10.1. INTRODUCTION

Each year, hundreds of thousands of people experience a new or recurrent stroke. This devastating acute neurologic condition is broadly categorized into ischemic (84%) and hemorrhagic (16%) stroke. Stroke is a leading cause of death and long-term disability around the world. Immediately after an ischemic episode, there is a significant rise in glutamate levels at the synapse, leading to a significant increase in intracellular calcium levels. This leads to a cascade of events ending in acute excitotoxicity and cell death. This process also stimulates the activation of various enzymes, notably calcium-dependent cPLA_2α, which liberates arachidonic acid from membrane phospholipids, making it a substrate to cyclooxygenase enzymes. At that point, through a coordinated system, all prostaglandin (PG) syntheses generate specific prostanoids, which are members of fatty acids that include PGD₂, PGE₂, PGF_2α, PGI₂, and TxA₂. These PGs exert their actions through specific high-affinity G protein-coupled receptors named DP1-DP2 (PGD₂ receptor 1-PGD₂ receptor 2), EP1-EP4 (PGE₂ receptor 1-4), FP (PGF_2α receptor), IP (PGI₂ receptor or prostacyclin receptor), and TP (thromboxane receptor) receptors, respectively. The focus here is on PGD₂, as it is the most abundant PG in the brain. Although it has been well studied for its role in sleep modulation, recently, the role of PGD₂ and its receptor DP1 has been implicated in acute neurologic conditions. Using genetic and pharmacologic tools, these new results reveal that PGD₂ and its receptor pathway have beneficial effects and protect the brain against acute neurologic conditions such as excitotoxicity and ischemic stroke. Additional studies using compounds that selectively activate the DP1 receptor (PGD₂ receptor 1) might pave the way for therapeutic testing of this target in clinical settings.

This chapter briefly reviews the pathophysiology of ischemic stroke and treatments proposed in preclinical models, and especially focus on PGD₂ and the role of its DP1 receptor in acute ischemic injury. With the understanding that blood flow plays a critical function in ischemic outcomes, a better appreciation of the role of PGD₂/PGD₂ receptor 1 (DP1) in cerebral blood flow will be presented. Finally, there will be a discussion to review whether the PGD₂ DP1 receptor can be used as a target to attenuate brain damage initiated by ischemic stroke or excitotoxicity.

10.2. STROKE PATHOPHYSIOLOGY

Stroke is a medical emergency stemming from acute functional or anatomical neurologic dysfunction caused by a disturbance in the blood supply to discrete areas in the brain. In general, stroke is broken down into two categories: ischemic and hemorrhagic, accounting for approximately 84% and 16% of the total stroke incidents, respectively (Go et al., 2013; Roger et al., 2012). Ischemic stroke is a condition in which the blood supply to a particular region of the brain is permanently or transiently restricted because of the obstruction of a blood vessel by a blood clot or by arterial stenosis, thus depriving the brain cells of the glucose, oxygen, and energy required for their function (Andersen et al., 2009; Chambers et al., 1987; Garcia, 1975; Sutherland et al., 2012). Ischemic stroke is further categorized into thrombotic or embolic stroke. Thrombosis is a condition in which a blood clot is formed at the site of the occlusion, whereas embolism is a condition in which a blood clot is formed in a distant major artery and travels to the occlusion site. Thrombi are formed in the intracranial arteries when the basal lamina is damaged and plaques are formed along the injured site. This process is further facilitated by the activation and aggregation of platelets at the injured site, further facilitating the coagulation cascade. This process by itself can lead to hypoperfusion or occlusion of the blood supply, and certain factors can lead to an increase in shear stress and can dislodge the plaque, which can then lead to occlusion of the blood vessels, causing a significant decrease in the blood flow and leading to an acute ischemic condition. The ischemic episode is also facilitated by atherosclerosis, a condition in which the arterial wall is thickened for various reasons, including the deposition of fatty materials, inflammation, accumulation of macrophages, and formation of multiple thrombi (Aoki et al., 2007; Becker, 1998; Chamorro, 2004; Duvall and Vorchheimer, 2004; Eltzschig and Eckle, 2011; Fenton et al., 1998; Kanematsu et al., 2011; Kargman et al., 1998; Kogure et al., 1996; Mendez et al., 1987). Ultimately, all of this results in reduced blood flow or rupture of the inner arterial wall and the release of the blood clot into the blood stream. This is in contrast to an embolic stroke, in which a blood clot formed at a distant site travels and lodges in a cerebral artery. Some prominent causes of emboli include microemboli breaking away from a plaque in the carotid artery, atrial fibrillation, patent foramen ovale, hypokinetic left ventricle, and vascular or cardiac surgical procedures (Jaillard et al., 1999; Wardlaw et al., 2001; Wolf et al., 1987).

10.3. HYPOXIA, FREE RADICAL DAMAGE, ENERGY DEPLETION, AND NEURONAL DEPOLARIZATION

The brain has a relatively high demand for oxygen and glucose, and similar to the heart, it does not have a high antioxidant system, making it most susceptible to various neurologic conditions, including stroke. As a result, in ischemic/hypoxic conditions, the focal impairment of cerebral blood flow restricts the delivery of vital substrates such as oxygen and glucose. This subsequently imbalances ionic gradients and membrane potentials are lost. Consequently, presynaptic channels are activated and excitatory amino acids such as glutamate are released into the synaptic cleft. Because of energy depletion, the presynaptic reuptake of excitatory amino acids is attenuated, resulting in the accumulation of a significant amount of glutamate in the extracellular space (Ardizzone et al., 2004; Dirnagl et al., 1999; Kemp and McKernan, 2002; Lipton, 1999; Lipton and Rosenberg, 1994; Sutherland et al., 2011; Wang, 2011). As a result, N-methyl-D-aspartate (NMDA) and metabotropic glutamate receptors are activated and an influx of Ca²⁺ and Na⁺ causes excitotoxicity and edema in the postsynaptic neurons (Figure 10.1). Excitotoxicity is one of the primary events propagating immediate cell death, whereas edema is one of the major determinants of the final outcome after stroke (Asano et al., 1985; Bhardwaj et al., 2000; Bounds et al., 1981; Choi, 1992; Dirnagl et al., 1999; Lynch and Guttmann, 2002; Macdonald and Stoodley, 1998; Manley et al., 2000; Urushitani et al., 2001).

FIGURE 10.1

Some of the major cellular pathophysiologic cascades associated with ischemic stroke. Occlusion of the blood vessel leads to cerebral ischemia, which subsequently leads to energy failure and presynaptic neuronal membrane depolarization. This causes massive (more...)

10.4. EXCITOTOXICITY, CALCIUM SIGNALING, AND ACTIVATION OF PROSTANOID SYNTHESIS

Neurons in an ischemic brain usually die by means of necrotic or delayed cell death mechanisms. An important insight into the mechanism of penumbral infarction was revealed by the pioneering work of Dr. Brian Meldrum’s laboratory showing that the preemptive blockade of the glutamate receptor reduced infarct size (Simon et al., 1984). During ischemic stroke, levels of excitatory amino acids, especially glutamate, increase rapidly within the affected area because of their synaptic release from core neurons undergoing ischemic depolarization. Glutamate regulates the activity of various excitatory metabotropic receptors, including the NMDA receptor, which is a Ca²⁺ membrane channel. Glutamate acts as an NMDA receptor agonist and increases Ca²⁺ influx to the postsynaptic neurons up to a toxic level, causing immediate injury to these neurons (Lipton, 1999; Smith, 2004). The use of a competitive and/or noncompetitive antagonist of the NMDA receptor can reduce experimental infarct volume to a significant level by antagonizing the effects of glutamate (Lipton, 1999). Based on these preclinical reports, a similar approach was further extended in clinical stroke settings; however, no appreciable beneficial effects were observed—most likely from the limitation for timely application of such drugs after the first symptoms of stroke onset.

An increase in the intracellular levels of Ca²⁺ also initiates a cascade of cytoplasmic and nuclear events that dictate the pathophysiology of the ailment. Some of these events include activation of proteolytic enzymes that degrade cytoskeletal and extracellular matrix proteins and activation of phospholipase A₂—notably cytosolic phospholipase A₂ (cPLA_2α), which initiates a proinflammatory cascade (Adams et al., 1996; Bazan, 2005; Bonventre, 1997; Kishimoto et al., 2010; Phillis et al., 2006; Phillis and O’Regan, 2004; Tanaka et al., 2003). PLA₂ acts on membrane-bound phospholipids and generates arachidonic acid (AA), which is subsequently converted into hydroxyeicosatetraenoic acid (HETE) and leukotriene through lipoxygenase (LOX) pathways, epoxyeicosatrienoic acid (EETs), and HETE through cytochrome P450 (CYP) pathways, or into prostanoids and thromboxanes through cyclooxygenase (COX) and prostaglandin (PG)/thromboxane synthase pathways (Bazan et al., 2002; Funk, 2001; Khanapure et al., 2007; Kudo and Murakami, 2002; Phillis et al., 2006; Wymann and Schneiter, 2008) (Figure 10.2). Thus, the initial insult after ischemic stroke causes a hostile environment with resilient excitotoxicity, the generation of oxygen- and nitrogen-free radicals and proteolytic enzymes, and the activation of an inflammatory cascade that initiates cellular, molecular, and hemodynamic events converting the center of the damage into an ischemic core. These events destroy brain cells in the ischemic core by lipolysis, proteolysis, disaggregation of microtubules, bioenergetic failure, and the breakdown of ion homeostasis (del Zoppo et al., 2000; Dirnagl et al., 1999; Iadecola and Alexander, 2001; Lo, 2008; Lo et al., 2003). This ischemic core is surrounded by a partially affected area often referred to as the ischemic penumbra, the peri-infarct area, or the area at risk. Either because of incomplete occlusion, hypoperfusion, or partial compensatory blood flow through collateral circulation, the ischemic penumbra has partially preserved energy metabolism (Bang et al., 2011; Frykholm et al., 2005; Liebeskind, 2005; Lo, 2008). This is the salvageable area; however, if left unattended and without treatment, this area can be overtaken by the advancing ischemic core through ongoing excitotoxicity and/or deleterious secondary cascades such as spreading membrane depolarization, edema, postischemic inflammation, and delayed cell death (del Zoppo et al., 2000; Dirnagl et al., 1999; Iadecola and Alexander, 2001; Lo, 2008; Lo et al., 2003). Although the primary cascade of excitotoxicity has been a target to treat stroke, because of the complex pathophysiology of stroke, many of the poststroke neuroprotective efforts are focused on salvaging the “penumbra” by minimizing secondary events.

FIGURE 10.2

Simplified schematic illustration of PG syntheses and their action on their high-affinity specific receptors. AAs are generated from membrane phospholipids, and then COX acts on AA to generate intermediate PG endoperoxide H (PGH₂). The tissue-specific (more...)

10.5. TREATMENTS AVAILABLE FOR STROKE

Although stroke is one of the leading causes of morbidity and mortality in developed nations, effective therapies are still elusive. Essentially, the only approved pharmacologic therapy against stroke is the use of thrombolytic agents such as tissue plasminogen activator (tPA) (del Zoppo and Koziol, 2007; Yamamoto et al., 1991; Zivin et al., 1985). However, because the use of tPA is highly time-dependent, the most beneficial effect of tPA treatment can only be obtained within ~4.5 hours after the onset of ischemia. If given beyond the stroke-onset therapeutic window of ~4.5 hours, tPA can lead to vascular rupture; thereby, transforming an ischemic stroke into a hemorrhagic stroke, a phenomenon known as hemorrhagic transformation (Deb et al., 2010; Rosell et al., 2008; Wang, 2011; Xing et al., 2011). Consequently, a significant amount of research money and effort has been devoted to actively pursuing cutting-edge research and subsequently translating any findings into clinical trials to elicit treatment options or to using other therapies that can potentially minimize tPA side effects and/or extend the therapeutic window of tPA. Some of these approaches include the use of NMDA receptor antagonists, free radical scavengers, vasodilators, matrix metalloproteinase inhibitors, thrombolytics and antithrombotics, platelet inhibitors, COX inhibitors, and many others (Chan, 2001; Cheng et al., 2006; Clark et al., 2001; Cunningham et al., 2005; Fang et al., 2006; Gerriets et al., 2003; Green and Ashwood, 2005; Grossetete and Rosenberg, 2008; Hinkle and Bowman, 2003; Hurley et al., 2002; Maeda et al.; Morita-Fujimura et al., 2001; Rao and Balachandran, 2002; Saleem et al., 2008; Serteser et al., 2002; Vartiainen et al., 2001; Weinberger, 2006; Wilson and Gelb, 2002; Zhao et al., 2006). Although some of these later compounds have had success at certain stages of the preclinical and clinical trials; unfortunately, none of them have been successful in resolving ischemic brain damage (Green, 2002; Ikonomidou and Turski, 2002). It is clear that there is an urgent need to pursue an effective therapeutic option or a combination of drugs that can target the various steps of the stroke cascade over time.

10.6. AA CASCADE

Essential fatty acids (EFAs), a subset of unsaturated fatty acids, play various physiologic and pathophysiologic roles in neural cells by regulating intracellular signaling. Because of the lack of the necessary enzymes that are required for their synthesis, humans obtain EFAs from external sources and then incorporate them into the phospholipids. In the brain, EFAs are released by the action of PLA₂ enzymes and they modulate various physiologic functions, including synaptic function, neuronal toxicity, cerebrovascular tone, neuroinflammation, and oxidative stress (Bazan, 2005; Doré et al., 2003; Kishimoto et al., 2010; Phillis and O’Regan, 2003; Sanchez-Mejia et al., 2008). The PLA₂ enzymes are a family of lipases that are categorized into 12 groups based on various factors such as biological activity, substrate specificity, activating factors, and localization (Burke and Dennis, 2009a, 2009b; Kudo and Murakami, 2002). In the brain, AA and docosahexaenoic acid are present in bilipid layers of brain cells and appear to be among the most important fatty acids because of their action in generating more free fatty acids and their biological activity. AA acts as a substrate for at least three well-studied pathways, which are the LOX, CYP, and COX/PG synthase pathways. These pathways are tissue specific, and often cell specific, and the final outcomes are highly dependent on the nature and site of injury.

10.7. COX AND NEURODEGENERATION

COX enzymes are rate-limiting enzymes associated with the conversion of AA into PGE₂, PGD₂, PGF_{2 α}, PGI₂, and TxA₂, collectively known as prostanoids. Two types of COX (COX-1 and COX-2) have been well studied. They are also known as PG endoperoxide H synthases-1 and -2. The two isozymes are quite similar and share ~60% homology in their amino acids. The COX-2 active site has a larger pocket, thus making it more accommodating for using fatty acids (Rouzer and Marnett, 2009; Smith et al., 2000). COX-1 is responsible for normal physiologic or “housekeeping” functions, whereas COX-2 is an inducible isoform involved in inflammation, mitogenesis, and signal transduction (Kam and See, 2000). Although COX-1 is generally considered to be constitutively expressed, depending on which “inducible” PG synthases it is coupled to, it can have effects on various inflammatory and other cellular and organelle pathways.

COX enzymes have catalytic and regulatory subunits and are bound to the endoplasmic reticulum and nuclear membrane. COX-2 immunoreactivity in neurons shows that it is localized to dendritic spines, which are the site of NMDA receptor–mediated neurotransmission (Kaufmann et al., 1996). COX-2 is expressed in the brain at a high basal level selectively in pyramidal neurons of hippocampal and cortical circuits in neurons of the amygdala. COX-2 is an important mediator of inflammation, including neuroinflammation (Feng et al., 1993; Gobbo and O’Mara, 2004). It has been reported that coordinated upregulation of cPLA₂ and COX-2 activities contribute to brain damage after cerebral ischemia and neuroinflammation (Bosetti and Weerasinghe, 2003; Sandhya et al., 1998). COX-2 plays an important role in brain injury caused by ischemia (Doré et al., 2003), kainic acid–induced seizures (Baik et al., 1999; Kelley et al., 1999), NMDA toxicity (Hewitt, 2000; Iadecola et al., 2001), Alzheimer disease (Xiang et al., 2002), and Parkinson disease (Teismann et al., 2003), along with other neurologic disorders (Consilvio et al., 2004; Madrigal et al., 2003). The effects of genetic manipulation of COX-2 on focal ischemia have been reported by several groups, including ours (Doré et al., 2003; Iadecola et al., 2001). In COX-2 knockout mice (COX-2^-/-), Iadecola and coworkers (Iadecola et al., 2001) found reduced cerebral infarction after middle cerebral artery occlusion (MCAO), whereas in our previous study, we found that overexpression of COX-2 enhanced cerebral infarction (Doré et al., 2003). Consistent with these results, we and others (Doré et al., 2003; Iadecola and Ross, 1997; Nakayama et al., 1998; Nogawa et al., 1997; Resnick et al., 1998) have shown that the use of specific COX-2 inhibitors significantly reduced the infarction in wild-type mice. However, we, for the first time, unveiled that COX-2–specific inhibitors were unable to significantly attenuate the infarction (Doré et al., 2003), notably in conditions in which COX-2 was already overexpressed. These conflicting results suggest that the basal level of COX-1 and other PG synthase enzymes are important factors to consider in addition to COX-2. Moreover, the unique and different roles of various PGs and their receptors in regulation of neuroinflammation and neuronal cell death should not be neglected.

The NSAIDs have been widely used to nonselectively target COX-induced inflammation. Since their discovery (Vane, 1971), NSAIDs have been used to inhibit COX and consequently the synthesis of PGs, and to play a vital role in the physiology and pathophysiology of the cell. Given the antiinflammatory effects of COX inhibitors, these compounds were proposed and successfully tested to be neuroprotective in diverse neurologic conditions. However, this promising arena essentially ceased when several clinical trials revealed adverse side-effects associated with COX inhibitors. For example, detrimental outcomes were observed in Merck’s Adenomatous Polyp PRevention On Vioxx (i.e., APPROVe) study, which resulted in the termination of this clinical trial and withdrawal of the COX-2 inhibitor Vioxx on September 30, 2004, and there was a similar end for Bextra, manufactured and marketed by Pfizer (Davies and Jamali, 2004; Lenzer, 2005; Singh, 2004; Topol, 2004). Essentially, only Celebrex is currently used for various other ailments. This opened a new debate on the pharmacological effects of COX inhibitors and their uses, and the focus of argument shifted toward PGs. Therefore, our laboratory and that of others have been especially interested in the various PG receptors, knowing that the majority of all drugs are targeting G protein–coupled receptors (GPCRs). Therefore, it is imperative to understand the importance of PG syntheses, their relationships, and the role of PGs and their receptors, notably in the cardiovascular and neuronal systems.

10.8. PG SYNTHESES

PGs are bioactive lipids involved in a myriad of diverse and essential homeostatic physiological and pathological functions. PGs are formed by most of the body’s cells and can act as autocrine or paracrine agent, or both. Unlike most of the other hormones, PGs are not stored but are synthesized de novo from AA, and are rapidly processed because of their short half-lives. As mentioned previously in the AA cascade section, PGH₂ serves as a common substrate and can be converted into the relatively stable PGs and thromboxanes by the action of specific synthases/isomerases. PGE synthase (cytosolic: cPGES-1; membrane-associated: mPGES-1 and mPGES-2), PG I synthase (PGIS), PG D synthase (hematopoietic-type: H-PGDS, and lipocalin-type: LPGDS), PG F synthase (PGFS), and thromboxane synthase (TxS) into PGE₂, PGI₂, PGD₂, PGF_2α, and TxA, respectively (Figure 10.2). Given the important roles that PGs play, PG synthase inhibitors have been tested in various disease conditions to better understand the role of their respective PGs (Kanekiyo et al., 2007; Murakami and Kudo, 2006; Qu et al., 2006; Santovito et al., 2009; Takemiya et al., 2010).

10.9. PGs AND THEIR HIGH-AFFINITY RECEPTORS

Each PG binds with different affinities to various GPCR designated as DP1-DP2 (PGD₂ receptor 1, PGD₂ receptor 2), EP1-EP4 (PGE₂ receptor 1-4), FP (PGF_{2 α} receptor), IP (prostacyclin receptor), and TP (thromboxane receptor) for PGD₂, PGE₂, PGF₂ a, PGI₂, and TxA₂, respectively, and exerts its physiologic and pathophysiologic effects through these receptors (Breyer et al., 2001; Coleman et al., 1995; Jones et al., 2009; Narumiya, 2009; Narumiya et al., 1999; Sharif et al., 1998; Woodward et al., 2011). Although the literature associates these prostanoids as essentially binding only with their receptor family members, in most cases, these receptors cross-react with other receptors. However, this has not been discussed and elaborated on well enough in literature.

In general, EP2, EP4, DP1, and IP are known to cause an increase of intracellular cyclic adenosine 3’,5’-monophosphate (cAMP), whereas EP1, FP, and TP cause an increase of intracellular free Ca²⁺ (Wright et al., 2001 and see Mohan et al. for a comprehensive review [Mohan et al., 2012]). These receptors share approximately 20% to 30% of their sequences with each other. We and others have previosuly exposed the “genealogy” of these receptors, which further supports the proposed classification of these receptors and their downstream cell signaling (Hirai et al., 2001; Mohan et al., 2012; Toh et al., 1995). However, caution should be used when impying it as a general rule because there are always exceptions to such rules. Most of the prostanoid receptors interact with a wide range of intracellular signaling pathways and facilitate receptor activation and functions. PGs play significant physiologic and pathophysiologic roles in circulation, vascular regulation, hypertension, sleep regulation, temperature regulation, parturition, ocular pressure, skin inflammation, airway maintenance, bowel syndromes, vasodilation, vasoconstriction, excitotoxicity, and stroke (Chemtob et al., 1990a, 1990b, 1995; Faraci and Heistad, 1998; Wright et al., 2001). In general, it has been shown that the receptors that activate the cAMP pathway lead to better outcomes after ischemic stroke, whereas those that activate the Ca²⁺ pathway lead to worse outcomes. However, this general perception is not true in all conditions, and exceptions have also been reported. Because PGD₂ is the most abundant and often neglected prostanoid, we will briefly expose additional focused information about this prostanoid and its main receptor, DP1. The other PGD₂ receptor was named DP2 once it was found that PGD₂ has some affinity toward this orphan receptor, previously known as CRTH₂ receptor (Nagata et al., 1999a). Moreover, this receptor did not evolve from the same phylogenetic tree as the other PG receptors (Mohan et al., 2012).

10.10. PGD₂ AND ITS METABOLISM

PGD₂ is generated from PGH₂ by the action of two distinct PGD synthases: L-PGDS and H-PGDS. PGD₂ was first identified in the late 1960s (Granstrom et al., 1968; Hayashi and Tanouchi, 1973), and a later study provided evidence that this PG is a potent inhibitor of platelet aggregation (Smith et al., 1974). Since then, the role of PGD₂ has been investigated in a wide range of pharmacological activities. The diverse activities of PGD₂ in regulating local blood flow, as a bronchial airway caliber, in leukocyte function, and so on, are mediated by its high-affinity interactions with its GPCRs. However, the half-life of PGD₂ is very short (about 1.5 minutes in blood); therefore, under certain conditions, it is rapidly metabolized. The main products that have been detected in vivo are Δ¹²PGJ₂ and 9α11βPGF₂ (Heinemann et al., 2003; Sandig et al., 2006b). Other putative metabolites are 13,14-dihydro-15-keto-PGD₂ 16, Δ¹²PGD₂, 15-deoxy-Δ^12,14PGD₂, and 15-deoxy-Δ^12,14PGJ₂ (Gazi et al., 2005; Monneret et al., 2002) (Figure 10.3). Although the exact mechanism of PGD₂ metabolism is still elusive, it has been postulated that 13,14-dihydro-15-keto-PGD₂, Δ¹²PGD₂, and 15-deoxy-Δ^12,14PGJ₂ are formed locally at the site of inflammation. It is important to note that all of these metabolites confine their activity to DP2 receptor, and their activity on the DP1 receptor has not been reported in the literature. Other metabolites of PGD₂ such as Δ¹²PGJ₂ and 15-deoxy- Δ^12,13PGJ₂ have effects on the resolution of inflammation by inhibiting cytokine production and the induction of apoptosis. These effects are mediated by the peroxisome proliferator-activated receptor-γ (PPARγ)-dependent or PPARγ-independent mechanisms (Forman et al., 1995; Rossi et al., 2000). Previous work from our laboratory also shows that J series PG (dPGJ₂ and 15-deoxy-Δ^12,14PGJ₂) treatments upregulate heme oxygenase and attenuate neuroinflammation (Zhuang et al., 2003a, 2003b).

FIGURE 10.3

PGD₂ metabolism and its effects. PGD₂ can act as autocrine or paracrine agent, or both, and exerts its effects mainly through its GPCR DP1 receptor, although some reports on peripheral systems suggest the action of PGD₂ through CRTH₂ (or DP2) receptors. (more...)

10.11. PGD₂ AND DP RECEPTORS

PGD₂ has peripheral and central physiologic effects. Some of the peripheral effects of PGD₂ include vasodilatation, bronchoconstriction, inhibition of platelet aggregation, glycogenolysis, vasoconstriction, allergic reaction mediation, and intraocular pressure reduction (Angeli et al., 2004; Casteleijn et al., 1988; Darius et al., 1994; Matsugi et al., 1995; Matsuoka et al., 2000; Narumiya and Toda, 1985; Sturzebecher et al., 1989; Whittle et al., 1983). Among all PGs, PGD₂ is the most abundant in the brain. In the central nervous system, under normal physiologic conditions, PGD₂ contributes to sleep induction, modulation of body temperature, olfactory function, hormone release, nociception, and neuromodulation (Eguchi et al., 1999; Gelir et al., 2005; Hayaishi, 2002; Hayaishi and Urade, 2002; Mizoguchi et al., 2001; Urade and Hayaishi, 1999). PGD₂ levels are significantly increased under pathologic conditions (Hata and Breyer, 2004; Hatoum et al., 2005; Luster and Tager, 2004; Naffah-Mazzacoratti et al., 1995; Seregi et al., 1990; Tegtmeier et al., 1990); however, whether this increase is harmful or beneficial is controversial. PGD₂ protects astrocyte cultures by increasing the production of neurotrophins (Angeli et al., 2004). It has also been shown that PGD₂ acts as an inflammatory mediator of allergic reactions, such as asthma and conjunctivitis, which are initiated by the immunoglobulin E–mediated type 1 response. Moreover, there are reports showing some deleterious effects of PGD₂, mainly regulated through the DP2 receptor or through PPARγ pathways (Almishri et al., 2005; Gazi et al., 2005; Kagawa et al., 2011; Nagata and Hirai, 2003; Nagata et al., 1999a).

10.12. DP1 RECEPTOR

PGD₂ exerts its biological action by binding and activating through distinct and specific cell receptors. Recent findings suggest that there are two types of the receptor for PGD₂ : the first is known as the DP1 or DP receptor and the second has recently been discovered and is known as chemoattractant receptor homologous molecule expressed on T helper type 2 cells (CRTH₂). CRTH₂ is also now known as the DP2 receptor; however, it has a different “genealogy” and a different homology compared with other prostanoid receptors (Abe et al., 1999; Hata et al., 2003; Mohan et al., 2012; Toh et al., 1995). CRTH₂ signaling is independent of PGD₂ production (Bohm et al., 2004; Sandig et al., 2006a) and has different biological functions and cellular distribution than the DP1 receptor (Hirai et al., 2001; Sawyer et al., 2002). It is located on the 11q12-q13.3, 19A, and 1q43 chromosomes in the human, mouse, and rat, respectively, and is encoded by the genes PTGDR2, Gpr44, and Ptgdr2 in the human, mouse, and rat, respectively. It contains 382 to 403 amino acids (Abe et al., 1999; Hata et al., 2003; Nagata et al., 1999b; Shichijo et al., 2003) and its structure closely resembles that of the formyl peptide receptor (formyl-Met-Leu-Phe) and the B leukotriene receptor. It is expressed on Th2-type lymphocytes, basophils, and eosinophils. DP2 is widely expressed in the brain, heart, stomach, ovary, testes, and skin, and it is biologically involved in eosinophil activation, chemotaxis, degranulation, and cytokine production.

Primarily, the anti-inflammatory and vasoregulatory properties of PGD₂ are associated with DP1 receptors; although, the proinflammatory effects of DP1 have also been reported (Angeli et al., 2004; Hammad et al., 2003; Matsuoka et al., 2000; Spik et al., 2005). DP1 is a GPCR coupled with Gαs and is located on the 14q22.1, 14B, and 15p14 chromosomes in the human, mouse, and rat, respectively. The DP1 receptor (encoded by the gene PTGDR) was first cloned in 1994, and it contains 357 to 359 amino acids (Boie et al., 1995; Hirata et al., 1994; Ishikawa et al., 1996; Wright et al., 1999). On the phylogenetic tree, this receptor shows significant sequence homology with IP and EP2 receptors of PGI₂ and PGE₂, respectively, and is distributed throughout the body, including in ciliary epithelial cells, the retinal choroid, the iris, eosinophils, platelets, the colon, and the brain. Physiologically, DP1 receptors are involved in inhibiting platelet aggregation and histamine release, and in the relaxation of myometrium and smooth muscles. Furthermore, any alteration in DP1 receptor results in an asthmatic response, reduced nicotinic-induced vasodilation, and sleep alteration. The human DP1 receptor binds strongly to PGD₂, followed by PGE₂, PGF₂, and PGI₂, and least to thromboxane A₂. These receptors are expressed in various tissues and cells, including bone marrow, small intestine, lung, stomach, mast cells, and brain, and are involved in various pathophysiological functions such as platelet activation, vasodilation (niacin flush), sleep regulation, and immune cell activation. The DP1 receptor stimulates adenylyl cyclase, leading to increased levels of cAMP and decreased platelet aggregation (Hata and Breyer, 2004). Recently, several selective agonists such as BW245C, AS702224, and TS-022, and antagonists such as MK-0524 (or Laropiprant) and BWA868C of the DP1 receptor are being used in various animal models (Cheng et al., 2006; Crider et al., 1999; Hirano et al., 2007; Kabashima and Narumiya, 2003; Van Hecken et al., 2007). The use of these pharmacologic agents and genetic manipulations is extremely helpful in providing insight into the mechanism of action of PGD₂ and the DP1 receptor (Table 10.1). The in vivo role of DP1 in the periphery has been well investigated (Angeli et al., 2004; Hata and Breyer, 2004; Koch et al., 2005), whereas until recently, its role in the brain was limited to studies related to sleep and eye movement (Campbell and Feinberg, 1996; Hayaishi and Urade, 2002; Obal and Krueger, 2003; Urade and Hayaishi, 1999).

TABLE 10.1

List of DP1 Receptor Agonists and Antagonists That Have Been Tested in Various Preclinical and Clinical Studies

10.13. THE ROLE OF PGD₂ AND DP1 RECEPTOR IN STROKE

PGD₂ has been studied extensively for its role in sleep-awake and thermoregulation studies. However, its importance in regulating brain injuries has recently been recognized. Based on the abundance of PGD₂ in the brain, we wanted to determine the role of PGD₂ and its DP1 receptor in ischemic stroke and excitotoxicity. Our data suggest that genetic deletion of DP1 receptors make mice more susceptible to ischemic brain injury (Saleem et al., 2007). There are several animal models reported to induce cerebral ischemia. In our studies, we used the filament model of transient cerebral ischemia. To induce cerebral ischemia or stroke, mice were anesthetized and a nylon monofilament coated with silicon was inserted into the internal carotid artery and forwarded up to the origin of the middle cerebral artery. With the help of laser Doppler flowmetry, cerebral blood flow was monitored. MCAO by the filament results in a significant (>80%) decrease in cerebral blood flow, confirming the occlusion. After the occlusion, the incision was temporarily sealed and the mice were placed in humidity- and temperature-regulated recovery units. To achieve the reperfusion, the mice were anesthetized, the incision was opened, and the nylon filament was retracted, which resulted in recirculation of the blood. In our study, we found that the neurologic deficit and brain infarction was significantly higher in DP1^-/- mice compared with wild-type mice. To confirm that this was through the direct effect of the DP1 receptor, we thoroughly investigated the cerebral vascular anatomy of wild-type and DP1^-/- mice. We found that the effect observed in our study was not an artifact from a difference in vascular anatomy.

Thereafter, in a follow-up study, we tested the effect of pharmacologic activation of the DP1 receptor by using a selective DP1 receptor agonist. We found that NMDA-induced excitotoxicity and cerebral ischemic brain damage was significantly attenuated by the DP1 receptor-selective agonist BW245C (Ahmad et al., 2010). In this study, we first showed that intrastriatal microinjection of NMDA resulted in significant brain damage that was significantly aggravated in DP1^-/- mice, whereas the DP1 receptor-selective agonist BW245C had a dose-dependent neuroprotective effect. Moreover, we also showed that the minimum effective dose (10 nmol) observed in the NMDA-induced toxicity paradigm was also significantly efficient in minimizing MCAO-induced brain damage. Similarly, the effect of the DP1 agonist BW245C was tested in an in vitro model of ischemia by using the dispersed neuronal culture and hippocampal slice cultures from wild-type mice (Liang et al., 2005). In that study, it was found that the DP1 agonist BW245C attenuated the glutamate-induced cell death and oxygen–glucose deprivation induced hippocampal slice culture degeneration. Recently, in a report investigating a new compound, GIF-0173, it was found that this compound had beneficial effects against cerebral ischemia by regulating the DP1 receptor (Thura et al., 2009). In an animal model of neonatal hypoxic-ischemic encephalopathy (HIE), one of the leading causes of acute mortality and chronic disability in infants and children, a group led by Dr. Masako Taniike found that PGD₂ protects brain against HIE (Taniguchi et al., 2007). Furthermore, they show that the level of PGD₂ is significantly upregulated in the HIE mouse brain. Their data suggest that the beneficial effect of the DP1 receptor could be from its role in endothelial cells and the vasculature.

As we have mentioned in the preceding sections, some of the PG receptors activate calcium signaling, whereas some activate the cAMP pathway. Activation of the cAMP pathway has been reported to have a protective effect and restores normal cellular process (Hanson et al., 1998; Ryde and Greene, 1988; Walton et al., 1999; Walton and Dragunow, 2000). Some of the direct intracellular targets for cAMP are protein kinase A (PKA), the exchange protein activated by cAMP (Epac), and cyclic nucleotide-gated ion channels (Bos, 2006; Craven and Zagotta, 2006; de Rooij et al., 1998; Murray and Shewan, 2008). However, cAMP-mediated activation of PKA is the most widely studied aspect of cAMP signaling (Murray, 2008; Tasken and Aandahl, 2004). There are numerous studies that propose that the activation of cAMP/PKA has a neuroprotective effect through the activation of various transcription factors, including cAMP-responsive element-binding protein (Mantamadiotis et al., 2002; Walton et al., 1999; Walton and Dragunow, 2000). Similarly, it has been reported that DP1 activation significantly augments cAMP levels, which then activate various pathways leading to neuroprotection. Moreover, PGD₂ is substantially produced in blood, and DP1 receptors are significantly present in vascular lining and endothelial cells. Previous reports suggest that DP1 activation by BW245C regulates hemodynamics in rats (Koch et al., 2005). Moreover, DP1 receptor activation has also been implicated in a clinical condition known as niacin flush, where use of niacin increases PGD₂, which then acts on DP1 and induces vasodilation, resulting in hot flushes on a patient’s skin. Activation of DP1 by the selective agonist BW245C decreases inflammation in murine models of dermatitis (Angeli et al., 2004). Interestingly, in clinical settings, BW245C was found to increase intraocular pressure (Shah et al., 1984). To further extend our findings on the role of the PGD₂ DP1 receptor in stroke, we tested the effect of the DP1 receptor agonist BW245C on cerebral blood flow before, during, and after ischemic stroke. It was astonishing that this compound was able to improve cerebral blood flow during and after stroke. Moreover, because imbalance hemostasis is also an important trigger of stroke onset or propagation, we tested the effect of BW245C on hemostasis (tail bleeding time and coagulation). To our amazement, we found that BW245C increased tail bleeding in vivo, and inhibited ex vivo blood coagulation. These novel works have been presented at various international scientific meetings and conferences (Ahmad et al., 2013a, 2013b).

Although the potential neuroprotective effect of the DP1 receptor is being reported, the signaling cascade leading to this neuroprotective effect is still unclear. Thus far, by using DP1 selective agents, various researchers are able to show that cAMP/PKA is one of the important pathways thorough which DP1 exerts its effect (Liang et al., 2005). This study also shows that PKA inhibitors were able to inhibit PGD₂ levels as well as PGD₂ -mediated neuroprotection. In another study that elegantly used DP1^-/- mice, it was shown that wild-type mice, after hypoxic ischemic brain injury, had better angiogenesis compared with DP1^-/- mice. From this, the authors suggest that the DP1 receptor–mediated beneficial effect after hypoxic ischemic brain injury could possibly be through its role in the vasculature. Based on these reports and reports from our laboratory, it is evident that activation of the PGD₂ DP1 receptor activates the cAMP/PKA pathway, resulting in the activation of transcription factor(s), cerebral blood flow improvement, and maintenance of hemostasis; however, more experiments and insights are required to fully exploit the role of DP1 in stroke. Therefore, more targeted preclinical studies are required to translate the potential of this treatment in clinical stroke.

10.14. CONCLUSION

The accumulating data thus far show that PGD₂ is substantially produced in the brain, blood, and vascular linings and that the DP1 receptor is expressed in endothelial and neural cells. Under acute or chronic neurodegeneration, this receptor has been shown to have beneficial effects that are achieved by regulating the downstream signaling cascade of cAMP or through regulating physiologic pathways such as blood flow and hemostasis. Although these are preliminary studies, they nevertheless propose the potential of the DP1 receptor as a novel therapeutic target to rescue the brain from neurodegeneration. The availability of selective ligands further facilitates this process and additional rigorous testing in comorbid conditions may pave the way for this target to be tested in clinical settings.

ACKNOWLEDGMENTS

This work was supported by grants from the American Heart Association (0830172N; to A.S.A.) and NIH (R01 NS046400-01; to S.D.). The authors would like to thank Rebecca Astrom for editing the manuscript, and all lab members for constructive feedback on the chapter.

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