Determining the effect of aging, recovery time, and post-stroke memantine treatment on delayed thalamic gliosis after cortical infarct

Gab Seok Kim,Jia-Wei Min,Sean P Marrelli,Monica G Goss,Fudong Liu,Abdullah Al Mamun,Ting Wu,Jessica M Stephenson,Jun Li

doi:10.1038/s41598-021-91998-3

Abstract

Secondary injury following cortical stroke includes delayed gliosis and eventual neuronal loss in the thalamus. However, the effects of aging and the potential to ameliorate this gliosis with NMDA receptor (NMDAR) antagonism are not established. We used the permanent distal middle cerebral artery stroke model (pdMCAO) to examine secondary thalamic injury in young and aged mice. At 3 days post-stroke (PSD3), slight microgliosis (IBA-1) and astrogliosis (GFAP) was evident in thalamus, but no infarct. Gliosis increased dramatically through PSD14, at which point degenerating neurons were detected. Flow cytometry demonstrated a significant increase in CD11b+/CD45int microglia (MG) in the ipsilateral thalamus at PSD14. CCR2-RFP reporter mouse further demonstrated that influx of peripheral monocytes contributed to the MG/Mϕ population. Aged mice demonstrated reduced microgliosis and astrogliosis compared with young mice. Interestingly, astrogliosis demonstrated glial scar-like characteristics at two years post-stroke, but not by 6 weeks. Lastly, treatment with memantine (NMDAR antagonist) at 4 and 24 h after stroke significantly reduced gliosis at PSD14. These findings expand our understanding of gliosis in the thalamus following cortical stroke and demonstrate age-dependency of this secondary injury. Additionally, these findings indicate that delayed treatment with memantine (an FDA approved drug) provides significant reduction in thalamic gliosis.

Highlights

MethodsAll procedures were performed in accordance with NIH guidelines for the care and use of laboratory animals and were approved by the Institutional Animal care and use committee of the University of Texas Health Science Center
We found that cortical stroke induces progressive and lasting gliosis associated with secondary injury in the ipsilateral thalamus
This thalamic injury is characterized by initial gliosis, followed by neuronal loss in the VPN and PoM nuclei

Summary

Methods

All procedures were performed in accordance with NIH guidelines for the care and use of laboratory animals and were approved by the Institutional Animal care and use committee of the University of Texas Health Science Center. For the PSD 14 memantine study, we randomly assigned animals to treatment groups (Vehicle; 10 mice, Memantine; 10 mice, 11–14 weeks old mice). One mouse in vehicle group and one mouse in the memantine group died during the stroke surgery and were excluded from the study. For the PSD 3 memantine study to measure primary infarction, we randomly assigned a total 12 mice to vehicle or memantine groups (Vehicle, 6 mice, Mem, 6 mice). One mouse in the vehicle treated group died during surgery and was excluded from the study. Four male Cx3cr1-TdT mice were used in this study (a microglia TdTomato reporter line)

Results

Discussion

Conclusion