Endothelin B receptor agonist,
IRL-1620, has been shown in previous studies, conducted in our lab, to provide significant neuroprotection at both 24h and 1 week following permanent
cerebral ischemia. It is possible that
IRL-1620 may be neuroprotective due to angiogenesis and neurogenesis. However, the effect of
IRL-1620 on neurovascular remodeling following
cerebral ischemia has not been established. The present study was conducted to determine the effect of
IRL-1620 [Suc-[Glu9,Ala11,15]-
Endothelin-1(8-12)] on astrocytes, neurons, and vascular endothelial cells after induction of
cerebral ischemia. Male Sprague-Dawley rats undergoing permanent
middle cerebral artery occlusion (MCAO) received three
intravenous injections of either vehicle or
IRL-1620 at 2, 4, and 6h post occlusion. At 24h post occlusion,
IRL-1620 treatment preserved neuronal numbers in the cortex, striatum and subventricular zone (SVZ) of the ischemic rat brain, while simultaneously enhancing the number of blood vessels labeled with
vascular endothelial growth factor (
VEGF) compared to vehicle treatment. By 1 week following MCAO,
VEGF-positive vessels/30 µm brain slice in the
IRL-1620 group numbered 11.33±2.13 versus 4.19±0.79 in the vehicle group (P<0.01). Additionally, animals receiving
IRL-1620 displayed increased number of proliferating cells (P<0.0001) and cells positively staining for
nerve growth factor (
NGF; P<0.0001) in the infarcted brain.
VEGF and
NGF protein expression significantly increased at 1 week post MCAO in the infarcted hemisphere of
IRL-1620 treated rats as compared to
sham (P<0.01). Pretreatment with
BQ788 blocked the effects of
IRL-1620, thus confirming the role of ETB receptors in the neurovascular remodeling actions of
IRL-1620. Results of the present study indicate that
IRL-1620, administered on the day of
infarct, is neuroprotective and enhances angiogenic and neurogenic remodeling following
cerebral ischemia.