Neuroinflammation as a Key Driver of Secondary Neurodegeneration Following Stroke?
Abstract
:1. Introduction
2. Acute Ischaemic Injury Cascade
3. Acute Neuroinflammation in Stroke
3.1. Microglia
3.2. Astrocytes
3.3. Peripheral Immune Cells
4. Chronic Neuroinflammation in Stroke
5. Neuroinflammation in SND
5.1. Microglia
5.2. Astrocytes
5.3. Peripheral Immune Cells
6. Post-Stroke Disorders & Inflammation
Post-Stroke Cognitive Impairment and Dementia
7. Anti-Inflammatories for the Treatment of Ischaemic Stroke
7.1. Acute Anti-Inflammatory Strategies
7.1.1. Minocycline
7.1.2. Fingolimod
7.1.3. Natalizumab
7.1.4. IL-1Ra
7.2. Challenges in Current/Past Neuroprotective Therapies
7.3. Secondary Neurodegeneration Treatment Strategies
8. Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AD | Alzheimer’s disease |
AMPA | amino-3-hydroxy-5-methyl-4-isoxazole propionic acid |
APP | amyloid precursor protein |
AQP4 | aquaporin 4 |
ATP | adenosine triphosphate |
Aβ | amyloid-beta |
BBB | blood-brain barrier |
BCCAo | bilateral common carotid artery occlusion |
CBF | cerebral blood flow |
CD | cluster of differentiation |
CNS | central nervous system |
CRP | C-reactive protein |
CSF | cerebrospinal fluid |
CSPGs | chondroitin sulphate proteoglycans |
ECM | extracellular matrix |
GFAP | Glial fibrillary acidic protein |
GS | glymphatic system |
Iba-1 | ionized calcium binding adaptor molecule 1 |
ICH | intracerebral haemorrhage |
IFN-γ | interferon-γ |
IL | interleukin |
IL-1Ra | interleukin-1 receptor antagonist |
LCN2 | lipocalin-2 |
LPS | lipopolysaccharide |
MCA | middle cerebral artery |
MCAo | middle cerebral artery occlusion |
MMP | matrix metalloproteinases |
MRI | magnetic resonance imaging |
mRS | modified Rankin scale |
NF-κB | nuclear factor kappa-light-chain-enhancer of activated B cells |
NIHSS | National Institute of Health Stroke Scale |
NMDA | N-Methyl-D-aspartate |
NO | nitric oxide |
OPN | osteopontin |
PET | positron emission tomography |
PSCI | post-stroke cognitive impairment |
PSD | post-stroke dementia |
ROS | reactive oxygen species |
SN | substantia nigra |
SND | secondary neurodegeneration |
TNF-α | tumor necrosis factor-alpha |
tPA | tissue plasminogen activators |
TSPO | translocator protein |
VaD | vascular dementia |
VPL | ventral posterolateral nucleus |
VPM | ventral posteromedial nucleus |
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Strain /Species | Stroke Model | Time Points Post-Stroke | Key Findings | |
---|---|---|---|---|
Ross & Ebner, 1990 [182] | Female BALB/c mice |
| 1–120 Days |
|
Herrera & Cuello, 1992 [192] | Male WR | Terminal pia-arachnoid vessel occlusion | 1, 4, 7, 15 and 30 Days |
|
Morioka, Kalehua & Streit, 1993 [177] | Male WR | Bipolar Coagulation (MCAo) | 20 Minutes 3, 6, 18 Hours 1, 2, 3, 5, 7, 14, 21, 28 Days 5, 6, 7 Weeks |
|
Acarin et al., 1999 [193] | Female and Male SDR | Injection of N-methyl-d-aspartate into the right sensorimotor cortex | 4 h, 10 h, 1, 3, 5, 7, 14 and 30 Days |
|
Dihne & Blocak, 2001 [194] | Male SDR | Transient MCAo | 1, 3, 7 and 14 Days |
|
Zhao et al., 2001 [195] | Male SDR | Permanent MCAo | 1, 4, 7 and 12 Days |
|
Dihne et al., 2002 [185] | Male SDR |
| 1, 3, 7, and 14 days |
|
Zhao et al., 2002 [196] | Male SDR | Permanent MCAo | 1, 2, 4, 7 and 12 Days |
|
Loos, Dihne & Block, 2003 [197] | Male SDR | Transient MCAo | 1, 3 and 7 Days |
|
Schroeter et al., 2006 [198] | Wild type and OPN KO mice | Photothrombotic | 3, 7 and 14 Days |
|
Justicia et al., 2008 [51] | Male WR | Transient MCAo | MR: 1–7, 10, 14, 20, and 24 weeks IHC: 3, 7, and 24 weeks |
|
Lipsanen, Hiltunen & Jolkkonen, 2011 [180] | Male WR (Ibuprofen-treated MCAo, MCAo, Sham) | Intraluminal filament model of MCAo | 29 Days |
|
Jiao et al., 2011 [199] | Male WR | Transient MCAo | 3, 7 and 30 Days |
|
Rodriguez-Grande et al., 2013 | Male C57/BL6 mice | Transient MCAo | 4 and 24 h 6 Days |
|
Walberer et al., 2014 [174] | Male WR | Intra-arterial injection of 2 TiO2 spheres (MCAo) | 7 Days and 7 Months |
|
Patience et al., 2015 [181] | Male C57B/6 mice | Photothrombotic | 28 Days |
|
Jones et al., 2015 [200] | Male C57BL/6 mice | Photothrombotic | 28 Days |
|
Weishaupt et al., 2016 [179] | Male SDR | Injection of endothelin-1 to induce stroke in the PFC | 28 Days |
|
Cao et al., 2017 [201] | Male C57BL/6 mice | Transient MCAo | 30 Days |
|
Kluge et al., 2017 [202] | Male HCM | Photothrombotic | 14 Days |
|
Anttila et al., 2018 [203] | Male SDR | Transient MCAo | 2, 7, 14, 28 and 112 Days |
|
Jones et al., 2018 [184] | Male HCM | Photothrombotic | 14 Days |
|
Kluge et al., 2018 [173] | Male HCM | Photothrombotic | 3, 7, 14, 28 and 56 Days |
|
Kluge et al., 2018 [204] | Young (2–4-month-old) and aged (22–23-month-old) Male C57BL/6J mice | Photothrombotic | 7 Days and 28 Days |
|
Ladwig et al., 2018 [205] | Male WR | Photothrombotic | 8 Days |
|
Sanchez-Bezanilla et al., 2019 [187] | Male C57BL/6 mice | Photothrombotic | 14 Days |
|
Li et al., 2020 [206] | Male wild type C57BL/6 and NLRP10-knockout (KO) mice | Transient MCAo | 7, 14 and 28 Days |
|
Cao et al., 2021 [207] | Male C57BL/6 mice | Permanent MCAo | 1, 3, 7, 14, 28, 56, and 84 Days |
|
Kim et al., 2021 [190] | Young (11–14 weeks) and aged (18–22 months) male C57BL/6J | Permanent MCAo | 3 and 14 Days 6 Weeks 2 Years |
|
Sanchez-Bezanilla et al., 2021 [101] | Male C57BL/6 mice | Photothrombotic | 7, 28 and 84 Days |
|
Drug | Year/Drug Trial | Stroke Type | Drug Onset | Administration Route | Timing | Sample Size | Main Outcome | Ref. |
---|---|---|---|---|---|---|---|---|
Minocycline | 2003 to 2005 | AIS | Within 24 h | 200 mg Orally | Daily for 5 days | 151 (n = 74 minocycline, n = 77 placebo) | Lower NIHSS and mRS, higher BI in the minocycline treated compared with control from day 7 to day 30 | Lampl et al. (2007) [280] |
2008 to 2009 (MINOS) | AIS | Within 6 h | 3.0, 4.5, 6.0, 10.0 mg/kg I.V. | Every 12 h for 3 days | 60 (n = 11 for 3.0 mg/kg, n = 4 for 4.5 mg/kg, n = 4 for 6.0 mg/kg, n = 41 for 10 mg/kg) | Minocycline is safe and well tolerated up to doses of 10 mg/kg alone and in combination with tPA | Fagan et al. (2010) [281] | |
2008 to 2009 (MINOS) | AIS | Within 6 h | 3.0, 4.5, 6.0, 10.0 mg/kg I.V. | Every 12 h for 3 days | 60 (n = 11 for 3.0 mg/kg, n = 4 for 4.5 mg/kg, n = 4 for 6.0 mg/kg, n = 41 for 10 mg/kg) | Lower plasma MMP-9 was seen among minocycline treated subjects in combination with tPA | Switzer et al. (2011) [282] | |
2008 to 2009 (MINOS) | AIS | Within 6 h | 3.0, 4.5, 6.0, 10.0 mg/kg I.V. | Every 12 h for 3 days | 60 (n = 11 for 3.0 mg/kg, n = 4 for 4.5 mg/kg, n = 4 for 6.0 mg/kg, n = 41 for 10 mg/kg) | MINOS patients had lower IL-6 at 24 h compared with the separately non-treated cohort | Switzer et al. (2012) [283] | |
2006 to 2008 | AIS | N/A | N/A | N/A | 29 | |||
Not disclosed | AIS | Within 24 h | 200 mg Orally | Daily for 5 days | 50 (n = 23 minocycline treated, n = 27 placebo) | Lower NIHSS score in the minocycline-treated compared with control on day 30 and 90, lower mRS and higher BI at 90 days also | Padma Srivastava et al. (2012) [284] | |
2009 to 2012 | AIS | Within 48 h | 200 mg Orally | Daily for 5 days | 139 | Terminated for futility | Singh et al. (2013) [285] | |
2010 to 2012 (PIMSS) | AIS and ICH | Within 24 h | 100 mg I.V. | Every 12 h for 2 days | 95 (n = 47 minocycline, n = 48 placebo) | Intravenous minocycline was safe but not efficacious | Kohler et al. (2013) [286] | |
2012 | AIS | Within 24 h | 200 mg Orally | Daily for 5 days | 53 (n = 26 minocycline, n = 27 placebo) | Lower NIHSS score in the minocycline-treated compared with control on day 90 | Amiri-Nikpour et al. (2015) [287] | |
2013 to 2016 | ICH | Within 24 h | 400 mg I.V. (First Dose) 400 mg Orally (Subsequent Doses) | Daily for 4 days | 16 (8 randomised to minocycline) | No differences were observed in inflammatory biomarkers, hematoma volume, or perihematomal oedema | Fouda et al. (2017) [88] | |
Fingolimod | 2012 to 2014 | AIS | Within 72 h | 0.5 mg Orally | Daily for 3 days | 22 (n = 11 fingolimod, n = 11 control) | Fingolimod recipients had lower circulating lymphocyte counts, milder neurological deficits, and higher BI scores, lower NIHSS and mRS scores | Fu et al. (2014) [288] |
2012 to 2014 | ICH | Within 72 h | 0.5 mg Orally | Daily for 3 days | 23 (n = 11 fingolimod, n = 12 control) | Fingolimod improved NIHSS, GCS, mRS and BI scores, and had lower circulating lymphocytes | Fu et al. (2014) [289] | |
2013 to 2015 | AIS | Within 4.5 h | 0.5 mg Orally | Daily for 3 days | 47 (n = 25 tPA alone, n = 22 tPA and fingolimod | Fingolimod patients had lower circulating lymphocytes, smaller lesion volumes, less haemorrhage and attenuated neurodeficits with lower NIHSS scores | Zhu et al. (2015) [290] | |
Natalizumab | 2013 to 2015 (ACTION) | AIS | Within 9 h | 300 mg I.V. | Single dose | 161 (n = 79 natalizumab, n = 82 placebo) | Natalizumab did not reduce infarct growth or improve NIHSS scores, however, improvements were seen in mRS and BI scores | Elkins et al. (2017) [291] |
2016 to 2017 (ACTION II) | AIS | Within 24 h | 300 and 600 mg I.V. | Single dose | 239 (n = 77 300 mg dose, n = 81 600 mg dose, n = 81 placebo) | Natalizumab did not improve patient outcomes at either dose | Elkind et al. (2020) [292] | |
IL-1Ra | 2001 to 2003 | AIS and cortical infarcts | Within 6 h | 100 mg I.V. 2 mg/hg/h infusion | Single 100 mg dose followed by 72 h of infusion | 34 (n = 17 IL-1Ra, n = 17 placebo) | Reduction in total white cell count, neutrophil count, NIHSS and mRS scores and plasma CRP and IL-6 in patients receiving IL-1ra compared with placebo | Emsley et al. (2005) [293] |
2001 to 2003 | AIS and cortical infarcts | Within 6 h | 100 mg I.V. 2 mg/hg/h infusion | Single 100 mg dose followed by 72 h of infusion | 34 (n = 17 IL-1Ra, n = 17 placebo) | Treatment with IL-1Ra reverses peripheral innate immune suppression | Smith et al. (2012) [294] | |
2014 to 2016 (SCIL-STROKE) | AIS | Within 5 h | 100 mg SC | Twice daily for 3 days | 80 (n = 39 IL-1Ra, n = 41 placebo) | Reduced plasma IL-6 and CRP, showed no improvement in mRS scores | Smith et al. (2018) [295] |
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Stuckey, S.M.; Ong, L.K.; Collins-Praino, L.E.; Turner, R.J. Neuroinflammation as a Key Driver of Secondary Neurodegeneration Following Stroke? Int. J. Mol. Sci. 2021, 22, 13101. https://doi.org/10.3390/ijms222313101
Stuckey SM, Ong LK, Collins-Praino LE, Turner RJ. Neuroinflammation as a Key Driver of Secondary Neurodegeneration Following Stroke? International Journal of Molecular Sciences. 2021; 22(23):13101. https://doi.org/10.3390/ijms222313101
Chicago/Turabian StyleStuckey, Shannon M., Lin Kooi Ong, Lyndsey E. Collins-Praino, and Renée J. Turner. 2021. "Neuroinflammation as a Key Driver of Secondary Neurodegeneration Following Stroke?" International Journal of Molecular Sciences 22, no. 23: 13101. https://doi.org/10.3390/ijms222313101