Abstract
Because stroke therapies are still limited and patients are often concerned by long-term sequelae with significant impairment of daily living, elaborated neuroprotective strategies are needed. During the last decades, research substantially improved the knowledge on cellular pathologies responsible for stroke-related tissue damage. In this context, the neurovascular unit (NVU) concept has been established, summarizing the affections of neurons, associated astrocytes and the vasculature. Although oligodendrocytes were already identified to play a major role in other brain pathologies, their role during stroke evolution and long-lasting tissue damage is poorly understood. This study aims to explore oligodendrocyte structures, i.e., oligodendrocytes and their myelin-associated proteins, after experimental focal cerebral ischemia. For translational issues, different ages and genotypes including an Alzheimer-like background were considered to mimic potential co-morbidities. Three- and 12-month-old wild-type and triple-transgenic mice were subjected to unilateral middle cerebral artery occlusion. Immunofluorescence labeling was performed on forebrain tissues affected by 24 h of ischemia to visualize the oligodendrocyte-specific protein (OSP), the myelin basic protein (MBP), and the neuron-glia antigen 2 (NG2) with reference to the ischemic lesion. Subsequent analyses concomitantly detected the vasculature and the 2′, 3′-cyclic nucleotide-3′-phosphodiesterase (CNPase) to consider the NVU concept and to explore the functional relevance of histochemical data on applied oligodendrocyte markers. While the immunosignal of NG2 was found to be nearly absent 24 h after ischemia onset, enhanced immunoreactivities for OSP and especially MBP were observed in close regional association to the vasculature. Added quantitative analyses based on inter-hemispheric differences of MBP-immunoreactivity revealed a shell-like pattern with a significant increase directly in the ischemic core, followed by a gradual decline toward the striatum, the ischemic border zone and the lateral neocortex. This observation was consistent in subsequent analyses on the potential impact of age and genetic background. Furthermore, immunoreactivities for CNPase, MBP, and OSP were found to be simultaneously enhanced. In conclusion, this study provides evidence for a critical role of oligodendrocyte structures in the early phase after experimental stroke, strengthening their involvement in the ischemia-affected NVU. Consequently, oligodendrocytes and their myelin-associated proteins may qualify as potential targets for neuroprotective and regenerative approaches in stroke.
Highlights
Ischemic stroke still ranges among the three most common causes of death worldwide, and survivors are often concerned by long-term sequels like aphasia and functional relevant limb paresis, resulting in an enormous personal and socio-economic burden (Kolominsky-Rabas et al, 1998; Benjamin et al, 2017)
Strategies for acute stroke treatment are currently focused on the recanalization of occluded cerebral vessels (Hankey, 2017), which can be facilitated by intravenous thrombolysis (Hacke et al, 2008) and – in the subpopulation of patients with large vessel occlusions – added mechanical thrombectomy (Goyal et al, 2016)
A first set of experiments focused on the detection of oligodendrocyte structures in brain areas affected by 24 h of focal cerebral ischemia
Summary
Ischemic stroke still ranges among the three most common causes of death worldwide, and survivors are often concerned by long-term sequels like aphasia and functional relevant limb paresis, resulting in an enormous personal and socio-economic burden (Kolominsky-Rabas et al, 1998; Benjamin et al, 2017). Strategies for acute stroke treatment are currently focused on the recanalization of occluded cerebral vessels (Hankey, 2017), which can be facilitated by intravenous thrombolysis (Hacke et al, 2008) and – in the subpopulation of patients with large vessel occlusions – added mechanical thrombectomy (Goyal et al, 2016). As these strategies only reach the minority of acute stroke patients (Dirks et al, 2011), research was intensified toward the pathophysiology of stroke evolution and related tissue damage (Dirnagl et al, 1999) to explore potential neuroprotective treatments. The complexity of interactions within the NVU and the associated BBB might help to understand the still existing translational roadblock, which means the lacking efficacy of preclinical wellestablished approaches under clinical conditions – as for instance shown for the free radical scavenger NXY-059 (Savitz, 2007; Endres et al, 2008)
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