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Monocyte chemoattractant protein-1 deficiency is protective in a murine stroke model
Paula M Hughes1, Peter R Allegrini, Markus Rudin
1Nervous System Research, Core Technology Area, Novartis Pharma AG, Basel, Switzerland.
Abstract:
Inflammatory processes have been implicated in the pathogenesis of brain damage after stroke. In rodent stroke models, focal ischemia induces several proinflammatory chemokines, including monocyte chemoattractant protein-1 (MCP-1). The individual contribution to ischemic tissue damage, however, is largely unknown. To address this question, the authors subjected MCP-1-deficient mice (MCP-1-/-) to permanent middle cerebral artery occlusion (MCAO). Measurement of basal blood pressure, cerebral blood flow, and blood volume revealed no differences between wild-type (wt) and MCP-1-/- mice. MCAO led to similar cerebral perfusion deficits in wt and MCP-1-/- mice, excluding differences in the MCA supply territory and collaterals. However, compared with wt mice, the mean infarct volume was 29% smaller in MCP-1-/- mice 24 hours after MCAO (P = 0.022). Immunostaining showed a reduction of phagocytic macrophage accumulation within infarcts and the infarct border in MCP-1-/- mice 2 weeks after MCAO. At the same time point, the authors found an attenuation of astrocytic hypertrophy in the infarct border and thalamus in MCP-1-/- mice. However, these effects on macrophages and astrocytes in MCP-1-/- mice occurred too late to suggest a protective role in acute infarct growth. Of note: at 6 hours after MCAO, MCP-1-/- mice produced significantly less interleukin-1beta in ischemic tissue; this might be related to tissue protection. The results of this study indicate that inhibition of MCP-1 signaling could be a new acute treatment approach to limit infarct size after stroke.
Insights
Monocyte chemoattractant protein-1 (MCP-1) plays a role in stroke-induced brain damage. Inhibiting MCP-1 signaling in mice reduced infarct size, suggesting a potential new treatment for acute stroke.
Area of Science:
- Neuroscience
- Immunology
- Pathophysiology
Background:
- Inflammatory processes contribute to brain damage following stroke.
- Proinflammatory chemokines, such as monocyte chemoattractant protein-1 (MCP-1), are induced by focal ischemia in rodent stroke models.
- The specific role of MCP-1 in ischemic tissue damage remains largely unknown.
Purpose of the Study:
- To investigate the individual contribution of MCP-1 to ischemic tissue damage after stroke.
- To determine the effect of MCP-1 deficiency on infarct volume and associated cellular responses.
Main Methods:
- Permanent middle cerebral artery occlusion (MCAO) was performed on MCP-1-deficient (MCP-1-/-) mice and wild-type (wt) controls.
- Cerebral blood flow, blood volume, and blood pressure were measured.
- Infarct volume was quantified 24 hours after MCAO; macrophage accumulation and astrogliosis were assessed 2 weeks post-MCAO.
Main Results:
- No significant differences in cerebral perfusion or blood pressure were observed between MCP-1-/- and wt mice.
- MCP-1-/- mice exhibited a 29% smaller mean infarct volume 24 hours after MCAO compared to wt mice.
- Reduced macrophage accumulation and attenuated astrogliosis were noted in MCP-1-/- mice, but these effects occurred too late to explain acute infarct reduction.
Conclusions:
- MCP-1 signaling contributes to ischemic brain damage after stroke.
- Early production of interleukin-1beta was reduced in MCP-1-/- mice, potentially contributing to tissue protection.
- Inhibition of MCP-1 signaling represents a potential therapeutic strategy for limiting infarct size in acute stroke.