Introduction: Tissue plasminogen activator (tPA) is the standard treatment for acute stroke but its widespread use is constrained by its narrow therapeutic window: better treatments are needed. Clinical stroke is heterogeneous in presentation and responsiveness to therapeutics. There are several methods of inducing acute cerebral ischemia in NHP and each model induces a differential pathology following occlusion. The goal of the current study was to characterize the PIT model of acute stroke in nonhuman primates.
Methods: First, the time course of brain infarction between PIT and permanent middle cerebral artery (pMCA) occlusion was compared. PIT and pMCA occlusion were performed in cynomolgus macaques (n = 3/procedure). Total brain infarction volume and the volume of viable tissue surrounding the ischemic core that eventually becomes necrotic (“penumbra”) over time was measured using FLAIR MR imaging, 3, 6, 24 hours, 3, 5 and 7 days post-occlusion. In addition, functionality (Neurologic Deficit Score; NDS) was assessed 24 hours, 3, 5 and 7 days post-occlusion. Second, tPA’s (n = 7) therapeutic time window was determined. tPA (0.9 mg/kg) was i.v. infused 1, 3 and 4.5 hours post-occlusion. Control animals (n = 7) received a saline infusion 3 hours post-occlusion. Total brain infarction volume and presence of intracerebral hemorrhage 24 hours post-occlusion were measured. NDS was also determined.
Results: First, significant brain infarction was observed 6 hours post-occlusion with FLAIR MR imaging in both models. Significant penumbral tissue was observed up to 6 hours post-occlusion. The brain infarction volume plateaued 5-7 days post-occlusion. In the second stage, tPA showed robust efficacy when it was infused 1 hour after occlusion. However, when tPA was infused either 3 or 4.5 hours post-occlusion, infarct volume and NDS were not different compared to saline treatment. Furthermore, significant intracranial hemorrhaging was observed when tPA was infused 3 or 4.5 hours post-occlusion.
Conclusion: The current study suggests that the PIT model mimics human thrombotic stroke. In addition, since significant risks associated with tPA can also observed, the PIT model can be used to compare novel treatments with tPA in terms of intracranial hemorrhaging.