mdl-100453 and Arterial-Occlusive-Diseases

Rats were given MDL 100,453 ((R)-4-Oxo-5-phosphononorvaline) in a pre-determined neuroprotective dose consisting of a bolus of 24.8 mg/kg followed by an infusion of 1.05 mg/kg*h for 24 h (MDL group; n = 8) or saline of the same volume (SALINE group; n = 8) 30 min. after the onset of a 90 min. period of middle cerebral artery occlusion. Eight animals underwent SHAM surgery. Rats were evaluated post-operatively for 14 days using seven neurological tests, including water maze. SALINE animals exhibited a pattern of neurological impairment compared to SHAMs (poor performance in five of the six motor/reflex tests) peaking five days post-injury. Relative to the SALINE group, the MDL group exhibited significantly improved outcome on two of the tests and a pattern of improved behavior on the remainder of the battery. By day 14 post-ischemia, all groups exhibited recovery on the motor/reflex tests. Learning ability was disrupted in the SALINE group on days 17 and 18, whereas the MDL group's performance was not distinguishable from the SHAM group in the water maze. Thus, a neuroprotective dose of MDL 100,453 produced a pattern of behavioral sparing in the immediate post-ischemic days that was uniquely different than saline. The addition of behavioral outcome measures to histological neuroprotection data adds significantly to the ability to better evaluate a putative neuroprotective compound.

Topics: Animals; Arterial Occlusive Diseases; Behavior, Animal; Cerebral Arteries; Cerebrovascular Disorders; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Grooming; Male; Maze Learning; Neuroprotective Agents; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Time Factors; Valine

The competitive N-methyl-D-aspartate antagonist MDL-100,453 has been shown to attenuate ischemic cell damage when administered after permanent focal cerebral ischemia. The aim of the present study was to measure the dose-response of cerebral infarcted volume to the agent administered 30 min after permanent middle cerebral artery occlusion and to test whether short-term infusion of this drug reduces ischemic cell damage. Thirty-five Sprague-Dawley rats were randomly assigned to 4 groups: low dose group, a bolus of 12.4 mg/kg MDL-100,453 followed by infusion of 31.7 mg/kg/h MDL-100,453; middle and high dose groups, bolus and infusion doses increased to 24.8 mg/kg, 63.3 mg/kg/h and 49.6 mg/kg, 126.7 mg/kg/h, respectively; and control group, saline used for bolus and infusion. Middle cerebral artery occlusion (MCAO) was induced by insertion of intraluminal suture. The infusion was accomplished by a microprocessor controlled pump connected to a jugular vein, which delivered drug or saline over a period of 9 h. Infarct volume was calculated using 2,3,5-triphenyltetrazolium chloride staining 24 h after MCAO. The infarct volumes were significantly reduced in both middle (46%) and high (52%) dose groups compared with the saline group (p < 0.05). No reduction of infarct volume was found in the low dose group. A statistically significant (p < 0.05), but poor inverse correlation existed between the average blood level of MDL-100,453 and infarct volume. We demonstrated that a short-term (9 h) intravenous administration of an appropriate dose of MDL-100,453 beginning 30 min after MCAO significantly reduces ischemic lesion volume at 24 h after onset of permanent focal cerebral ischemia.

Topics: Animals; Arterial Occlusive Diseases; Brain Ischemia; Cerebral Arteries; Cerebral Infarction; Dose-Response Relationship, Drug; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Infusions, Intravenous; Male; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Valine