The Experts below are selected from a list of 7998 Experts worldwide ranked by ideXlab platform
Jerold Chun - One of the best experts on this subject based on the ideXlab platform.
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Activation of Macrophages by Lysophosphatidic Acid through the Lysophosphatidic Acid Receptor 1 as a Novel Mechanism in Multiple Sclerosis Pathogenesis
Molecular Neurobiology, 2020Co-Authors: Jennifer Fransson, Jerold Chun, Ana Isabel Gómez-conde, Jesús Romero-imbroda, Oscar Fernández, Laura Leyva, Fernando Rodríguez Fonseca, Celine Louapre, Anne Baron Van-evercooren, Violetta ZujovicAbstract:Multiple sclerosis (MS) is a neuroinflammatory disease whose pathogenesis remains unclear. Lysophosphatidic Acid (LPA) is an endogenous phospholipid involved in multiple immune cell functions and dysregulated in MS. Its receptor LPA_1 is expressed in macrophages and regulates their activation, which is of interest due to the role of macrophage activation in MS in both destruction and repair. In this study, we studied the genetic deletion and pharmaceutical inhibition of LPA_1 in the mouse MS model, experimental autoimmune encephalomyelitis (EAE). LPA_1 expression was analyzed in EAE mice and MS patient immune cells. The effect of LPA and LPA_1 on macrophage activation was studied in human monocyte-derived macrophages. We show that lack of LPA_1 activity induces milder clinical EAE course and that Lpar1 expression in peripheral blood mononuclear cells (PBMC) correlates with onset of relapses and severity in EAE. We see the same over-expression in PBMC from MS patients during relapse compared with progressive forms of the disease and in stimulated monocyte-derived macrophages. LPA induced a proinflammatory-like response in macrophages through LPA_1, providing a plausible way in which LPA and LPA_1 dysregulation can lead to the inflammation in MS. These data show a new mechanism of LPA signaling in the MS pathogenesis, prompting further research into its use as a therapeutic target biomarker.
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Molecular mechanism of Lysophosphatidic Acid-induced hypertensive response
Nature Publishing Group, 2019Co-Authors: Kuniyuki Kano, Jerold Chun, Takao Shimizu, Satoshi Ishii, Asuka Inoue, Hirotaka Matsumoto, Hiroshi Yukiura, Motomu Kanai, Junken AokiAbstract:Abstract Lysophosphatidic Acid (LPA) is a blood-derived bioactive lipid with numerous biological activities exerted mainly through six defined G protein-coupled receptors (LPA1-LPA6). LPA was first identified as a vasoactive compound because it induced transient hypertension when injected intravenously in rodents. Here, we examined the molecular mechanism underlying the LPA-induced hypertensive response. The LPA-induced hypertensive response was significantly attenuated by pretreatment with a Rho kinase inhibitor, which blocks Gα12/13 signaling. Consistent with this, the response was weakened in KO mice of LPA4, a Gα12/13-coupling LPA receptor. KO mice of another Gα12/13-coupling LPA receptor, LPA6, also showed an attenuated LPA-induced hypertensive response. However, LPA6 KO mice also displayed attenuated pressor responses to an adrenergic agent and abnormal blood vessel formation. Using several LPA analogs with varied affinity for each LPA receptor, we found a good correlation between the hypertensive and LPA4 agonistic activities. Incubated mouse plasma, which contained abundant LPA, also induced a hypertensive response. Interestingly the response was completely abolished when the plasma was incubated in the presence of an ATX inhibitor. Together, these results indicate that circulating LPA produced by ATX contributes to the elevation of blood pressure through multiple LPA receptors, mainly LPA4
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Lysophosphatidic Acid and its receptor lpa1 mediate carrageenan induced inflammatory pain in mice
European Journal of Pharmacology, 2018Co-Authors: Malavika Srikanth, Jerold Chun, Wee Siong Chew, Tatsuma Hind, Siew Mon Lim, Nicholas Wei Jie Hay, Jasmine Hui Min Lee, Rich Rivera, Weiyi Ong, Deron R HerrAbstract:Lysophosphatidic Acid receptor 1 (LPA1) is one of six G protein-coupled receptors (GPCRs) activated by the bioactive lipid, Lysophosphatidic Acid (LPA). Previous studies have shown that LPA1 signaling plays a major role in the pathophysiology of neuropathic pain. It has also been shown that the inhibition of phospholipase A2, an enzyme upstream of LPA synthesis, reduces mechanical allodynia in experimental inflammatory orofacial pain. This suggests that the LPA-LPA1 axis may mediate inflammatory pain in addition to its known role in neuropathic pain, but this activity has not been reported. LPA1 signaling was disrupted in mice with both genetic and pharmacological approaches. Mice were then evaluated for behavioral and molecular characteristics of allodynia in a model for inflammatory orofacial pain. Pain behavior was significantly attenuated in LPA1 knockout mice relative to wild-type littermate controls. A similar significant attenuation in allodynia was observed when mice were treated with an LPA1 antagonist, AM095, following validation of its potency and selectivity. This was accompanied by a marked reduction in phosphorylated cAMP response element-binding protein (pCREB) labelling in the cerebral cortex. Interestingly, the reduction in allodynia was observed with central, but not systemic drug administration. Taken together, our findings indicate that LPA1 signaling in the central nervous system (CNS) plays a key role in mediating orofacial inflammatory pain, identifying LPA1 as a potential therapeutic target for treating inflammatory pain with a brain-penetrant drug.
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lpa1 receptor mediated thromboxane a2 release is responsible for Lysophosphatidic Acid induced vascular smooth muscle contraction
The FASEB Journal, 2017Co-Authors: Peter T Dancs, Stefan Offermanns, Junken Aoki, Jerold Chun, Eva Ruisanchez, Andrea Balogh, Cecilia Rita Panta, Zsuzsanna Miklos, Rolf M Nusing, Gabor TigyiAbstract:Lysophosphatidic Acid (LPA) has been recognized recently as an endothelium-dependent vasodilator, but several lines of evidence indicate that it may also stimulate vascular smooth muscle cells (VSMCs), thereby contributing to vasoregulation and remodeling. In the present study, mRNA expression of all 6 LPA receptor genes was detected in murine aortic VSMCs, with the highest levels of LPA1, LPA2, LPA4, and LPA6 In endothelium-denuded thoracic aorta (TA) and abdominal aorta (AA) segments, 1-oleoyl-LPA and the LPA1-3 agonist VPC31143 induced dose-dependent vasoconstriction. VPC31143-induced AA contraction was sensitive to pertussis toxin (PTX), the LPA1&3 antagonist Ki16425, and genetic deletion of LPA1 but not that of LPA2 or inhibition of LPA3, by diacylglycerol pyrophosphate. Surprisingly, vasoconstriction was also diminished in vessels lacking cyclooxygenase-1 [COX1 knockout (KO)] or the thromboxane prostanoid (TP) receptor (TP KO). VPC31143 increased thromboxane A2 (TXA2) release from TA of wild-type, TP-KO, and LPA2-KO mice but not from LPA1-KO or COX1-KO mice, and PTX blocked this effect. Our findings indicate that LPA causes vasoconstriction in VSMCs, mediated by LPA1-, Gi-, and COX1-dependent autocrine/paracrine TXA2 release and consequent TP activation. We propose that this new-found interaction between the LPA/LPA1 and TXA2/TP pathways plays significant roles in vasoregulation, hemostasis, thrombosis, and vascular remodeling.-Dancs, P. T., Ruisanchez, E., Balogh, A., Panta, C. R., Miklos, Z., Nusing, R. M., Aoki, J., Chun, J., Offermanns, S., Tigyi, G., Benyo, Z. LPA1 receptor-mediated thromboxane A2 release is responsible for Lysophosphatidic Acid-induced vascular smooth muscle contraction.
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lpa1 receptor mediated thromboxane a2 release is responsible for Lysophosphatidic Acid induced vascular smooth muscle contraction
The FASEB Journal, 2017Co-Authors: Peter T Dancs, Stefan Offermanns, Junken Aoki, Jerold Chun, Eva Ruisanchez, Andrea Balogh, Cecilia Rita Panta, Zsuzsanna Miklos, Rolf M Nusing, Gabor TigyiAbstract:Lysophosphatidic Acid (LPA) has been recognized recently as an endothelium-dependent vasodilator, but several lines of evidence indicate that it may also stimulate vascular smooth muscle cells (VSM...
Hiroshi Ueda - One of the best experts on this subject based on the ideXlab platform.
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Lysophosphatidic Acid LPA1 and LPA3 receptors play roles in the maintenance of late tissue plasminogen activator-induced central poststroke pain in mice
Elsevier, 2019Co-Authors: Hiroshi Ueda, Hiroyuki Neyama, Keita Sasaki, Chiho Miyama, Ryusei IwamotoAbstract:We developed a mouse model for central post-stroke pain (CPSP), a centrally-originated neuropathic pain (NeuP). In this mode, mice were first injected with Rose Bengal, followed by photo-irradiation of left middle cerebral artery (MCA) to generate thrombosis. Although the MCA thrombosis was soon dissolved, the reduced blood flow remained for more than 24 h due to subsequent occlusion of microvessels. This photochemically induced thrombosis (PIT) model showed a hypersensitivity to the electrical stimulation of both sides of paw, but did not show any abnormal pain in popular thermal or mechanical nociception tests. When tissue-type plasminogen activator (tPA) was injected 6 h after the PIT stress, tPA-dependent hypersensitivity to the electrical paw stimulation and stable thermal and mechanical hyperalgesia on both sides for more than 17 or 18 days after the PIT treatment. These hyperalgesic effects were abolished in Lysophosphatidic Acid receptor 1 (LPA1)- and Lysophosphatidic Acid receptor 3 (LPA3)-deficient mice. When Ki-16425, an LPA1 and LPA3 antagonist was treated twice daily for 6 days consecutively, the thermal and mechanical hyperalgesia at day 17 and 18 were significantly reversed. The liquid chromatography–mass spectrometry (LC–MS/MS) analysis revealed that there is a significant increase in several species of LPA molecules in somatosensory S-I and medial dorsal thalamus (MD), but not in striatum or ventroposterior thalamus. All these results suggest that LPA1 and LPA3 signaling play key roles in the development and maintenance of CPSP. Keywords: Central poststroke pain, Lysophosphatidic Acid, LC–MS/MS, Photochemically induced thrombosis, tP
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Lysophosphatidic Acid 3 receptor mediated feed forward production of Lysophosphatidic Acid an initiator of nerve injury induced neuropathic pain
Molecular Pain, 2009Co-Authors: Hitoshi Uchida, Junken Aoki, Jerold Chun, Jun Nagai, Makoto Inoue, Hiroshi UedaAbstract:Background We previously reported that intrathecal injection of lysophosphatidylcholine (LPC) induced neuropathic pain through activation of the Lysophosphatidic Acid (LPA)-1 receptor, possibly via conversion to LPA by autotaxin (ATX).
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Lysophosphatidic Acid 3 receptor mediated feed forward production of Lysophosphatidic Acid an initiator of nerve injury induced neuropathic pain
Molecular Pain, 2009Co-Authors: Hitoshi Uchida, Junken Aoki, Jerold Chun, Jun Nagai, Makoto Inoue, Hiroshi UedaAbstract:Background: We previously reported that intrathecal injection of lysophosphatidylcholine (LPC) induced neuropathic pain through activation of the Lysophosphatidic Acid (LPA)-1 receptor, possibly via conversion to LPA by autotaxin (ATX). Results: We examined in vivo LPA-induced LPA production using a biological titration assay with B103 cells expressing LPA1 receptors. Intrathecal administration of LPC caused time-related production of LPA in the spinal dorsal horn and dorsal roots, but not in the dorsal root ganglion, spinal nerve or sciatic nerve. LPC-induced LPA production was markedly diminished in ATX heterozygotes, and was abolished in mice that were deficient in LPA 3 , but not LPA 1 or LPA 2 receptors. Similar time-related and LPA3 receptor-mediated production of LPA was observed following intrathecal administration of LPA. In an in vitro study using spinal cord slices, LPA-induced LPA production was also mediated by ATX and the LPA 3 receptor. Intrathecal administration of LPA, in contrast, induced neuropathic pain, which was abolished in mice deficient in LPA1 or LPA3 receptors. Conclusion: These findings suggest that feed-forward LPA production is involved in LPA-induced neuropathic pain.
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evidence for Lysophosphatidic Acid 1 receptor signaling in the early phase of neuropathic pain mechanisms in experiments using ki 16425 a Lysophosphatidic Acid 1 receptor antagonist
Journal of Neurochemistry, 2009Co-Authors: Misaki Matsumoto, Makoto Inoue, Weijiao Xie, Hiroshi UedaAbstract:Lysophosphatidic Acid is a bioactive lipid mediator with neuronal activities. We previously reported a crucial role for Lysophosphatidic Acid 1 receptor-mediated signaling in neuropathic pain mechanisms. Intrathecal administration of Lysophosphatidic Acid (1 nmol) induced abnormal pain behaviors, such as thermal hyperalgesia, mechanical allodynia, A-fiber hypersensitization, and C-fiber hyposensitization, all of which were also observed in partial sciatic nerve injury-induced neuropathic pain. Ki-16425 (30 mg/kg, i.p.), a Lysophosphatidic Acid 1 receptor antagonist, completely blocked Lysophosphatidic Acid-induced neuropathic pain-like behaviors, when administered 30 min but not 90 min before Lysophosphatidic Acid injection, suggesting that Ki-16425 is a short-lived inhibitor. The blockade of nerve injury-induced neuropathic pain by Ki-16425 was maximum as late as 3 h after the injury but not after this critical period. The administration of Ki-16425 at 3 h but not at 6 h after injury also blocked neurochemical changes, including up-regulation of voltage-gated calcium channel alpha(2)delta-1 subunit expression in dorsal root ganglion and reduction of substance P expression in the spinal dorsal horn. All of these results using Ki-16425 suggest that Lysophosphatidic Acid 1 receptor-mediated signaling which underlies the development of neuropathic pain works at an early stage of the critical period after nerve injury.
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lysophosphatidylcholine induces neuropathic pain through an action of autotaxin to generate Lysophosphatidic Acid
Neuroscience, 2008Co-Authors: Makoto Inoue, Junken Aoki, Jerold Chun, W Xie, Yosuke Matsushita, Hiroshi UedaAbstract:Lysophosphatidic Acid receptor (LPA(1)) signaling initiates neuropathic pain and several pathological events in a partial sciatic nerve injury model. Recently, we reported that Lysophosphatidic Acid (LPA) induces neuropathic pain as well as demyelination and pain-related protein expression changes via LPA(1) receptor signaling. Lysophosphatidylcholine (LPC), also known as lysolecithin, which is hydrolyzed by autotaxin/ATX into LPA, induces similar plastic changes. Here, we attempted to clarify whether ATX and LPA(1) receptor signaling is involved in the LPC-induced neuropathic pain. In wild-type mice, a single intrathecal (i.t.) injection of LPC induced mechanical allodynia and thermal hyperalgesia 2 days after injection; this persisted for 7 days at least. On the other hand, LPC-induced mechanical allodynia and thermal hyperalgesia were completely abolished in mice lacking an LPA(1) receptor gene. Furthermore, the LPC-induced response was also significantly, but partially reduced in heterozygous mutant mice for the ATX gene. These findings suggest that intrathecally-injected LPC is converted to LPA by ATX, and this LPA activates the LPA(1) receptor to initiate neuropathic pain.
Junken Aoki - One of the best experts on this subject based on the ideXlab platform.
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2-Carba-Lysophosphatidic Acid is a novel β-Lysophosphatidic Acid analogue with high potential for Lysophosphatidic Acid receptor activation and autotaxin inhibition
'Springer Science and Business Media LLC', 2021Co-Authors: Keiko Fukasawa, Mari Gotoh, Akiharu Uwamizu, Takatsugu Hirokawa, Masaki Ishikawa, Yoshibumi Shimizu, Shinji Yamamoto, Kensuke Iwasa, Keisuke Yoshikawa, Junken AokiAbstract:Abstract Cyclic phosphatidic Acid (cPA) is a naturally occurring phospholipid mediator that, along with its chemically stabilized analogue 2-carba-cyclic phosphatidic Acid (2ccPA), induces various biological activities in vitro and in vivo. Although cPA is similar to Lysophosphatidic Acid (LPA) in structure and synthetic pathway, some of cPA biological functions apparently differ from those reported for LPA. We previously investigated the pharmacokinetic profile of 2ccPA, which was found to be rapidly degraded, especially in Acidic conditions, yielding an unidentified compound. Thus, not only cPA but also its degradation compound may contribute to the biological activity of cPA, at least for 2ccPA. In this study, we determined the structure and examined the biological activities of 2-carba-Lysophosphatidic Acid (2carbaLPA) as a 2ccPA degradation compound, which is a type of β-LPA analogue. Similar to LPA and cPA, 2carbaLPA induced the phosphorylation of the extracellular signal-regulated kinase and showed potent agonism for all known LPA receptors (LPA1–6) in the transforming growth factor-α (TGFα) shedding assay, in particular for LPA3 and LPA4. 2carbaLPA inhibited the lysophospholipase D activity of autotaxin (ATX) in vitro similar to other cPA analogues, such as 2ccPA, 3-carba-cPA, and 3-carba-LPA (α-LPA analogue). Our study shows that 2carbaLPA is a novel β-LPA analogue with high potential for the activation of some LPA receptors and ATX inhibition
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Molecular mechanism of Lysophosphatidic Acid-induced hypertensive response
Nature Publishing Group, 2019Co-Authors: Kuniyuki Kano, Jerold Chun, Takao Shimizu, Satoshi Ishii, Asuka Inoue, Hirotaka Matsumoto, Hiroshi Yukiura, Motomu Kanai, Junken AokiAbstract:Abstract Lysophosphatidic Acid (LPA) is a blood-derived bioactive lipid with numerous biological activities exerted mainly through six defined G protein-coupled receptors (LPA1-LPA6). LPA was first identified as a vasoactive compound because it induced transient hypertension when injected intravenously in rodents. Here, we examined the molecular mechanism underlying the LPA-induced hypertensive response. The LPA-induced hypertensive response was significantly attenuated by pretreatment with a Rho kinase inhibitor, which blocks Gα12/13 signaling. Consistent with this, the response was weakened in KO mice of LPA4, a Gα12/13-coupling LPA receptor. KO mice of another Gα12/13-coupling LPA receptor, LPA6, also showed an attenuated LPA-induced hypertensive response. However, LPA6 KO mice also displayed attenuated pressor responses to an adrenergic agent and abnormal blood vessel formation. Using several LPA analogs with varied affinity for each LPA receptor, we found a good correlation between the hypertensive and LPA4 agonistic activities. Incubated mouse plasma, which contained abundant LPA, also induced a hypertensive response. Interestingly the response was completely abolished when the plasma was incubated in the presence of an ATX inhibitor. Together, these results indicate that circulating LPA produced by ATX contributes to the elevation of blood pressure through multiple LPA receptors, mainly LPA4
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lpa1 receptor mediated thromboxane a2 release is responsible for Lysophosphatidic Acid induced vascular smooth muscle contraction
The FASEB Journal, 2017Co-Authors: Peter T Dancs, Stefan Offermanns, Junken Aoki, Jerold Chun, Eva Ruisanchez, Andrea Balogh, Cecilia Rita Panta, Zsuzsanna Miklos, Rolf M Nusing, Gabor TigyiAbstract:Lysophosphatidic Acid (LPA) has been recognized recently as an endothelium-dependent vasodilator, but several lines of evidence indicate that it may also stimulate vascular smooth muscle cells (VSM...
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lpa1 receptor mediated thromboxane a2 release is responsible for Lysophosphatidic Acid induced vascular smooth muscle contraction
The FASEB Journal, 2017Co-Authors: Peter T Dancs, Stefan Offermanns, Junken Aoki, Jerold Chun, Eva Ruisanchez, Andrea Balogh, Cecilia Rita Panta, Zsuzsanna Miklos, Rolf M Nusing, Gabor TigyiAbstract:Lysophosphatidic Acid (LPA) has been recognized recently as an endothelium-dependent vasodilator, but several lines of evidence indicate that it may also stimulate vascular smooth muscle cells (VSMCs), thereby contributing to vasoregulation and remodeling. In the present study, mRNA expression of all 6 LPA receptor genes was detected in murine aortic VSMCs, with the highest levels of LPA1, LPA2, LPA4, and LPA6 In endothelium-denuded thoracic aorta (TA) and abdominal aorta (AA) segments, 1-oleoyl-LPA and the LPA1-3 agonist VPC31143 induced dose-dependent vasoconstriction. VPC31143-induced AA contraction was sensitive to pertussis toxin (PTX), the LPA1&3 antagonist Ki16425, and genetic deletion of LPA1 but not that of LPA2 or inhibition of LPA3, by diacylglycerol pyrophosphate. Surprisingly, vasoconstriction was also diminished in vessels lacking cyclooxygenase-1 [COX1 knockout (KO)] or the thromboxane prostanoid (TP) receptor (TP KO). VPC31143 increased thromboxane A2 (TXA2) release from TA of wild-type, TP-KO, and LPA2-KO mice but not from LPA1-KO or COX1-KO mice, and PTX blocked this effect. Our findings indicate that LPA causes vasoconstriction in VSMCs, mediated by LPA1-, Gi-, and COX1-dependent autocrine/paracrine TXA2 release and consequent TP activation. We propose that this new-found interaction between the LPA/LPA1 and TXA2/TP pathways plays significant roles in vasoregulation, hemostasis, thrombosis, and vascular remodeling.-Dancs, P. T., Ruisanchez, E., Balogh, A., Panta, C. R., Miklos, Z., Nusing, R. M., Aoki, J., Chun, J., Offermanns, S., Tigyi, G., Benyo, Z. LPA1 receptor-mediated thromboxane A2 release is responsible for Lysophosphatidic Acid-induced vascular smooth muscle contraction.
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Lysophosphatidic Acid as a lipid mediator with multiple biological actions
Journal of Biochemistry, 2015Co-Authors: Shizu Aikawa, Takafumi Hashimoto, Kuniyuki Kano, Junken AokiAbstract:Lysophosphatidic Acid (LPA) is one of the simplest glycerophospholipids with one fatty Acid chain and a phosphate group as a polar head. Although LPA had been viewed just as a metabolic intermediate in de novo lipid synthetic pathways, it has recently been paid much attention as a lipid mediator. LPA exerts many kinds of cellular processes, such as cell proliferation and smooth muscle contraction, through cognate G protein-coupled receptors. Because lipids are not coded by the genome directly, it is difficult to know their patho- and physiological roles. However, recent studies have identified several key factors mediating the biological roles of LPA, such as receptors and producing enzymes. In addition, studies of transgenic and gene knockout animals for these LPA-related genes, have revealed the biological significance of LPA. In this review we will summarize recent advances in the studies of LPA production and its roles in both physiological and pathological conditions.
Makoto Inoue - One of the best experts on this subject based on the ideXlab platform.
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Lysophosphatidic Acid 3 receptor mediated feed forward production of Lysophosphatidic Acid an initiator of nerve injury induced neuropathic pain
Molecular Pain, 2009Co-Authors: Hitoshi Uchida, Junken Aoki, Jerold Chun, Jun Nagai, Makoto Inoue, Hiroshi UedaAbstract:Background We previously reported that intrathecal injection of lysophosphatidylcholine (LPC) induced neuropathic pain through activation of the Lysophosphatidic Acid (LPA)-1 receptor, possibly via conversion to LPA by autotaxin (ATX).
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Lysophosphatidic Acid 3 receptor mediated feed forward production of Lysophosphatidic Acid an initiator of nerve injury induced neuropathic pain
Molecular Pain, 2009Co-Authors: Hitoshi Uchida, Junken Aoki, Jerold Chun, Jun Nagai, Makoto Inoue, Hiroshi UedaAbstract:Background: We previously reported that intrathecal injection of lysophosphatidylcholine (LPC) induced neuropathic pain through activation of the Lysophosphatidic Acid (LPA)-1 receptor, possibly via conversion to LPA by autotaxin (ATX). Results: We examined in vivo LPA-induced LPA production using a biological titration assay with B103 cells expressing LPA1 receptors. Intrathecal administration of LPC caused time-related production of LPA in the spinal dorsal horn and dorsal roots, but not in the dorsal root ganglion, spinal nerve or sciatic nerve. LPC-induced LPA production was markedly diminished in ATX heterozygotes, and was abolished in mice that were deficient in LPA 3 , but not LPA 1 or LPA 2 receptors. Similar time-related and LPA3 receptor-mediated production of LPA was observed following intrathecal administration of LPA. In an in vitro study using spinal cord slices, LPA-induced LPA production was also mediated by ATX and the LPA 3 receptor. Intrathecal administration of LPA, in contrast, induced neuropathic pain, which was abolished in mice deficient in LPA1 or LPA3 receptors. Conclusion: These findings suggest that feed-forward LPA production is involved in LPA-induced neuropathic pain.
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evidence for Lysophosphatidic Acid 1 receptor signaling in the early phase of neuropathic pain mechanisms in experiments using ki 16425 a Lysophosphatidic Acid 1 receptor antagonist
Journal of Neurochemistry, 2009Co-Authors: Misaki Matsumoto, Makoto Inoue, Weijiao Xie, Hiroshi UedaAbstract:Lysophosphatidic Acid is a bioactive lipid mediator with neuronal activities. We previously reported a crucial role for Lysophosphatidic Acid 1 receptor-mediated signaling in neuropathic pain mechanisms. Intrathecal administration of Lysophosphatidic Acid (1 nmol) induced abnormal pain behaviors, such as thermal hyperalgesia, mechanical allodynia, A-fiber hypersensitization, and C-fiber hyposensitization, all of which were also observed in partial sciatic nerve injury-induced neuropathic pain. Ki-16425 (30 mg/kg, i.p.), a Lysophosphatidic Acid 1 receptor antagonist, completely blocked Lysophosphatidic Acid-induced neuropathic pain-like behaviors, when administered 30 min but not 90 min before Lysophosphatidic Acid injection, suggesting that Ki-16425 is a short-lived inhibitor. The blockade of nerve injury-induced neuropathic pain by Ki-16425 was maximum as late as 3 h after the injury but not after this critical period. The administration of Ki-16425 at 3 h but not at 6 h after injury also blocked neurochemical changes, including up-regulation of voltage-gated calcium channel alpha(2)delta-1 subunit expression in dorsal root ganglion and reduction of substance P expression in the spinal dorsal horn. All of these results using Ki-16425 suggest that Lysophosphatidic Acid 1 receptor-mediated signaling which underlies the development of neuropathic pain works at an early stage of the critical period after nerve injury.
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lysophosphatidylcholine induces neuropathic pain through an action of autotaxin to generate Lysophosphatidic Acid
Neuroscience, 2008Co-Authors: Makoto Inoue, Junken Aoki, Jerold Chun, W Xie, Yosuke Matsushita, Hiroshi UedaAbstract:Lysophosphatidic Acid receptor (LPA(1)) signaling initiates neuropathic pain and several pathological events in a partial sciatic nerve injury model. Recently, we reported that Lysophosphatidic Acid (LPA) induces neuropathic pain as well as demyelination and pain-related protein expression changes via LPA(1) receptor signaling. Lysophosphatidylcholine (LPC), also known as lysolecithin, which is hydrolyzed by autotaxin/ATX into LPA, induces similar plastic changes. Here, we attempted to clarify whether ATX and LPA(1) receptor signaling is involved in the LPC-induced neuropathic pain. In wild-type mice, a single intrathecal (i.t.) injection of LPC induced mechanical allodynia and thermal hyperalgesia 2 days after injection; this persisted for 7 days at least. On the other hand, LPC-induced mechanical allodynia and thermal hyperalgesia were completely abolished in mice lacking an LPA(1) receptor gene. Furthermore, the LPC-induced response was also significantly, but partially reduced in heterozygous mutant mice for the ATX gene. These findings suggest that intrathecally-injected LPC is converted to LPA by ATX, and this LPA activates the LPA(1) receptor to initiate neuropathic pain.
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initiation of neuropathic pain requires Lysophosphatidic Acid receptor signaling
Nature Medicine, 2004Co-Authors: Makoto Inoue, Jerold Chun, James J. A. Contos, Harunor Rashid, Ryousuke Fujita, Hiroshi UedaAbstract:Lysophosphatidic Acid (LPA) is a bioactive lipid with activity in the nervous system mediated by G-protein-coupled receptors. Here, we examined the role of LPA signaling in the development of neuropathic pain by pharmacological and genetic approaches, including the use of mice lacking the LPA1 receptor. Wild-type animals with nerve injury develop behavioral allodynia and hyperalgesia paralleled by demyelination in the dorsal root and increased expression of both the protein kinase C γ-isoform within the spinal cord dorsal horn and the α2δ1 calcium channel subunit in dorsal root ganglia. Intrathecal injection of LPA induced behavioral, morphological and biochemical changes similar to those observed after nerve ligation. In contrast, mice lacking a single LPA receptor (LPA1, also known as EDG2) that activates the Rho–Rho kinase pathway do not develop signs of neuropathic pain after peripheral nerve injury. Inhibitors of Rho and Rho kinase also prevented these signs of neuropathic pain. These results imply that receptor-mediated LPA signaling is crucial in the initiation of neuropathic pain.
Gabor Tigyi - One of the best experts on this subject based on the ideXlab platform.
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lpa1 receptor mediated thromboxane a2 release is responsible for Lysophosphatidic Acid induced vascular smooth muscle contraction
The FASEB Journal, 2017Co-Authors: Peter T Dancs, Stefan Offermanns, Junken Aoki, Jerold Chun, Eva Ruisanchez, Andrea Balogh, Cecilia Rita Panta, Zsuzsanna Miklos, Rolf M Nusing, Gabor TigyiAbstract:Lysophosphatidic Acid (LPA) has been recognized recently as an endothelium-dependent vasodilator, but several lines of evidence indicate that it may also stimulate vascular smooth muscle cells (VSM...
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lpa1 receptor mediated thromboxane a2 release is responsible for Lysophosphatidic Acid induced vascular smooth muscle contraction
The FASEB Journal, 2017Co-Authors: Peter T Dancs, Stefan Offermanns, Junken Aoki, Jerold Chun, Eva Ruisanchez, Andrea Balogh, Cecilia Rita Panta, Zsuzsanna Miklos, Rolf M Nusing, Gabor TigyiAbstract:Lysophosphatidic Acid (LPA) has been recognized recently as an endothelium-dependent vasodilator, but several lines of evidence indicate that it may also stimulate vascular smooth muscle cells (VSMCs), thereby contributing to vasoregulation and remodeling. In the present study, mRNA expression of all 6 LPA receptor genes was detected in murine aortic VSMCs, with the highest levels of LPA1, LPA2, LPA4, and LPA6 In endothelium-denuded thoracic aorta (TA) and abdominal aorta (AA) segments, 1-oleoyl-LPA and the LPA1-3 agonist VPC31143 induced dose-dependent vasoconstriction. VPC31143-induced AA contraction was sensitive to pertussis toxin (PTX), the LPA1&3 antagonist Ki16425, and genetic deletion of LPA1 but not that of LPA2 or inhibition of LPA3, by diacylglycerol pyrophosphate. Surprisingly, vasoconstriction was also diminished in vessels lacking cyclooxygenase-1 [COX1 knockout (KO)] or the thromboxane prostanoid (TP) receptor (TP KO). VPC31143 increased thromboxane A2 (TXA2) release from TA of wild-type, TP-KO, and LPA2-KO mice but not from LPA1-KO or COX1-KO mice, and PTX blocked this effect. Our findings indicate that LPA causes vasoconstriction in VSMCs, mediated by LPA1-, Gi-, and COX1-dependent autocrine/paracrine TXA2 release and consequent TP activation. We propose that this new-found interaction between the LPA/LPA1 and TXA2/TP pathways plays significant roles in vasoregulation, hemostasis, thrombosis, and vascular remodeling.-Dancs, P. T., Ruisanchez, E., Balogh, A., Panta, C. R., Miklos, Z., Nusing, R. M., Aoki, J., Chun, J., Offermanns, S., Tigyi, G., Benyo, Z. LPA1 receptor-mediated thromboxane A2 release is responsible for Lysophosphatidic Acid-induced vascular smooth muscle contraction.
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aiming drug discovery at Lysophosphatidic Acid targets
British Journal of Pharmacology, 2010Co-Authors: Gabor TigyiAbstract:Lysophosphatidic Acid (LPA, 1-radyl-2-hydroxy-sn-glycero-3-phosphate) is the prototype member of a family of lipid mediators and second messengers. LPA and its naturally occurring analogues interact with G protein-coupled receptors on the cell surface and a nuclear hormone receptor within the cell. In addition, there are several enzymes that utilize LPA as a substrate or generate it as a product and are under its regulatory control. LPA is present in biological fluids, and attempts have been made to link changes in its concentration and molecular composition to specific disease conditions. Through their many targets, members of the LPA family regulate cell survival, apoptosis, motility, shape, differentiation, gene transcription, malignant transformation and more. The present review depicts arbitrary aspects of the physiological and pathophysiological actions of LPA and attempts to link them with select targets. Many of us are now convinced that therapies targeting LPA biosynthesis and signalling are feasible for the treatment of devastating human diseases such as cancer, fibrosis and degenerative conditions. However, successful targeting of the pathways associated with this pleiotropic lipid will depend on the future development of as yet undeveloped pharmacons.
