Increased Cortical Cell Loss and Prolonged Hemodynamic Depression after Traumatic Brain Injury in Mice Lacking the IP Receptor for Prostacyclin

Abstract

Prostacyclin is the major arachidonic acid metabolite of the vascular endothelium and is produced mainly via the cyclooxygenase-2 pathway. By acting on the prostacyclin (IP) receptor on platelets and vascular smooth muscle cells, prostacyclin exerts vasodilatory and antiaggregative/antiadhesive effects. Previous studies have shown that prostacyclin production increases after brain trauma, but the importance of prostacyclin for posttraumatic hemodynamic alterations and neuron survival has not been investigated. This study evaluated if endogenous prostacyclin plays a role in the pathophysiologic process in the brain after brain trauma. This was performed by comparing prostacyclin (IP) receptor-deficient (IP À/À ) mice and mice with functional IP receptor (IP + / + ) after a controlled cortical injury regarding contusion volume, cerebral blood flow ([ 14 C]iodoantipyrine autoradiography), number of perfused capillaries (fluorescein isothiocyanate-dextran fluorescence technique), the transfer constant (K i ) for [51 Cr]EDTA, and brain water content (wet vs dry weight) in the injured and contralateral cortex. Contusion volume was increased in IP À/À mice compared with IP + / + mice. Three hours after trauma, cortical blood flow was decreased in the injured cortex of both groups and the reduction in blood flow in the cortex of the IP À/À mice persisted from 3 to 24 h, whereas blood flow approached normal values in the IP + / + mice after 24 h. No differences could be detected between the two genotypes regarding other hemodynamic parameters. We conclude that the prostacyclin IP receptor is beneficial for neuron survival after brain trauma in mice, an effect that may be mediated by improved cortical perfusion.

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

“…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. 3,34 However, no previous studies have addressed the role of PGI 2 in regulation of APP processing. Recognition of the ability of PGI 2 to regulate expression and non-amyloidogenic processing of APP suggests that this mechanism might be an important contributor to overall neurovascular protective functions of PGI 2 .…”

“…[1][2][3][4] The endothelium is a major source of PGI 2 which is generated in response to a number of different stimuli including vascular injury.…”

“…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.…”

“…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.…”

Effects of Prostacyclin on Cerebral Blood Flow and Vasospasm After Subarachnoid Hemorrhage

“…It is a potent vasodilator and inhibitor of leukocyte activation, platelet aggregation, and leukocyte-endothelial interactions, all of which are properties with a hypothetical impact on the development of DIND. 5 Animal studies and in vitro studies have demonstrated positive effects of prostacyclin on cerebral blood flow (CBF) and vasospasm, [6][7][8][9][10] and an imbalance in the prostacyclin-prostaglandin ratio has been proposed as a cause of vasospasm. 6,11 Although results from in vitro and animal studies are promising, few studies exist that investigate the possible effects of prostacyclin on cerebral…”