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Beyond the Primary Infarction: Focus on Mechanisms Related to Secondary Neurodegeneration after Stroke

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 23927

Special Issue Editor

1. School of Pharmacy, Monash University Malaysia, Bandar Sunway, Subang Jaya 47500, Selangor, Malaysia
2. School of Biomedical Sciences and Pharmacy and the Priority Research Centre for Stroke and Brain Injury, The University of Newcastle, University Dr, Callaghan, NSW 2308, Australia
Interests: stroke recovery; neurodegeneration; brain plasticity; neuroinflammation; stress biology; growth hormone; tyrosine hydroxylase

Special Issue Information

Dear Colleagues,

There is now emerging evidence that stoke can cause progressive loss of remote brain regions that are connected to the primary infarction site, a process termed as secondary neurodegeneration. Secondary neurodegeneration has been consistently observed in the thalamus, substantia nigra and recently in the hippocampus. Further, secondary neurodegeneration has been linked to several post-stroke functional disturbances, such as cognitive impairment, depression and fatigue. Whilst post-stroke secondary neurodegeneration was first reported decades ago, the underlying mechanisms remain to be elucidated. Recent studies in preclinical stroke models and in humans have documented several key neuropathological features, such as Wallerian degeneration, blood-brain-barrier breakdown, inflammatory processes and accumulation of waste products or neurotoxic proteins. As secondary neurodegeneration unfolds over a longer time scale after stroke, this provides a potential therapeutic target with extended time window. We are seeking preclinical and clinical studies that expand our understanding on the mechanisms related to secondary neurodegeneration after stroke as well as the development of novel strategies that can ameliorate secondary neurodegeneration, leading to functional recovery.

Dr. Lin Kooi Ong
Guest Editor

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Keywords

  • stroke
  • secondary neurodegeneration
  • molecular mechanisms
  • Wallerian degeneration
  • blood-brain-barrier breakdown
  • amyloid-β
  • tau
  • glymphatic
  • neuroinflammation
  • microglia
  • astrocytes
  • brain recovery
  • cognitive impairment
  • therapeutic
  • translational research

Published Papers (7 papers)

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Editorial

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3 pages, 179 KiB  
Editorial
Beyond the Primary Infarction: Focus on Mechanisms Related to Secondary Neurodegeneration after Stroke
by Lin Kooi Ong
Int. J. Mol. Sci. 2022, 23(24), 16024; https://doi.org/10.3390/ijms232416024 - 16 Dec 2022
Cited by 1 | Viewed by 1211
Abstract
Recently, a growing body of evidence has indicated that secondary neurodegeneration after stroke occurs at remote regions of the brain that are connected to the primary infarction site [...] Full article

Research

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23 pages, 6877 KiB  
Article
Recovery of Post-Stroke Spatial Memory and Thalamocortical Connectivity Following Novel Glycomimetic and rhBDNF Treatment
by Josh Houlton, Olga V. Zubkova and Andrew N. Clarkson
Int. J. Mol. Sci. 2022, 23(9), 4817; https://doi.org/10.3390/ijms23094817 - 27 Apr 2022
Cited by 1 | Viewed by 2296
Abstract
Stroke-induced cognitive impairments remain of significant concern, with very few treatment options available. The involvement of glycosaminoglycans in neuroregenerative processes is becoming better understood and recent advancements in technology have allowed for cost-effective synthesis of novel glycomimetics. The current study evaluated the therapeutic [...] Read more.
Stroke-induced cognitive impairments remain of significant concern, with very few treatment options available. The involvement of glycosaminoglycans in neuroregenerative processes is becoming better understood and recent advancements in technology have allowed for cost-effective synthesis of novel glycomimetics. The current study evaluated the therapeutic potential of two novel glycomimetics, compound A and G, when administered systemically five-days post-photothrombotic stroke to the PFC. As glycosaminoglycans are thought to facilitate growth factor function, we also investigated the combination of our glycomimetics with intracerebral, recombinant human brain-derived neurotrophic factor (rhBDNF). C56BL/6J mice received sham or stroke surgery and experimental treatment (day-5), before undergoing the object location recognition task (OLRT). Four-weeks post-surgery, animals received prelimbic injections of the retrograde tracer cholera toxin B (CTB), before tissue was collected for quantification of thalamo-PFC connectivity and reactive astrogliosis. Compound A or G treatment alone modulated a degree of reactive astrogliosis yet did not influence spatial memory performance. Contrastingly, compound G+rhBDNF treatment significantly improved spatial memory, dampened reactive astrogliosis and limited stroke-induced loss of connectivity between the PFC and midline thalamus. As rhBDNF treatment had negligible effects, these findings support compound A acted synergistically to enhance rhBDNF to restrict secondary degeneration and facilitate functional recovery after PFC stroke. Full article
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16 pages, 7752 KiB  
Article
Enhancing Post-Stroke Rehabilitation and Preventing Exo-Focal Dopaminergic Degeneration in Rats—A Role for Substance P
by Sibylle Frase, Franziska Löffler and Jonas A. Hosp
Int. J. Mol. Sci. 2022, 23(7), 3848; https://doi.org/10.3390/ijms23073848 - 31 Mar 2022
Cited by 5 | Viewed by 2012
Abstract
Dopaminergic signaling is a prerequisite for motor learning. Delayed degeneration of dopaminergic neurons after stroke is linked to motor learning deficits impairing motor rehabilitation. This study investigates safety and efficacy of substance P (SP) treatment on post-stroke rehabilitation, as this neuropeptide combines neuroprotective [...] Read more.
Dopaminergic signaling is a prerequisite for motor learning. Delayed degeneration of dopaminergic neurons after stroke is linked to motor learning deficits impairing motor rehabilitation. This study investigates safety and efficacy of substance P (SP) treatment on post-stroke rehabilitation, as this neuropeptide combines neuroprotective and plasticity-promoting properties. Male Sprague Dawley rats received a photothrombotic stroke within the primary motor cortex (M1) after which a previously acquired skilled reaching task was rehabilitated. Rats were treated with intraperitoneal saline (control group, n = 7) or SP-injections (250 µg/kg) 30 min before (SP-pre; n = 7) or 16 h (SP-post; n = 6) after rehabilitation training. Dopaminergic neurodegeneration, microglial activation and substance P-immunoreactivity (IR) were analyzed immunohistochemically. Systemic SP significantly facilitated motor rehabilitation. This effect was more pronounced in SP-pre compared to SP-post animals. SP prevented dopaminergic cell loss after stroke, particularly in the SP-pre condition. Despite its proinflammatory propensity, SP administration did not increase stroke volumes, post-stroke deficits or activation of microglia in the midbrain. Finally, SP administration prevented ipsilesional hypertrophy of striatal SPergic innervation, particularly in the SP-post condition. Mechanistically, SP-pre likely involved plasticity-promoting effects in the early phase of rehabilitation, whereas preservation of dopaminergic signaling may have ameliorated rehabilitative success in both SP groups during later stages of training. Our results demonstrate the facilitating effect of SP treatment on motor rehabilitation after stroke, especially if administered prior to training. SP furthermore prevented delayed dopaminergic degeneration and preserved physiological endogenous SPergic innervation. Full article
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8 pages, 2187 KiB  
Communication
Knockout of the P2Y6 Receptor Prevents Peri-Infarct Neuronal Loss after Transient, Focal Ischemia in Mouse Brain
by Stefan Milde and Guy C. Brown
Int. J. Mol. Sci. 2022, 23(4), 2304; https://doi.org/10.3390/ijms23042304 - 19 Feb 2022
Cited by 7 | Viewed by 1973
Abstract
After stroke, there is a delayed neuronal loss in brain areas surrounding the infarct, which may in part be mediated by microglial phagocytosis of stressed neurons. Microglial phagocytosis of stressed or damaged neurons can be mediated by UDP released from stressed neurons activating [...] Read more.
After stroke, there is a delayed neuronal loss in brain areas surrounding the infarct, which may in part be mediated by microglial phagocytosis of stressed neurons. Microglial phagocytosis of stressed or damaged neurons can be mediated by UDP released from stressed neurons activating the P2Y6 receptor on microglia, inducing microglial phagocytosis of such neurons. We show evidence here from a small trial that the knockout of the P2Y6 receptor, required for microglial phagocytosis of neurons, prevents the delayed neuronal loss after transient, focal brain ischemia induced by endothelin-1 injection in mice. Wild-type mice had neuronal loss and neuronal nuclear material within microglia in peri-infarct areas. P2Y6 receptor knockout mice had no significant neuronal loss in peri-infarct brain areas seven days after brain ischemia. Thus, delayed neuronal loss after stroke may in part be mediated by microglial phagocytosis of stressed neurons, and the P2Y6 receptor is a potential treatment target to prevent peri-infarct neuronal loss. Full article
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15 pages, 5918 KiB  
Article
Corticosterone Administration Alters White Matter Tract Structure and Reduces Gliosis in the Sub-Acute Phase of Experimental Stroke
by Katarzyna Zalewska, Rebecca J. Hood, Giovanni Pietrogrande, Sonia Sanchez-Bezanilla, Lin Kooi Ong, Sarah J. Johnson, Kaylene M. Young, Michael Nilsson and Frederick R. Walker
Int. J. Mol. Sci. 2021, 22(13), 6693; https://doi.org/10.3390/ijms22136693 - 22 Jun 2021
Cited by 5 | Viewed by 2473
Abstract
White matter tract (WMT) degeneration has been reported to occur following a stroke, and it is associated with post-stroke functional disturbances. White matter pathology has been suggested to be an independent predictor of post-stroke recovery. However, the factors that influence WMT remodeling are [...] Read more.
White matter tract (WMT) degeneration has been reported to occur following a stroke, and it is associated with post-stroke functional disturbances. White matter pathology has been suggested to be an independent predictor of post-stroke recovery. However, the factors that influence WMT remodeling are poorly understood. Cortisol is a steroid hormone released in response to prolonged stress, and elevated levels of cortisol have been reported to interfere with brain recovery. The objective of this study was to investigate the influence of corticosterone (CORT; the rodent equivalent of cortisol) on WMT structure post-stroke. Photothrombotic stroke (or sham surgery) was induced in 8-week-old male C57BL/6 mice. At 72 h, mice were exposed to standard drinking water ± CORT (100 µg/mL). After two weeks of CORT administration, mice were euthanised and brain tissue collected for histological and biochemical analysis of WMT (particularly the corpus callosum and corticospinal tract). CORT administration was associated with increased tissue loss within the ipsilateral hemisphere, and modest and inconsistent WMT reorganization. Further, a structural and molecular analysis of the WMT components suggested that CORT exerted effects over axons and glial cells. Our findings highlight that CORT at stress-like levels can moderately influence the reorganization and microstructure of WMT post-stroke. Full article
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Review

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14 pages, 795 KiB  
Review
Neuronal Loss after Stroke Due to Microglial Phagocytosis of Stressed Neurons
by Guy C. Brown
Int. J. Mol. Sci. 2021, 22(24), 13442; https://doi.org/10.3390/ijms222413442 - 14 Dec 2021
Cited by 29 | Viewed by 4304
Abstract
After stroke, there is a rapid necrosis of all cells in the infarct, followed by a delayed loss of neurons both in brain areas surrounding the infarct, known as ‘selective neuronal loss’, and in brain areas remote from, but connected to, the infarct, [...] Read more.
After stroke, there is a rapid necrosis of all cells in the infarct, followed by a delayed loss of neurons both in brain areas surrounding the infarct, known as ‘selective neuronal loss’, and in brain areas remote from, but connected to, the infarct, known as ‘secondary neurodegeneration’. Here we review evidence indicating that this delayed loss of neurons after stroke is mediated by the microglial phagocytosis of stressed neurons. After a stroke, neurons are stressed by ongoing ischemia, excitotoxicity and/or inflammation and are known to: (i) release “find-me” signals such as ATP, (ii) expose “eat-me” signals such as phosphatidylserine, and (iii) bind to opsonins, such as complement components C1q and C3b, inducing microglia to phagocytose such neurons. Blocking these factors on neurons, or their phagocytic receptors on microglia, can prevent delayed neuronal loss and behavioral deficits in rodent models of ischemic stroke. Phagocytic receptors on microglia may be attractive treatment targets to prevent delayed neuronal loss after stroke due to the microglial phagocytosis of stressed neurons. Full article
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45 pages, 1831 KiB  
Review
Neuroinflammation as a Key Driver of Secondary Neurodegeneration Following Stroke?
by Shannon M. Stuckey, Lin Kooi Ong, Lyndsey E. Collins-Praino and Renée J. Turner
Int. J. Mol. Sci. 2021, 22(23), 13101; https://doi.org/10.3390/ijms222313101 - 3 Dec 2021
Cited by 57 | Viewed by 7952
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 [...] Read more.
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. Full article
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