Intraarterial urokinase produces significant attenuation of infarction volume in an embolic focal ischemia model

Exp Neurol. 1998 Dec;154(2):330-5. doi: 10.1006/exnr.1998.6925.

Abstract

A number of models of focal ischemia have been created to mimic acute middle cerebral artery (MCA) occlusion. In the present series of experiments, we report our observations on the thrombin model of MCA occlusion and the neuroprotective effects of intraarterial thrombolysis with two doses of urokinase (2500 and 5000 units/kg). In all experiments male Wistar rats were used and the animals were allowed to recover for 48 h before assessment of neurobehavioral performance on a four-point scale. The extent of cerebral hemispheric damage was calculated as the percentage of brain infarction using TTC staining. Occlusion of the MCA was effected by the introduction of an autologous blood clot into the internal carotid artery (ICA) approximately 2 mm from the origin of the MCA. This clot was formed by the drawing of 10 microl of blood into a bovine thrombin (20 microg per animal) containing intraarterial catheter, which was inserted into the right ECA. After standing for 15 min to allow clot formation, the catheter was advanced gently through the ICA to the site of injection. MCA occlusion produced a consistent large infarction in all animals. Urokinase infusion (i.a. ) was started 2 h after arterial occlusion in the initial series. In animals treated with low dose urokinase infusion there was mild protection. Animals treated with high dose urokinase infusion showed a highly significant improvement in the motor recovery and a decrease in the extent of infarction compared to control animals. In the final group, the infusion of urokinase was delayed for 3 h. While producing protection in some animals, it also produced intracerebral hemorrhage in two of eight animals. Thus delay of infusion to 180 min increased the risk of hemorrhage. This model may in the future be used to test the protective effects of combination therapy with thrombolysis and neuroprotective medications.

MeSH terms

  • Animals
  • Arterial Occlusive Diseases / drug therapy
  • Arterial Occlusive Diseases / pathology
  • Brain / blood supply
  • Brain / pathology
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / pathology
  • Cerebral Infarction / drug therapy*
  • Cerebral Infarction / pathology
  • Disease Models, Animal
  • Injections, Intra-Arterial
  • Intracranial Embolism and Thrombosis / drug therapy*
  • Intracranial Embolism and Thrombosis / pathology
  • Male
  • Neurologic Examination
  • Plasminogen Activators / pharmacology*
  • Rats
  • Rats, Wistar
  • Thrombin
  • Urokinase-Type Plasminogen Activator / pharmacology*

Substances

  • Plasminogen Activators
  • Thrombin
  • Urokinase-Type Plasminogen Activator