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Matrix metalloproteinase (MMP)-12 expression has a negative impact on sensorimotor function following intracerebral
Jennifer E A Wells1, Jeff Biernaskie, Aleksandra Szymanska
1Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, 3330 Hospital Drive, Calgary, Alberta, T2N 4N1, Canada.
Abstract:
We investigated the role of matrix metalloproteinases (MMPs) in a mouse model of intracerebral haemorrhage (ICH). Transcripts encoding nine of the 23 known mammalian MMPs were measured. MMP-12 levels were the most elevated. To evaluate the role of MMP-12 in ICH, haemorrhages were induced in wild-type (WT) and MMP-12 null mice. The results show that MMP-12 null mice exhibited significant functional recovery of forelimb reaching and reduced dependence on the ipsilateral forelimb compared to WT mice. There was also a trend for improved sensory function in the tape removal test. With respect to single pellet skilled reaching, MMP-12 null mice recovered to a level that was not significantly different from sham at 14 and 28 days post-ICH. In contrast, WT animals demonstrated a persistent impairment relative to sham controls throughout the survival period (P < 0.05). The cylinder task revealed a lesion-induced reliance on the ipsilateral forelimb that was apparent at day 7 in both MMP-12 null and WT mice (P < 0.05), but only persisted in WT mice at 14 days post-ICH (P < 0.05). Differences in functional outcome could not be explained by tissue sparing. However, Iba1 immunostaining indicated that more cells bearing macrophage morphology were recruited to the lesion area in WT mice. This is the first study to profile the expression patterns of a number of the known MMPs following ICH in mice. The data indicate that MMP-12 expression following haemorrhagic stroke is deleterious and contributes to the development of secondary injury in this disease.
Insights
Matrix metalloproteinase-12 (MMP-12) worsens outcomes after intracerebral hemorrhage (ICH). MMP-12 null mice showed improved functional recovery and reduced secondary injury compared to wild-type mice following ICH.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Intracerebral hemorrhage (ICH) is a severe neurological condition with limited treatment options.
- Matrix metalloproteinases (MMPs) are implicated in tissue remodeling and inflammation, but their specific roles in ICH are not fully understood.
- MMP-12 was identified as a highly expressed MMP following ICH in preliminary analyses.
Purpose of the Study:
- To investigate the role of matrix metalloproteinase-12 (MMP-12) in functional recovery and secondary injury following intracerebral hemorrhage (ICH) in a mouse model.
- To determine if the absence of MMP-12 improves outcomes after ICH.
Main Methods:
- Intracerebral hemorrhage was induced in wild-type (WT) and MMP-12 null mice.
- Functional recovery was assessed using behavioral tests including forelimb reaching, tape removal, and the cylinder task.
- Histological analysis, including Iba1 immunostaining, was performed to evaluate lesion characteristics and immune cell infiltration.
Main Results:
- MMP-12 null mice demonstrated significantly improved functional recovery in forelimb reaching and reduced ipsilateral forelimb dependence compared to WT mice.
- While both groups showed initial reliance on the unaffected limb, this deficit persisted longer in WT mice.
- No significant differences in tissue sparing were observed, but WT mice showed increased recruitment of Iba1-positive cells with macrophage morphology to the lesion site.
Conclusions:
- MMP-12 expression following ICH is detrimental and contributes to secondary injury.
- Targeting or inhibiting MMP-12 may represent a therapeutic strategy to improve outcomes after hemorrhagic stroke.
- This study provides the first comprehensive profiling of MMP expression in ICH and highlights MMP-12 as a key mediator of post-stroke damage.
