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.
Brief episodes of hypotension have been shown to cause acute brain damage in
animal models. We used a rat hemorrhagic shock model to assess functional
outcome and to measure the relative neuronal damage at 1, 4 and 14 days
post-injury (3 min of hypotension). All rats underwent a neurological assessment
including motor abilities, sensory system evaluation and retrograde memory at
post-hypotensive insult. Brains were harvested and stained for Fluorojade C and
Nissl. Stereology was used to analyze Fluorojade C and Nissl stained brain
sections to quantitatively detect neuronal damage after the hypotensive insult.
Statistical analysis was performed using Graphpad Prism 5 with the Bonferroni
test at a 95% confidence interval after ANOVA. A Mixed Effect Model was used
for the passive avoidance evaluation. Stereologically counted fluorojade
positive cells in the hippocampus revealed significant differences in neuronal
cell injury between control rats and rats that received 3 min of hypotension one
day after insult. Quantification of Nissl positive neuronal cells showed a
significant decrease in the number hippocampal cells at day 14. No changes in
frontal cortical cells were evident at any time, no significative changes in
neurological assessments as well. Our observations show that brief periods of
hemorrhage-induced hypotension actually result in neuronal cell damage in
Sprague–Dawley rats even if the extent of neuronal damage that was
incurred was not significant enough to cause changes in motor or sensory
behavior.
Scoring systems are used to measure behavioral deficits in stroke research. Video-assisted training is used to standardize stroke-related neurologic deficit scoring in humans. We hypothesized that a video-assisted training and certification program can improve inter-rater reliability in assessing neurologic function after middle cerebral artery occlusion in rats. Three expert raters scored neurologic deficits in post-middle cerebral artery occlusion rats using three published systems having different complexity levels (3, 18, or 48 points). The system having the highest point estimate for the correlation between neurologic score and infarct size was selected to create a video-assisted training and certification program. Eight trainee raters completed the video-assisted training and certification program. Inter-rater agreement (i score) and agreement with expert consensus scores were measured before and after video-assisted training and certification program completion. The 48-point system correlated best with infarct size. Video-assisted training and certification improved agreement with expert consensus scores (pretraining ¼ 65 AE 10, posttraining ¼ 87 AE 14, 112 possible scores, P < 0.0001), median number of trainee raters with scores within AE2 points of the expert consensus score (pretraining ¼ 4, posttraining ¼ 6.5, P < 0.01), categories with i > 0.4 (pretraining ¼ 4, posttraining ¼ 9), and number of categories with an improvement in the i score from pretraining to posttraining (n ¼ 6). Video-assisted training and certification improved trainee inter-rater reliability and agreement with expert consensus behavioral scores in rats after middle cerebral artery occlusion. Video-assisted training and certification may be useful in multilaboratory preclinical studies.
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