title: PGE2 EP1 receptor deletion attenuates 6-OHDA-induced Parkinsonism in mice: old switch, new target.
abstract: Recent experimental data on Parkinson's disease (PD) predicts the critical role of inflammation in the progression of neurodegeneration and the promising preventive effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Previous studies suggest that NSAIDs minimize cyclooxygenase-2 (COX-2) activity and thereby attenuate free radical generation. Prostaglandin E2 (PGE2) is an important product of COX activity and plays an important role in various physiologic and pathophysiologic conditions through its EP receptors (EP1-EP4). Part of the toxic effect of PGE2 in the central nervous system has been reported to be through the EP1 receptor; however, the effect of the EP1 receptor in PD remains elusive. Therefore, in our pursuit to determine if deletion of the PGE2 EP1 receptor will attenuate 6-hydroxy dopamine (6-OHDA)-induced Parkinsonism, mice were given a unilateral 6-OHDA injection into the medial forebrain bundle. We found that apomorphine-induced contralateral rotations were significantly attenuated in the 6-OHDA-lesioned EP1(-/-) mice compared with the 6-OHDA-lesioned WT mice. Quantitative analysis showed significant protection of dopaminergic neurons in the substantia nigra pars compacta of the 6-OHDA-lesioned EP1(-/-) mice. To the best of our knowledge, this is the first in vivo study to implicate the PGE2 EP1 receptor in toxin-induced Parkinsonism. We propose the PGE2 EP1 receptor as a new target to better understand some of the mechanisms leading to PD.
authors: Department of Anesthesiology, University of Florida College of Medicine, PO Box 100159, Gainesville, FL 32610-0254, USA.
authors: Abdullah Shafique
authors: AS
authors: Ahmad
authors: Takayuki
authors: T
authors: Maruyama
authors: Shuh
authors: S
authors: Narumiya
authors: Sylvain
authors: S
authors: Doré
mesh_terms: D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D015232:Dinoprostone / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D007267:Injections; D008474:Medial Forebrain Bundle / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D016627:Oxidopamine / Q000008:administration & dosage / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
chemical_list: D018491:Dopamine Agonists; D009419:Nerve Tissue Proteins; C545636:Ptger1 protein, mouse; D058306:Receptors, Prostaglandin E, EP1 Subtype; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D015232:Dinoprostone; D001058:Apomorphine
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