Abstract TP85: The Kca3.1 Tram-34 Reduces Selective Neuronal Loss, Microglial Activation and Sensorimotor Deficits Following Brief Middle-cerebral Artery Occlusion (mcao) in the Rat


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Abstract

Introduction: We have previously shown that 15min distal MCAo in the spontaneously hypertensive rat (SHR) consistently induces isolated selective neuronal loss (SNL) and topographically congruent microglial activation (MA), together with slowly recovering sensori-motor deficit (SMD) (Ejaz et al, Stroke, 2015). Whether MA exacerbates SNL in the reperfused penumbra is unclear. We tested whether reducing MA by means of the KCa3.1 blocker TRAM-34 also impacts SNL and SMD in this model.Methods: 15min microclip distal MCAo was performed in 12 isoflurane-anesthetized adult male SHRs, randomized in two groups of n=6 rats, a control group and a treated group that received TRAM-34 40mg/kg i.p. bd for 1 week starting 12hrs post-MCAo, then od for 3 weeks. To quantify SMD, the sticky label test was administered 3 times a week for 28 days. NeuN and Iba4 immunoflorescence was then performed. Manual delineation of areas of SNL and MA was carried out by two independent assessors on randomly presented IF sections, and volumes of SNL and MA were determined. Both assessments were done blinded to subject’s group.Results: Although less so than in controls, SMD was significant in the TRAM-34 group (p<.001 and .01, respectively), with a significant Group x Time interaction (p=0.004, repeated-measures ANOVA) and a trend for faster recovery from day 7 in the latter. On IF, the volume (mm3) of MA was lower in the TRAM-34 relative to control group (1.33 ± 1.7 vs 0.27 ± 0.46), which also applied to SNL (1.41 ± 1.79 vs 0.28 ± 0.41) (p = 0.018 and 0.015, respectively; two-sample t-test).Conclusion: In this pilot study, the expected marked reduction in MA induced by TRAM34 was associated with concomitant reductions in SNL and faster SMD recovery. Thus, the early administration of an MA blocker following treatment-induced reperfusion in the clinical setting might reduce cell damage in the salvaged penumbra and in turn enhance neurological recovery.

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