatia Other information about the project.