Article Figures & Data
Figures
- Figure 1
Activation of matrix metalloproteinases (MMPs) and blood-brain barrier (BBB) disruption after ischaemic stroke. Schematic representation of the plausible downstream activation of multiple MMPs and rupture of the BBB after transient cerebral ischaemia and reperfusion. MMP-12 is produced from cells as a proenzyme that is inactive (pro-MMP-12), which then goes through autolytic processing to become active. Other proenzymes, such as pro-MMP-2 and pro-MMP-3, are activated by activated MMP-12. Several additional proenzymes, including pro-MMP-1 and pro-MMP-9, are activated by activated MMP-3. Together, these active MMPs degrade multiple extracellular matrix (ECM) and tight junction (TJ) proteins, disrupt BBB and allow blood cells to infiltrate and enter the brain. This figure was created with biorender.com under a paid subscription.
- Figure 2
Role of MMP-12 in ischaemic stroke. The potential molecular changes and pathophysiological processes by which elevated MMP-12 contributes to brain injury and sensorimotor and cognitive impairments after an ischaemic stroke are depicted schematically. BBB, blood-brain barrier; ECM, extracellular matrix; IL-6, interleukin-6; MBP, myelin basic protein; MCP-1, monocyte chemoattractant protein-1; MMP, matrix metalloproteinase; TJs, tight junction proteins; TNFα, tumour necrosis factor α. This figure was created with biorender.com under a paid subscription.
Tables
- Table 1
MMP-12 levels increase in the brain after cerebral ischaemia followed by reperfusion
Species Stroke induction method Results (related to MMP-12 expression) Reference Mouse Permanent CAO and 50 min hypoxia MMP-12 expressed in microglia and neurons on day 1 post-CAO.
Increased MMP-12 mRNA and protein expression on day 3.Svedin et al, Developmental Neuroscience 200940 Rat 2 hour MCAO Increased MMP-12 mRNA and protein expression on post-ischaemic days 1, 3, 5, 7 and 14.
MMP-12 expressed in neurons, oligodendrocytes and microglia/macrophages on day 7.Chelluboina et al, Scientific Reports 201535 Rat 2 hour MCAO Increased MMP-12 expression immediately after ischaemia (1 hour, 2 hours and 4 hours MCAO); increase more pronounced on day 1. Chelluboina et al, Stroke 201536 Mouse 1 hour MCAO Increased MMP-12 mRNA expression on post-ischaemic day 1. Nalamolu et al, Stroke and Vascular Neurology 201841 Mouse Photothrombotic cortical ischaemia Increased MMP-12 mRNA expression on post-ischaemic day 3.
MMP-12 expressed in microglia.Hohjoh et al, Neuroscience Letters 202042 Mouse 1 hour MCAO Increased protein expression of MMP-12 on post-ischaemic day 1. Arruri et al, Neurochemistry International 202237 Rat 2 hour MCAO Increased mRNA expression of MMP-12 on post-ischaemic days 1, 3, and 7.
MMP-12 expression not elevated in contralateral hemisphere.Challa et al, Frontiers in Neuroscience 202239 CAO, carotid artery occlusion; MCAO, middle cerebral artery occlusion.
- Table 2
MMP-12 suppression/inhibition following ischaemic stroke is beneficial
Species Stroke induction method Test item Dose (ROA) Time of injection Results Reference Rat 2 hour MCAO MMP-12 shRNA 1 mg/kg (IV) 1 day AR Reduced infarct size, apoptosis and TNFα expression.
Decreased MMP-9 expression and MBP degradation.Chelluboina et al, Scientific Reports 201535 Rat 2 hour MCAO MMP-12 shRNA 1 mg/kg (IV and IA) Immediately (within 30 min) AR Reduced BBB disruption, tight junction proteins degradation and infarct size.
Decreased expression of MMP-9 and tPA.Chelluboina et al, Stroke 201536 Rat 2 hour MCAO MMP-12 shRNA 1 mg/kg (IV) Immediately (within 30 min) AR Reduced expression of microglial markers (CD68, IL-10, Arg1 and TGFβ) and MMPs (7, 9, 11 and 14). Challa et al, Stroke 202238 Mouse 1 hour MCAO MMP-12 siRNA 35 nmol (IV) Immediately (5 min) AR Reduced infarct volume, tight junction protein degradation, expression of inflammatory mediators (MCP-1, TNFα and IL-6) and cleaved caspase-3.
Improved motor and cognitive functions.Arruri et al, Neurochemistry International 202237 Rat 2 hour MCAO MMP-12 shRNA 1 mg/kg (IV) Immediately AR, 3 hour AR, or 6 hour AR
Immediately AR and on day 7 and 14 ARImproved sensory and motor functions.
Immediate treatment was superior to delayed treatments.
Acute and chronic MMP-12 suppression are equally effective.Challa et al, Frontiers in Neuroscience 202239 MCAO, middle cerebral artery occlusion; ROA, route of administration; IV, intravenous; IA, intra-arterial; AR, after reperfusion; tPA, tissue-type plasminogen activator; MBP, myelin basic protein; BBB, blood-brain barrier; MCP-1, monocyte chemoattractant protein-1; TNF, tumour necrosis factor; IL, interleukin; Arg, arginase; TGF, transforming growth factor.
- Article
- Abstract
- Introduction
- MMP-12 expression increases after IS
- Role of MMP-12 in post-stroke pathogenesis
- Unique molecular interactions of MMP-12 and mechanistic insights
- MMP-12 involvement in poststroke functional deficits and recovery
- Perspectives, limitations, challenges and future directions
- Conclusions
- Ethics statements
- Acknowledgments
- Footnotes
- References
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