Putative Role of Prostaglandin Receptor in Intracerebral Hemorrhage

Abstract

Each year, approximately 795,000 people experience a new or recurrent stroke. Of all strokes, 84% are ischemic, 13% are intracerebral hemorrhage (ICH) strokes, and 3% are subarachnoid hemorrhage strokes. Despite the decreased incidence of ischemic stroke, there has been no change in the incidence of hemorrhagic stroke in the last decade. ICH is a devastating disease 37–38% of patients between the ages of 45 and 64 die within 30 days. In an effort to prevent ischemic and hemorrhagic strokes we and others have been studying the role of prostaglandins and their receptors. Prostaglandins are bioactive lipids derived from the metabolism of arachidonic acid. They sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. Most prostaglandins are produced from specific enzymes and act upon cells via distinct G-protein coupled receptors. The presence of multiple prostaglandin receptors cross-reactivity and coupling to different signal transduction pathways allow differentiated cells to respond to prostaglandins in a unique manner. Due to the number of prostaglandin receptors, prostaglandin-dependent signaling can function either to promote neuronal survival or injury following acute excitotoxicity, hypoxia, and stress induced by ICH. To better understand the mechanisms of neuronal survival and neurotoxicity mediated by prostaglandin receptors, it is essential to understand downstream signaling. Several groups including ours have discovered unique roles for prostaglandin receptors in rodent models of ischemic stroke, excitotoxicity, and Alzheimer disease, highlighting the emerging role of prostaglandin receptor signaling in hemorrhagic stroke with a focus on cyclic-adenosine monophosphate and calcium (Ca2+) signaling. We review current ICH data and discuss future directions notably on prostaglandin receptors, which may lead to the development of unique therapeutic targets against hemorrhagic stroke and brain injuries alike.

Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection

“…Emerging allosteric potentiators and antagonists have already proved valuable tools to explore the roles of EP2 receptor under normal or disease conditions [35-37, 64, 86, 104]; however, development of EP2-targeted drugs for therapeutic use will require careful attention to temporal and probably spatial extent of drug action to avoid widespread effects. For example, transient and early delivery of EP2 allosteric potentiators might provide neuroprotection in acute neuronal injuries from excitotoxic conditions such as ischemic and hemorrhagic strokes [127], whereas delayed inhibition of EP2 via selective antagonists would be expected to reduce brain inflammation and injury in chronic inflammation-associated neurological disorders such as epilepsy, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Targeted block of EP2 might also be useful to combat peripheral inflammation and pain, or to slow tumor progression.…”

Therapeutic window for cyclooxygenase-2 related anti-inflammatory therapy after status epilepticus

“…Extensive studies in the past decade reveal that PGE 2 signaling via EP2 mediates pro-inflammatory effects in models of innate immunity (Ganesh et al, 2013; Johansson et al, 2013; Montine et al, 2002), AD (Johansson et al, 2015; Liang et al, 2005), ALS (Liang et al, 2008) and more recently status epilepticus (SE) (Jiang et al, 2012; Jiang et al, 2013), and slows the clearance of toxic substances such as amyloid beta (Aβ) peptides (Keene et al, 2010; Shie et al, 2005a; Shie et al, 2005b) and α-synuclein (Jin et al, 2007). Although advances have been made in our knowledge of degenerative diseases, there remains controversy whether upregulated COX-2 and PGE 2 /EP2 signaling in the brain are net beneficial or detrimental (Andreasson, 2010; Jiang et al, 2010; Jiang and Dingledine, 2013a; Mohan et al, 2012), highlighting the delicate balance of pro- and anti-inflammatory responses following CNS injuries. Therefore, the therapeutic window for quelling COX-2-engaged neuroinflammation might vary with the injury types.…”

Contribution of PGE2 EP1 receptor in hemin-induced neurotoxicity

“…Activation of these PGE 2 receptors can regulate intracellular levels of cyclic adenosine monophosphate and/or calcium ([Ca 2+ ] i ) (Kim et al, 2002; Linhart et al, 2003). The effects of PGE 2 are regulated by its respective affinity for its receptors and their relative abundance, which we recently reviewed (Mohan et al, 2012). Although the neurotoxicity of hemin has been previously demonstrated, the role of prostaglandins and their cognate receptors in hemin-induced neurotoxicity remains not fully understood.…”