Protective effects of 5-HT1A receptor agonists against neuronal damage demonstrated in vivo and in vitro.
The aim of the present study was to evaluate the neuroprotective effect of the 5-hydroxytryptamine1A (5-HT1A) agonists, CM 57493 and urapidil, in vivo and in vitro, respectively. In vivo permanent occlusion of the middle cerebral artery (MCA) was performed in male Wistar rats. Forty-eight hours after electrocoagulation of the MCA the infarct volume was determined. Pretreatment of the rat with the 5-HT1A agonist urapidil significantly reduced infarct development. The neuroprotective effect of the agent was restricted to the cortical area; the striatal damage was not influenced. As the stimulation of the 5-HT1A receptor by serotonin is supposed to induce inhibitory, hyperpolarizing effects by opening of a Ca(2+)-independent neuronal K+ ionophore, the efficacy of agonistic drugs directly on the neuron was investigated in vitro. Cyanide-induced cytotoxic hypoxia as well as glutamate-induced excitotoxicity were performed using primary neuronal cell cultures from chick embryo cerebral hemispheres. Treatment with the 5-HT1A agonists urapidil and CM 57493 significantly increased protein content of hypoxic cultures. CM 57493 added to the culture medium (1-10 microM) during and up to 24 h after glutamate exposure ameliorated viability of the neurons. The results demonstrate neuroprotective potency of the 5-HT1A agonists, urapidil and CM 57493, when applied under hypoxic, excitotoxic and ischemic conditions in vivo and in vitro, respectively. Both, presynaptically induced inhibition of glutamate release as well as postsynaptically induced inhibition of neuronal excitability could be discussed as possible mechanisms of action of the 5-HT1A receptor agonism.
Peruche
B
B
Institut für Pharmakologie und Toxikologie, Phillips-Universität, Marburg/Lahn, Federal Republic of Germany.
Backhauss
C
C
Prehn
J H
JH
Krieglstein
J
J
D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D018698:Glutamic Acid / Q000633:toxicity; D066298:In Vitro Techniques; D007511:Ischemia / Q000139:chemically induced; D008297:Male; D018696:Neuroprotective Agents; D010879:Piperazines / Q000819:agonists; D011725:Pyridines / Q000037:antagonists & inhibitors; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D018696:Neuroprotective Agents; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D018698:Glutamic Acid; C045604:CM 57493; C015568:urapidil