| Autor: |
Orfila, James E, Burch, Amelia, Dietz, Robert, Schroeder, Christian, Mitchell, Danae, Minjarez, Crystal, Coakley, Kelley, Patsos, olivia, Herson, Paco S |
| Zdroj: |
Stroke (Ovid); February 2022, Vol. 53 Issue: Supplement 1 pAWP248-AWP248, 1p |
| Abstrakt: |
Adult stroke is the a leading cause of mortality and morbidity, with significant sequelae including memory deficits. Despite intense research, no pharmacological interventions are currently available to improve cognitive outcome following ischemic stroke (MCAO). Studies suggest that the non-selective transient receptor potential M2 (TRPM2) channels may contribute to brain injury, specifically in males. This study used electrophysiology and neurobehavior to investigate whether TRPM2 could restore cognitive impairments 30 days after MCAO. To assess the functional role of TRPM2 channels, our novel TRPM2 channel antagonist tat-M2NX was administered intravenously 29 days following MCAO, with contextual fear conditioning performed to measure memory function in mice on day 31. Sham operated mice exhibited intact spatial memory, as indicated by high an increase in freezing behavior (65.44% ± 4.167, N=6) whereas) whereas MCAO mice treated with tat-Scr treated reduced freezing behavior (36.7%, ± 24.4 N=7). . Administration of tatM2NX resulted in improved memory function (72.26% ± 10.98 n=9) compared to tatSCR-treated mice. To assess the effect of MCAO on hippocampal long-term potentiation (LTP), a well-accepted model of learning and memory, extracellular field recordings of CA1 neurons were performed in acute hippocampal slices prepared 31 days after MCAO. Under control conditions, a physiological theta burst stimulation (40 pulses, 100Hz) resulted in LTP that increased the slope of fEPSP to 70.8%, n=5 of baseline MCAO injured mice had impaired LTP (121.1%, n=5). However, mice treated with tat-M2NX on day 30 and recorded on day 31 preserved LTP (185.4, n=5), consistent with improved memory function above. This study suggests that TRPM2 channels contribute to the functional memory impairment seen after MAO at delayed timepoints. Therefore, targeting TRPM2 channel activity may be a potential therapeutic approach to improve long-term functional outcome following MCAO. |
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