Anti-VCAM-1 Antibodies did not Protect against Ischemic Damage Either in Rats Or in Mice

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.

Antioxidant CR-6 Protects against Reperfusion Injury after a Transient Episode of Focal Brain Ischemia in Rats

“…A simple neurological test on a nine-point scale (0 = no deficit to 9 = highest handicap) was performed before killing the animals, as reported previously (Justicia et al, 2006). Four tests were followed: (1) spontaneous activity (moving/exploring = 0, moving without exploration = 1, no moving or only when pulled by the tail = 2); (2) circling to the left (none = 0, when elevated by the tail and pushed or pulled = 1, spontaneously = 2, circling without displacement (spinning top) = 3); (3) resistance to left forepaw stretching (not stretching allowed = 0, stretching allowed = 1, no resistance = 2); and (4) parachute reflex (symmetrical = 0, asymmetrical = 1, contralateral forelimb retracted = 2).…”

Intravascular cell replacement therapy for stroke

“…Vascular cell adhesion molecule-1 has been shown to reach a peak level 24 hours after experimental stroke. 45 At the bedside, soluble VCAM-1 concentration in plasma is increased in patients with acute stroke. 6 Intercellular adhesion molecule-1 levels have been elevated as early as 4 hours after stroke with sustained levels for up to 1 week.…”

“…4 Anatomically, adhesion molecule upregulation as well as chemokine expression has been shown to be highest in the stroke-affected penumbral region. 35,45 Blocking the different pathways of chemoattraction and cell adhesion in stroke-affected rodents reduced the number of infiltrating inflammatory cells. 4 In mice lacking ICAM-1, a significant reduction in inflammatory cellular infiltrate and a reduction in lesion size was noted.…”

Imaging Brain Inflammation with [11C]PK11195 by PET and Induction of the Peripheral-Type Benzodiazepine Receptor after Transient Focal Ischemia in Rats

“…At 24 h after ischemia, a neurological test in a 9-point scale (0 = absence of functional impairment) was performed to evaluate the functional lesion, as reported (Justicia et al, 2006). Animals scoring 2 points or less were removed from the study.…”