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Anti-VCAM-1 antibodies did not protect against ischemic damage either in rats or in mice
Carles Justicia1, Abraham Martín, Santiago Rojas
1Department of Pharmacology and Toxicology, IIBB-CSIC, IDIBAPS, Barcelona, Spain.
Insights
Vascular cell adhesion molecule-1 (VCAM-1) increased in the brain after stroke, but blocking it did not reduce stroke damage or leukocyte infiltration. VCAM-1 blockade is not a viable stroke treatment strategy.
Area of Science:
- Neuroscience
- Immunology
- Cardiovascular Research
Background:
- Cerebral ischemia induces inflammation and leukocyte infiltration into brain tissue.
- Leukocyte adhesion to the vascular wall is mediated by adhesion molecules like VCAM-1.
- Understanding VCAM-1's role in stroke is crucial for developing therapeutic strategies.
Purpose of the Study:
- To quantify in vivo VCAM-1 expression in the brain, heart, and lungs following transient middle cerebral artery occlusion (MCAO) in rats.
- To evaluate the therapeutic potential of blocking VCAM-1 in reducing ischemic brain damage in rats and mice.
- To investigate the effect of VCAM-1 blockade on leukocyte infiltration in the ischemic brain.
Main Methods:
- Transient middle cerebral artery occlusion (MCAO) was performed in rats and mice.
- In vivo quantification of VCAM-1 expression using radiolabeled anti-VCAM-1 antibody and immunohistochemistry.
- Administration of blocking anti-VCAM-1 antibodies or control antibodies post-MCAO.
- Assessment of neurological scores in rats and infarct volume in rats and mice.
Main Results:
- VCAM-1 expression was significantly upregulated in the ischemic brain microvasculature (4-fold at 24h) and also observed in the contralateral hemisphere and heart, but not lungs.
- Anti-VCAM-1 treatment did not protect against ischemic damage in either rats or mice.
- VCAM-1 blockade reduced monocyte/macrophage/microglia infiltration but did not decrease neutrophil, lymphocyte, or total leukocyte infiltration.
Conclusions:
- Transient focal ischemia leads to vascular VCAM-1 upregulation in the brain and remote organs.
- Blocking VCAM-1 does not offer therapeutic benefits for stroke treatment.
- VCAM-1's role in stroke pathophysiology may be complex, and its blockade is not a promising therapeutic avenue.
Abstract:
Cerebral ischemia triggers an inflammatory process involving the infiltration of leukocytes to the parenchyma. Circulating leukocytes adhere to the vascular wall through adhesion molecules. Here we quantified the in vivo expression of vascular cell adhesion molecule-1 (VCAM-1) in the brain, heart and lungs from 6 to 48 h after transient middle cerebral artery (MCA) occlusion in rats, by intravenous injection of a tracer radiolabelled anti-VCAM-1 antibody. The vascular localization of VCAM-1 was verified by immunohistochemistry after in vivo injection of the antibody. Vascular cell adhesion molecule-1 was strongly induced (4-fold at 24 h) in the microvasculature of the ischemic area, and, to a lesser extent, in the contralateral hemisphere and in a remote organ, the heart, but not in the lungs, indicating that the inflammatory process propagates beyond the injured brain. We injected intravenously either blocking doses of anti-VCAM-1 antibodies or control antibodies after MCA occlusion in rats and mice. We evaluated the neurological score in rats, and infarct volume at 2 days in rats and at 4 days in mice. Anti-VCAM-1 did not protect against ischemic damage either in rats or in mice. Vascular cell adhesion molecule-1 blockade significantly decreased the number of ED1 (labeling monocytes /macrophages/reactive microglia)-positive cells in the ischemic rat brain. However, it did not reduce the numbers of infiltrating neutrophils and lymphocytes, and total leukocytes (CD45 positive), which showed a trend to increase. The results show vascular upregulation of VCAM-1 after transient focal ischemia, but no benefits of blocking VCAM-1, suggesting that this is not a therapeutical strategy for stroke treatment.
