Hepatocyte growth factor (HGF), efficacious in preclinical models of acute central nervous system injury, is burdened by administration of full-length proteins. A multiinstitutional consortium investigated the efficacy of BB3, a small molecule with HGF-like activity that crosses the blood-brain barrier in rodent focal ischemic stroke using Stroke Therapy Academic Industry Roundtable (STAIR) and Good Laboratory Practice guidelines. In rats, BB3, begun 6 hours after temporary middle cerebral artery occlusion (tMCAO) reperfusion, or permanent middle cerebral artery occlusion (pMCAO) onset, and continued for 14 days consistently improved long-term neurologic function independent of sex, age, or laboratory. BB3 had little effect on cerebral infarct size and no effect on blood pressure. BB3 increased HGF receptor c-Met phosphorylation and synaptophysin expression in penumbral tissue consistent with a neurorestorative mechanism from HGF-like activity. In mouse tMCAO, BB3 starting 10 minutes after reperfusion and continued for 14 days improved neurologic function that persisted for 8 weeks in some, but not all measures. Study in animals with comorbidities and those exposed to common stroke drugs are the next steps to complete preclinical assessment. These data, generated in independent, masked, and rigorously controlled settings, are the first to suggest that the HGF pathway can potentially be harnessed by BB3 for neurologic benefit after ischemic stroke.
The use of anesthetics and sedatives has been suggested to be a contributor to Alzheimer's disease neuropathogenesis. We wanted to address the in vivo relevance of those substances in the Tg2576 Alzheimer's mouse model. Tg7526 mice were anesthesia-sedated for 90 min once a week for 4 weeks. Y maze, Congo Red, and amyloid beta (Aβ) immunochemistry were performed. We did not find any significant change in the navigation behavior of the exposed mice compared to the controls. Significantly less deposition of Aβ in the CA1 area of the hippocampus and frontal cortex of mice exposed to isoflurane, propofol, diazepam, ketamine, and pentobarbital was observed. In the dentate gyrus, Aβ deposition was significantly greater in the group treated with pentobarbital. Congo Red staining evidenced significantly fewer fibrils in the cortex of mice exposed to diazepam, ketamine, or pentobarbital. The adopted repetitive exposure did not cause a significant detriment in Tg7526 mouse.
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