Genetic Deletion of Prostacyclin IP Receptor Exacerbates Transient Global Cerebral Ischemia in Aging Mice

Abstract

Transient global cerebral ischemia causes delayed neuronal death in the hippocampal CA1 region. It also induces an up regulation of cyclooxygenase 2 (COX-2), which generates several metabolites of arachidonic acid, known as prostanoids, including Prostaglandin I2 (PGI2). The present study investigated whether the PGI2 IP receptor plays an important role in brain injury after global cerebral ischemia in aged mice. Adult young (2–3 months) and aged (12–15 months) male C57Bl/6 wild-type (WT) or IP receptor knockout (IP KO) mice underwent a 12 min bilateral common carotid artery occlusion (BCCAO) or a sham surgery. Behavior tests (neurologic deficit and T-maze) were performed 3 and 7 days after BCCAO. After seven days of reperfusion, the numbers of cells positive for markers of neurons, astrocytes, microglia, myeloperoxidase (MPO) and phosphorylated CREB (p-CREB) were evaluated immunohistochemically. Interestingly, in young and aged IP KO ischemic mice, there was a significant increase (p < 0.01) in cognitive deficit, hippocampal CA1 pyramidal neuron death, microglia and MPO activation, while p-CREB was reduced as compared to their corresponding WT controls. These data suggest that following ischemia, IP receptor deletion contributes to memory and cognitive deficits regulated by the CREB pathway and that treatment with IP receptor agonists could be a useful target to prevent harmful consequences.

Expression and Processing of Amyloid Precursor Protein in Vascular Endothelium

“…Endothelium-derived prostacyclin (PGI 2 ) is a potent vasodilator and anticoagulant and plays an essential role in preservation of cerebrovascular homeostasis under pathological conditions (59,124,160,186). The actions of PGI 2 are mediated by activation of PGI 2 receptor (IP receptor) as well as peroxisome proliferator-activated receptor ␦ (PPAR␦).…”

Endogenous level of TIGAR in brain is associated with vulnerability of neurons to ischemic injury

“…The oxidative stress associated with excessive production of reactive oxygen species (ROS) is a fundamental mechanism of brain damage in stroke [1][2][3] . The vulnerability of neurons to ischemic injury increases with age [4] , and it has also been reported that neonatal mice are more prone to ROS-induced damage [5,6] . Neonatal stroke leads to morbidity and severe long-term neurological and cognitive defi cits, including cerebral palsy.…”

Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α in cerebral microvessels

“…Endothelium-derived PGI 2 is an essential molecule responsible for preservation of cerebrovascular homeostasis under pathological conditions when blood vessels are exposed to injury induced by stroke, inflammation, and brain trauma. [1][2][3]6,7,43,44 Indeed, PGI 2 has been identified as a major protective product of arachidonic acid metabolism within the vasculature. 6 In the cerebral circulation, elevated production of PGI 2 in response to vascular injury is designed to prevent aggregation of platelets, to preserve blood flow, and to inhibit aberrant remodeling of injured vascular wall.…”

“…3,43,44,67 Moreover, systemic administration of PGI 2 analogue, beraprost, attenuated neuronal damage caused by ischemic stroke 67 thereby suggesting that activation of vascular IP receptors may contribute to tissue protective effects of beraprost. In the present study, we provide in vitro evidence that activation of IP receptors increases expression and a-processing of APP and generation of neuroprotective and anticoagulant cleavage product sAPPa.…”