Assessing the Effects of Cytoprotectants on Selective Neuronal Loss, Sensorimotor Deficit and Microglial Activation after Temporary Middle Cerebral Occlusion.

Julius V Emmrich,Heike Wulff,Sohail Ejaz,Young T Hong,Tim D Fryer,David J Williamson,Sergey Sitnikov,Jean-Claude Baron,Franklin I Aigbirhio

doi:10.3390/brainsci9100287

Abstract

Although early reperfusion after stroke salvages the still-viable ischemic tissue, peri-infarct selective neuronal loss (SNL) can cause sensorimotor deficits (SMD). We designed a longitudinal protocol to assess the effects of cytoprotectants on SMD, microglial activation (MA) and SNL, and specifically tested whether the KCa3.1-blocker TRAM-34 would prevent SNL. Spontaneously hypertensive rats underwent 15 min middle-cerebral artery occlusion and were randomized into control or treatment group, which received TRAM-34 intraperitoneally for 4 weeks starting 12 h after reperfusion. SMD was assessed longitudinally using the sticky-label test. MA was quantified at day 14 using in vivo [11C]-PK111195 positron emission tomography (PET), and again across the same regions-of-interest template by immunofluorescence together with SNL at day 28. SMD recovered significantly faster in the treated group (p = 0.004). On PET, MA was present in 5/6 rats in each group, with no significant between-group difference. On immunofluorescence, both SNL and MA were present in 5/6 control rats and 4/6 TRAM-34 rats, with a non-significantly lower degree of MA but a significantly (p = 0.009) lower degree of SNL in the treated group. These findings document the utility of our longitudinal protocol and suggest that TRAM-34 reduces SNL and hastens behavioural recovery without marked MA blocking at the assessed time-points.

Highlights

In acute stroke, due to proximal artery occlusion, mechanical thrombectomy (MT) can rescue the tissue at risk of infarction, i.e., the ischemic penumbra [1]
Brain cytoprotectants [4] may prevent detrimental processes that occur post-reperfusion and affect the rescued penumbra [5,6]. One such process is selective neuronal loss (SNL), documented in rodents subjected to temporary middle cerebral artery occlusion (MCAo) as patchy neuronal loss without extracellular matrix disruption nor death of other brain or vascular cells
The present study aimed to evaluate the feasibility of longitudinally assessing the effects of pharmacological agents on sensorimotor deficit (SMD), microglial activation and neuronal loss induced by transient focal cerebral ischemia in rodents

Summary

Introduction

Due to proximal artery occlusion, mechanical thrombectomy (MT) can rescue the tissue at risk of infarction, i.e., the ischemic penumbra [1]. Brain cytoprotectants [4] may prevent detrimental processes that occur post-reperfusion and affect the rescued penumbra [5,6]. One such process is selective neuronal loss (SNL), documented in rodents subjected to temporary middle cerebral artery occlusion (MCAo) as patchy neuronal loss without extracellular matrix disruption nor death of other brain or vascular cells (see [7] and [8] for review). Neocortical SNL affects sensorimotor behaviour in rats [9,10], and has been documented in the rescued penumbra in stroke patients [11,12,13,14].

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Conclusion