The neurotoxicity of tunicamycin.
The neurotoxicity of tunicamycin, an inhibitor of glycosylation of glycoproteins and a potential anti-tumour agent, was investigated by injection of the chemical directly into the lateral ventricle of the brain of rats. A delayed neurological syndrome developed due to anoxic necrosis of brain cells and spongy degeneration of the white matter. In many brains the lesion had the characteristic features of an infarct. Since the predominant lesion was vascular, the action of tunicamycin on blood vessels was investigated in vitro using rabbit aortic rings. In this system the normal relaxation response to acetylcholine in aortic rings pre-contracted with noradrenaline was progressively inhibited as exposure of the ring to tunicamycin increased from 2 h to 5 h. This relaxation response depends on the release of endothelium-derived relaxing factor from endothelial cells. Hence it is proposed that the important primary target in tunicamycin neurotoxicity is endothelial cells of the brain microvessels.
Leaver
D D
DD
Department of Pharmacology, University of Melbourne, Victoria, Australia.
Schneider
K M
KM
Rand
M J
MJ
Anderson
R M
RM
Gage
P W
PW
Malbon
R
R
D000818:Animals; D001011:Aorta / Q000187:drug effects; D001688:Biological Products / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D004121:Dimethyl Sulfoxide / Q000633:toxicity; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009569:Nitric Oxide; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D014415:Tunicamycin / Q000633:toxicity*
D001688:Biological Products; D014415:Tunicamycin; D009569:Nitric Oxide; D004121:Dimethyl Sulfoxide