Citicoline for treatment of experimental focal ischemia: histologic and behavioral outcome.
We evaluated the effect of chronic administration of CDP-choline, an intermediate of phospholipid synthesis, on outcome from middle cerebral artery occlusion, ranging from 30 to 120 min in duration in spontaneously hypertensive rats. Rats were randomly assigned to either CDP-choline 500 mg kg-1 or saline. CDP-choline treatment was initiated by intraperitoneal injection 15 min after the onset of ischemia and continued once a day for 14 days. Morphologic damage and behavioral dysfunction (motor and sensorimotor performance) were evaluated, and the maximal morphologic damage (Volmax), maximal behavioral dysfunction (BDmax) as well as the duration of ischemia producing half-maximal morphologic damage (T50) or behavioral dysfunction (BD50) were calculated using a curve-fitting program (ALLFIT). Ischemia in control animals produced a Volmax of 103.3 +/- 13.6 mm3. CDP-choline did not affect this value (Volmax of 101.6 +/- 11.4 mm3). However, CDP-choline significantly extended the T50 from 38.3 +/- 5.9 to 60.5 +/- 4.3 min (p < 0.05). Similar to the morphologic outcome, CDP-choline had no effect on BDmax but significantly extended BD50 from 41.9 +/- 4.6 to 72.9 +/- 24.5 min (p < 0.05). Our results suggest that the effectiveness of CDP-choline is greater in animals demonstrating submaximal ischemic injury which in this model is produced by 30-75 min of ischemia (effect on T50 and BD50), than in animals suffering maximal ischemic injury produced by ischemia longer than 75 min (no effect on Volmax and BDmax). These results may reflect a threshold of biological membrane damage within which CDP-choline is able to restore phospholipid content/arrangement and retain membrane integrity.
Aronowski
J
J
Department of Neurology, University of Texas-Houston, Medical School 77030, USA.
Strong
R
R
Grotta
J C
JC
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy; D001284:Atrophy; D001522:Behavior, Animal / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002544:Cerebral Infarction / Q000188:drug therapy / Q000473:pathology; D003566:Cytidine Diphosphate Choline / Q000494:pharmacology*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology
D018696:Neuroprotective Agents; D018697:Nootropic Agents; D003566:Cytidine Diphosphate Choline