Progress in understanding the pathophysiology of cerebral ischemia: the almitrine-raubasine approach.
Cerebral ischemia occurs frequently and is disabling. In addition to preventing and correcting risks factors, drugs prevent cell death induced by ischemia-hypoxia. Precise knowledge of the pathophysiology of cerebral ischemia is the prerequisite for drug development, and the main proofs of efficiency are histopathological and clinical (i.e., the results of controlled studies). Different animal models are considered valid for global, focal, or multifocal ischemia. These models have enabled the identification of deleterious phenomena that could be corrected or neutralized by drugs: hypoxia, lactic acidosis, release of neurotransmitters, influx of calcium, activation of phospholipase A2, release of excitatory amino acids, excess of free radicals, and neuronal cell metabolic paralysis (decrease of oxygen and glucose consumption). The chronology of these events clearly described herein will prompt the choice of the best drug, based on the delay between the ischemic event and the decision to treat. The main pharmacological effects required are the following: antagonism of hypoperfusion, oxygenation improvement, blockade of calcium influx and neurotransmitters action, reduction of acidosis and potassium efflux, blockade of arachidonic cascade and free radicals production, and antiedematous effect. The analysis of almitrine-raubasine (Duxil) pharmacological properties will be used as an example of these potentially anti-ischemic drugs. Almitrine-raubasine pharmacological studies indicate that this drug has several beneficial effects on cerebral ischemic processes. These studies have dealt with effects of hypobaric hypoxia on deoxyglucose uptake in the rat, protective effects on permanent or temporary cerebral ischemia-induced neurobehavioral problems in the gerbil, and preservation of the glycogen content and of the swelling in astrocytes after bilateral occlusion of the carotid arteries in the rabbit.
Bentué-Ferrer
D
D
Laboratoire de Pharmacologie Expérimentale et Clinique, Faculté de Médecine, Rennes, France.
Decombe
R
R
Reymann
J M
JM
Schatz
C
C
Allain
H
H
D015765:Almitrine / Q000627:therapeutic use*; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000503:physiopathology*; D004195:Disease Models, Animal; D004338:Drug Combinations; D006801:Humans; D046948:Secologanin Tryptamine Alkaloids; D015016:Yohimbine / Q000031:analogs & derivatives* / Q000627:therapeutic use
D004338:Drug Combinations; D046948:Secologanin Tryptamine Alkaloids; D015016:Yohimbine; C005709:raubasine; D015765:Almitrine