ABSTRACT
Experiments on nonlinear rats subjected to global transient cerebral ischemia revealed the ability of glutamic acid to improve cerebral circulation. Consequently, the excitatory amino acid can produce adverse (neurotoxic) and positive (anti-ischemic) effects in cerebral ischemia. The cerebrovascular effect of glutamic acid in cerebral ischemia is attenuated on the background action of the MNDA receptor blocker MK-801 (0.5 mg/kg intravenously) and eliminated by bicuculline. When glutamic acid is combined with the non-competitive MNDA receptor antagonist MK-801, neither one nor another drug shows its vasodilator effect. The results are indicative of the interaction between excitatory and inhibitory systems on the level of cerebral vessels and once again confirm our previous conclusion about the decisive role of GABA(A) receptors in brain vessels in the implementation of anti-ischemic activity of endogenous compounds (melatonin) and well-known pharmacological substances (mexidol, afobazole), and new chemical compounds based on GABA-containing lipid derivatives.
Subject(s)
Brain Ischemia/drug therapy , Glutamic Acid/pharmacology , Neuroprotective Agents/pharmacology , Receptors, GABA-A/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Animals, Outbred Strains , Bicuculline/pharmacology , Brain Ischemia/pathology , Carotid Artery, Common/surgery , Cerebrovascular Circulation/drug effects , Coronary Occlusion/pathology , Dizocilpine Maleate/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , GABA-A Receptor Antagonists/pharmacology , Male , Neuroprotective Agents/antagonists & inhibitors , Rats , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitorsABSTRACT
It was investigated the effect of two adamantane derivatives, memantine and 5-hydroxyadamantan-2-one (5-HA), in patients with cerebrovascular disorders. In vitro studies showed that 5-HA, unlike memantine, exhibited antiplatelet activity. Experiments showed that memantine reduced cerebral blood flow in the brain cortex of intact rats and those under conditions of transient global ischemia, whereas 5-HA only selectively improved blood flow in ischemic brain and was superior to the reference drug nimodipine. The obtained data indicate the leading role of the GABA-ergic (rather than glutamatergic mechanisms) in implementation of the anti-ischemic cerebrovascular activity.
Subject(s)
Adamantane/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Hypoxia-Ischemia, Brain/drug therapy , Ischemic Attack, Transient/drug therapy , Memantine/pharmacology , Adamantane/analogs & derivatives , Adenosine Diphosphate/pharmacology , Aged , Animals , Animals, Outbred Strains , Blood Platelets/drug effects , Cells, Cultured , Cerebral Cortex/blood supply , Cerebral Cortex/drug effects , Cerebral Cortex/pathology , Cerebrovascular Circulation/drug effects , Epinephrine/pharmacology , Female , Humans , Hypoxia-Ischemia, Brain/pathology , Ischemic Attack, Transient/pathology , Laser-Doppler Flowmetry , Male , Middle Aged , Nimodipine/pharmacology , Platelet Aggregation/drug effects , Rats , Vasodilator Agents/pharmacologyABSTRACT
NMDA receptor antagonist MK-801 (dizocilpine) increases the local blood flow in the cerebral cortex in rats under transient global ischemia (TGI) conditions to a greater degree than in intact animals. The GABA receptor blocker bicuculline in most experiments eliminates or reduces the MK-801 induced increase in the blood flow after TGI, which is indicative of the participation of GABAergic mechanism of cerebrovascular tone control in the observed MK-801 activity.
