Neuronal and microvascular alterations induced by the cholinergic toxin AF64A in the rat retina.
The choline analogue ethylcholine mustard aziridinium ion (AF64A) produces both neuronal and non-neuronal alterations in the rat retina. The possible involvement of the retinal capillaries in the origin of the apparently non-specific lesions has been investigated. Two hours after a single intraocular injection of 5 nmol AF64A, ultrastructural alterations were observed in neurons of the inner nuclear layer and the ganglion cell layer, where cholinergic cells are located. One week later, the number of cholinergic neurons, identified by choline acetyltransferase immunohistochemistry, was decreased to 65% of control, the neurons located in the inner nuclear layer being more sensitive than those in the ganglion cell layer. The same dose of AF64A also induced ultrastructural changes in retinal capillaries, which showed a significant increase in the number of pinocytotic vesicles and microvilli in the endothelial cells, 2-5 h after the toxin administration. One day later, arterioles and capillaries presented contracted profiles and the lumen was occasionally lost. The sensitivity of endothelial cells to the toxic effects of AF64A may be explained by the presence in the cerebral endothelium of a choline transport mechanism with an affinity close to that of cerebral synaptosomes. In vitro, both neuronal and endothelial choline uptake systems were equally sensitive to the toxin inhibitory effect. The early and severe vascular alterations induced in the retinal microvessels by AF64A may produce changes in blood perfusion and capillary permeability that could account for the apparently non-specific histological damage.
Departamento de Morfología, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
P
P
Gómez-Ramos
E
E
Galea
C
C
Estrada
D000818:Animals; D001388:Aziridines / Q000494:pharmacology*; D002196:Capillaries / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D002794:Choline / Q000031:analogs & derivatives* / Q000494:pharmacology; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology*; D010786:Photoreceptor Cells / Q000187:drug effects / Q000502:physiology*; D010873:Pinocytosis; D051381:Rats; D011919:Rats, Inbred Strains; D012160:Retina / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D013574:Synaptosomes / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure
D001388:Aziridines; D009467:Neuromuscular Depolarizing Agents; C044894:ethylcholine aziridinium; D002795:Choline O-Acetyltransferase; D002794:Choline