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.

We have previously demonstrated that a cortical stroke causes persistent impairment of hippocampal‐dependent cognitive tasks concomitant with secondary neurodegenerative processes such as amyloid‐β accumulation in the hippocampus, a region remote from the primary infarct. Interestingly, there is emerging evidence suggesting that deposition of amyloid‐β around cerebral vessels may lead to cerebrovascular structural changes, neurovascular dysfunction, and disruption of blood–brain barrier integrity. However, there is limited knowledge about the temporal changes of hippocampal cerebrovasculature after cortical stroke. In the current study, we aimed to characterise the spatiotemporal cerebrovascular changes after cortical stroke. This was done using the photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Cerebrovascular morphology as well as the co‐localisation of amyloid‐β with vasculature and blood–brain barrier integrity were assessed in the cortex and hippocampal regions at 7, 28 and 84 days post‐stroke. Our findings showed transient cerebrovascular remodelling in the peri‐infarct area up to 28 days post‐stroke. Importantly, the cerebrovascular changes were extended beyond the peri‐infarct region to the ipsilateral hippocampus and were sustained out to 84 days post‐stroke. When investigating vessel diameter, we showed a decrease at 84 days in the peri‐infarct and CA1 regions that were exacerbated in vessels with amyloid‐β deposition. Lastly, we showed sustained vascular leakage in the peri‐infarct and ipsilateral hippocampus, indicative of a compromised blood–brain‐barrier. Our findings indicate that hippocampal vasculature may represent an important therapeutic target to mitigate the progression of post‐stroke cognitive impairment.

Stroke is the leading cause of acquired disability. The development of acute ischemic stroke treatments, such as mechanical thrombectomy and tissue plasminogen activator, has resulted in more patients surviving the initial insult. However, long‐term complications, such as post‐stroke cognitive impairment (PSCI) and dementia (PSD), are at an all‐time high. Notably, 80% of stroke survivors suffer from cognitive impairment, and a history of stroke doubles a patient's lifetime risk of developing dementia. A combination of greater life expectancy, an increase in the number of strokes in young individuals, and improved survival have inherently increased the number of years patients are living post‐stroke, highlighting the critical need to understand the long‐term effects of stroke, including how pathological changes in the brain might give rise to functional and behavioral changes in stroke survivors. Even with this increased risk of PSCI and PSD in stroke survivors, understanding of how the stroke itself develops into these conditions remains incomplete. Recently, secondary neurodegeneration (SND) following stroke has been linked with PSCI and PSD. SND is the degeneration of brain regions outside the original stroke site. Degeneration in these sites is thought to arise due to functional diaschisis with the infarct core; however, observation of SND pathology in multiple regions without direct connectivity to the stroke infarct suggests that the degeneration in these regions is likely more complex. Moreover, pathological hallmarks of dementia, such as a deposition of neurodegenerative proteins and iron, cell death, inflammation and blood–brain barrier alterations, have all been found in regions such as the thalamus, hippocampus, basal ganglia, amygdala and prefrontal cortex following stroke. Hence, in this review, we present the current understanding of PSCI and PSD in the context of SND and outline how remote anatomical and molecular changes may drive the development of these conditions.

We have previously demonstrated that a cortical stroke causes persistent impairment of hippocampal-dependent cognitive tasks concomitant with secondary neurodegenerative processes such as amyloid-β accumulation in the hippocampus, a region remote from the primary infarct. Interestingly, there is emerging evidence suggesting that deposition of amyloid-β around cerebral vessels may lead to cerebrovascular structural changes, neurovascular dysfunction, and disruption of blood-brain barrier integrity. However, there is limited knowledge about the temporal changes of hippocampal cerebrovasculature after cortical stroke. In the current study, we aimed to characterise the spatiotemporal cerebrovascular changes after cortical stroke. This was done using the photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Cerebrovascular morphology as well as the colocalization of amyloid-β with vasculature and blood-brain-barrier integrity were assessed in the cortex and hippocampal regions at 7, 28 and 84 days post-stroke. Our findings showed transient cerebrovascular remodelling in the peri-infarct area up to 28 days post-stroke. Importantly, the cerebrovascular changes were extended beyond the peri-infarct region to the ipsilateral hippocampus and were sustained out to 84 days post-stroke. When investigating vessel diameter, we showed a decrease at 84 days in the peri-infarct and CA1 regions that was exacerbated in vessels with amyloid-β deposition. Lastly, we showed sustained vascular leakage in the peri-infarct and ipsilateral hippocampus, indicative of a compromised blood-brain-barrier. Our findings indicate that hippocampal vasculature may represent an important therapeutic target to mitigate the progression of post-stroke cognitive impairment.