Neuroinflammation as a Key Driver of Secondary Neurodegeneration Following Stroke?

Abstract

Ischaemic stroke involves the rapid onset of focal neurological dysfunction, most commonly due to an arterial blockage in a specific region of the brain. Stroke is a leading cause of death and common cause of disability, with over 17 million people worldwide suffering from a stroke each year. It is now well-documented that neuroinflammation and immune mediators play a key role in acute and long-term neuronal tissue damage and healing, not only in the infarct core but also in distal regions. Importantly, in these distal regions, termed sites of secondary neurodegeneration (SND), spikes in neuroinflammation may be seen sometime after the initial stroke onset, but prior to the presence of the neuronal tissue damage within these regions. However, it is key to acknowledge that, despite the mounting information describing neuroinflammation following ischaemic stroke, the exact mechanisms whereby inflammatory cells and their mediators drive stroke-induced neuroinflammation are still not fully understood. As a result, current anti-inflammatory treatments have failed to show efficacy in clinical trials. In this review we discuss the complexities of post-stroke neuroinflammation, specifically how it affects neuronal tissue and post-stroke outcome acutely, chronically, and in sites of SND. We then discuss current and previously assessed anti-inflammatory therapies, with a particular focus on how failed anti-inflammatories may be repurposed to target SND-associated neuroinflammation.

Keywords: anti-inflammatories; astrocytes; cerebral ischaemia; dementia; inflammation; microglia; neuroprotection; stroke; therapeutic.

Figure 1

Neuroinflammation in Secondary Neurodegeneration following Experimental Stroke. Astrocytes are first increased within the thalamus, hippocampus and substantia nigra (SN) at ~one to two days post-stroke [32,185,186]. Astrocytic scar formation is first apparent in thalamic nuclei at seven weeks post-stroke [51]. Activated microglia are first increased within the thalamus, hippocampus and SN at one to three days post-stroke [177], with specific microglia (loss of process extension with intact phagocytotic functioning) seen in the thalamus at seven days and up to fifty-six days post-stroke [173,202]. Neuronal damage is noted after glial reactivity (~five to seven days) [185,186,199]. Tau phosphorylation in the thalamus [46] and hippocampus [48], and Aβ and APP deposition in the thalamus, is observed at seven days post-stroke [43]. Conversely, Aβ in the hippocampus is not apparent until three weeks post-stroke [47]. T cell infiltration into the thalamus is observed at fourteen days post-stroke [184]. APP deposition adopted plaque-like morphology and was colocalized with microglia at seven weeks post-stroke and Aβ plaques were colocalized with microglia at seven months [174] and was surrounded by an astrocytic scar at nine months post-stroke [43]. ‘↑’ denotes an increase. Created with BioRender© (https://biorender.com) (accessed on 30 November 2021).