Administration of a Sigma Receptor Agonist Delays MCAO-Induced Neurodegeneration and White Matter Injury.
Many pharmacological treatments for stroke have afforded protection in rodent models but failed to show efficacy in clinical trials. This discrepancy may be due to the lack of long-term functional studies. Previously, delayed administration of the sigma receptor agonist 1,3-di-o-tolylguanidine (DTG) reduced infarct volume after middle cerebral artery occlusion (MCAO) in rats. The present study was conducted to determine whether the protective effects of DTG lead to improvements in behavioral functioning. Rats were subjected to MCAO and administered 7.5, 1.5, or 0.75 mg/kg DTG beginning 24 h post-surgery. Histological outcomes (96 h, 2 weeks, and 5 weeks) were compared with performance on a series of behavioral tests (2 and 4 weeks). Fluoro-Jade staining and immunohistochemistry were used to assess infarct volume and immune cell recruitment. All doses significantly reduced infarct volume and perturbation of striatal white matter tracts at 96 h. These reductions were associated with decreased numbers of CD11b-positive amoeboid microglia/macrophages. Despite short-term efficacy, DTG failed to improve behavioral outcomes or reduce infarct volumes after 96 h. While DTG may prove beneficial as a short-term therapy, these data highlight the importance of long-term functional recovery when evaluating novel therapies to treat stroke.
Leonardo
Christopher C
CC
Department of Molecular Pharmacology and Physiology, College of Medicine, University of South Florida, MDC Box 9, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA cleonard@health.usf.edu.
Hall
Aaron A
AA
Collier
Lisa A
LA
Green
Suzanne M
SM
Willing
Alison E
AE
Pennypacker
Keith R
KR