topiramate and Cerebral-Hemorrhage

28 male Long-Evans rats prepared with lesions of the middle cerebral artery displayed deficits in spatial navigational learning in a simple version of the Morris Water Maze task not seen in animals prepared with the same injury but administered 4 treatments with topiramate after surgery.

Topics: Animals; Cerebral Hemorrhage; Disease Models, Animal; Fructose; Learning Disabilities; Male; Maze Learning; Neuroprotective Agents; Rats; Rats, Long-Evans; Topiramate

Thrombolysis is increasingly being used in treating acute ischemic stroke but it is also accompanied with a serious complication of cerebral hemorrhage in a dose-dependent fashion. As a lower dose may result in decreased effectiveness, we tested the efficacy of combining a neuroprotective agent, topiramate (TPM), with lower doses of intra-arterial urokinase in an embolic stroke model. Focal ischemia was produced by introduction of an autogenous thrombus into the right middle cerebral artery. Urokinase was infused via the ipsilateral internal carotid artery and neuroprotective agent, TPM, was administrated intra-peritoneally 2 h following ischemic insult. The animals were assigned to five groups: (1) control group (n=6); (2) urokinase 5000 units/kg (n=8); (3) urokinase at 2500 units/kg (n=8); (4) topiramate at 20 mg/kg (n=8); (5) urokinase at 2500 units/kg and topiramate at 20 mg/kg (n=8). Neurobehavioral outcome and the degree of brain infarct volume were assessed at 24 h. Three animals in the group treated by high dose urokinase developed intracranial hemorrhage but none in other groups. Animals in all medication-groups showed significant improvement in neurobehavioral score. Post-ischemia treatment with urokinase or TPM alone significantly attenuated brain infarct volume (low-dose urokinase, 39.1+/-13.0%, p<0.05; high-dose, 18.4+/-8.5%, p<0.001; TPM, 20. 1+/-11.2%, p<0.001) when compared to the control (54.2+/-9.04%). Addition of TPM to low dose urokinase achieved better neuroprotection (8.2+/-6.0%) than any single-drug-treated groups. Our data suggests that combination of low dose urokinase with a neuroprotective agent may benefit ischemic stroke treatment by improving neurologic recovery, attenuating infarction size, and reducing the risk of cerebral hemorrhage.

Topics: Animals; Brain; Brain Ischemia; Cerebral Hemorrhage; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fructose; Infarction, Middle Cerebral Artery; Injections, Intra-Arterial; Injections, Intraperitoneal; Intracranial Thrombosis; Male; Neuroprotective Agents; Rats; Rats, Wistar; Topiramate; Urokinase-Type Plasminogen Activator

Recent studies have shown that the use of thrombolysis in the setting of acute stroke is associated with an increased risk of cerebral hemorrhage. The time of onset of symptoms to initiation of medication and the dose levels of the thrombolytic agents are important determinants for the risk of cerebral hemorrhage. The authors evaluated the time course of thrombolysis-related hemorrhages in experimental settings and tested whether the addition of neuroprotective medication augments the efficacy of thrombolysis and reduces the incidence of hemorrhages.. Male Wistar rats were subjected to right middle cerebral artery embolization with an autologous thrombus and were then randomly assigned to one of the following groups: Group 1, saline-treated (2 hours after ischemic insult) animals as controls; Groups 2 to 4, high-dose urokinase (5,000 U/kg) at 2, 3, and 6 hours after the insult; Group 5, low-dose urokinase (2,500 U/kg) at 2 hours after the insult; Group 6, 20 mg/kg topiramate (TPM) at 2 hours after the insult; Group 7, a combination of 20 mg/kg TPM at 2 hours and low-dose urokinase (2,500 U/kg) at 6 hours after the insult; and Group 8, 20 mg/kg TPM (20 mg/kg) at 2 hours and high-dose urokinase (5,000 U/kg) at 2 hours after the insult. Neurological behavior and the infarct volume in the brain were assessed following cerebral embolism and the various treatments. All animals in the single therapy and low-dose combination groups survived surgery. Three of eight animals treated with high-dose urokinase alone at 6 hours and three of six animals in the combined high-dose urokinase and TPM group developed fatal intracerebral hemorrhages. There was a significantly better neurological outcome at 24 hours in the animals treated with either medication compared with controls. The volume of the infarct in the saline-treated group was 54.2 +/- 9%. The use of TPM at 2 hours led to a decrease in the infarct to 20.1 +/- 11.2% (p < 0.01). Treatment with urokinase at 6 hours after the occlusion showed a trend toward protection; the infarct volume was 31.9 +/- 14.1% (p < 0.05). The addition of TPM to low- or high-dose urokinase achieved better neuroprotection (8.2 +/- 6% and 11.9 +/- 10.7%, respectively; both p < 0.01).. In this study the authors show that the volume of the infarct can be significantly decreased with 2 to 6-hour delayed intraarterial thrombolysis with urokinase and that the efficacy of thrombolysis may be enhanced by combining neuroprotective agents like TPM. It is also shown that low-dose combination therapy may decrease the likelihood of cerebral hemorrhage.

Topics: Acute Disease; Animals; Brain Ischemia; Cerebral Hemorrhage; Disease Models, Animal; Drug Therapy, Combination; Fructose; Incidence; Infarction, Middle Cerebral Artery; Injections, Intra-Arterial; Intracranial Embolism; Male; Neurologic Examination; Neuroprotective Agents; Placebos; Plasminogen Activators; Random Allocation; Rats; Rats, Wistar; Risk Factors; Stroke; Thrombolytic Therapy; Time Factors; Topiramate; Treatment Outcome; Urokinase-Type Plasminogen Activator