Cyclosporin A in blood and brain tissue following intra-carotid injections in normal and stroke-induced rats.
Administration of Cyclosporin A (CsA) to rats undergoing reversible global or focal ischemia has been demonstrated to be variably neuroprotective. As CsA does not readily cross the blood-brain barrier, the variability may be due to differences in bioavailability of CsA to the ischemic brain. We have, therefore, quantitated CsA levels in blood and brain following intra-carotid injection in rats undergoing permanent right middle cerebral artery (MCA) occlusion using a three-vessel model of focal cerebral ischemia. After 30 min of three-vessel occlusion, CsA (10 mg/kg) was injected into the left external carotid artery followed by reversal of the left common carotid artery occlusion. At various times post-injection, blood samples were collected from the vena cava and samples of ischemic or sham-operated cortex were obtained for CsA quantitation by tandem mass spectrometry. Pharmacokinetic parameters were determined using non-linear mixed-effects modeling. CsA areas under the curve between normal and stroke-induced rats were not significantly different in blood (18355 vs. 19405 ng x h/ml, NS) or in brain tissue (15664 vs. 14931 ng x h/g, NS). These results demonstrate that intra-carotid injection of CsA results in high levels in brain (brain-blood ratio from 0.5 to 1). No significant differences in blood and brain exposure were observed between normal and stroke-induced rats. Therefore, reduced cerebral blood flow in the ischemic territory did not limit CsA availability to the cortex. In addition, CsA intra-carotid administration was neuroprotective following 24 h recovery as there was a significant decrease in the infarct area of the affected hemisphere compared to saline injected rats as estimated by TTC staining of viable tissue.
Vachon
Pascal
P
MDS Pharma Services, Ville St-Laurent, Montréal, Québec, Canada.
Beaudry
Francis
F
Marier
Jean-Francois
JF
Ste-Marie
Line
L
Montgomery
Jane
J
D000818:Animals; D001921:Brain / Q000378:metabolism*; D017536:Carotid Artery, Common; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics*; D020244:Infarction, Middle Cerebral Artery / Q000097:blood / Q000378:metabolism; D007269:Injections, Intra-Arterial; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000097:blood / Q000378:metabolism*
D016572:Cyclosporine