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Updated: Jun 7, 2026
A Magnetic Resonance Imaging Protocol for Stroke Onset Time Estimation in Permanent Cerebral Ischemia
Published on: September 16, 2017
Selective MMP-inhibition with Ro 28-2653 in acute experimental stroke--a magnetic resonance imaging efficacy study
S Nagel1, P V Heinemann, S Heiland
1Department of Neurology, University of Heidelberg, Heidelberg, Germany.
Abstract:
Blood-brain-barrier (BBB) breakdown due to matrix metalloproteinase (MMP) activity following stroke is often associated with cerebral edema, larger infarct volumes and bad outcome. In the present study we examined a novel MMP-inhibitor (Ro 28-2653) with high selectivity for MMP2, MMP9 and membrane type 1-MMP in an acute stroke model comparing two different treatment regimens. We subjected rats to 90 min of focal cerebral ischemia followed by 3 days or 7 days of reperfusion, respectively, using the middle cerebral artery (MCA) filament occlusion technique. Ro 28-2653 was administered daily in a vehicle solution for 2 days or 6 days after ischemia, respectively. We assessed the behavior with a functional neuroscore and infarct volumes as well as blood-brain-barrier (BBB) breakdown with magnetic resonance imaging (MRI) after 3 and 7 days. Infarct edema volumes, BBB breakdown and behavior at 3 days were significantly attenuated in rats treated for 2 days with Ro 28-2653 as compared to vehicle and untreated controls. After 6 days of treatment however, infarct and BBB breakdown volumes as well as behavior did not differ significantly between the groups at 7 days. The new high selective MMP-inhibitor Ro 28-2653 significantly reduced brain injury only when administered in the first 2 days after focal cerebral ischemia. Prolonged treatment for 6 days did not show any beneficial effects possibly due to interference with protective restorative processes.
Insights
A novel matrix metalloproteinase (MMP) inhibitor, Ro 28-2653, reduced stroke-induced brain injury when given within 2 days post-ischemia. Extended treatment did not improve outcomes, suggesting timing is critical for MMP inhibitor efficacy.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Matrix metalloproteinase (MMP) activity contributes to blood-brain barrier (BBB) disruption after stroke, leading to cerebral edema, larger infarcts, and poor outcomes.
- Matrix metalloproteinases (MMPs), particularly MMP2 and MMP9, play a significant role in the pathogenesis of ischemic stroke.
- Understanding the role of MMPs in stroke is crucial for developing effective therapeutic interventions.
Purpose of the Study:
- To investigate the efficacy of a novel, selective MMP inhibitor (Ro 28-2653) in an acute stroke model.
- To compare the effects of two different treatment durations (2 days vs. 6 days) of Ro 28-2653 on stroke outcomes.
- To evaluate the impact of Ro 28-2653 on brain injury, blood-brain barrier (BBB) integrity, and functional recovery after focal cerebral ischemia.
Main Methods:
- Rats underwent 90 minutes of middle cerebral artery (MCA) occlusion to induce focal cerebral ischemia.
- Ro 28-2653, a selective inhibitor of MMP2, MMP9, and membrane type 1-MMP, was administered daily for 2 or 6 days post-ischemia.
- Outcomes including functional neuroscore, infarct volume, and BBB breakdown were assessed using magnetic resonance imaging (MRI) at 3 and 7 days post-stroke.
Main Results:
- Early administration (2 days) of Ro 28-2653 significantly reduced infarct and edema volumes, BBB breakdown, and improved functional behavior at 3 days post-stroke.
- In contrast, prolonged treatment (6 days) did not yield significant differences in infarct/BBB volumes or behavior at 7 days compared to controls.
- The beneficial effects of Ro 28-2653 were observed only when treatment was initiated within the initial 2 days following focal cerebral ischemia.
Conclusions:
- The novel MMP inhibitor Ro 28-2653 demonstrates therapeutic potential in acute ischemic stroke, but its efficacy is time-dependent.
- Early intervention with Ro 28-2653 can mitigate acute brain injury and BBB disruption following stroke.
- Prolonged treatment beyond the acute phase may not provide additional benefits and could potentially interfere with natural recovery processes.
