title: Dopamine receptor modulation of hypoxic-ischemic neuronal injury in striatum of newborn piglets.
abstract: Dopamine receptors regulate glutamatergic neurotransmission and Na(+),K(+)-ATPase via protein kinase A (PKA) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32)-dependent signaling. Consequently, dopamine receptor activation may modulate neonatal hypoxic-ischemic (H-I) neuronal damage in the selectively vulnerable putamen enriched with dopaminergic receptors. Piglets subjected to two durations of hypoxia followed by asphyxic cardiac arrest were treated with a D1-like (SCH23390) or D2-like (sulpiride) receptor antagonist. At 4 days of recovery from less severe H-I, the remaining viable neurons in putamen were 60% of control, but nearly completely salvaged by pretreatment with SCH23390 or sulpiride. After more severe H-I in which only 18% of neurons were viable, partial neuroprotection was seen with SCH23390 pretreatment (50%) and posttreatment (39%) and with sulpiride pretreatment (35%), but not with sulpiride posttreatment (24%). Dopamine was significantly elevated in microdialysis samples from putamen during asphyxia and the first 15 mins of reoxygenation. Pretreatment with SCH23390 or sulpiride largely attenuated the increased nitrotyrosine and the decreased Na(+),K(+)-ATPase activity that occurred at 3 h after severe H-I. Pretreatment with SCH23390, but not sulpiride, also attenuated H-I-induced increases in PKA-dependent phosphorylation of Thr34 on DARPP-32, Ser943 on the alpha subunit of Na(+),K(+)-ATPase, and Ser897 of the N-methyl-D-aspartate (NMDA) receptor NR1 subunit. These findings indicate that D1 and D2 dopamine receptor activation contribute to neuronal death in newborn putamen after H-I in association with increased protein nitration and decreased Na(+),K(+)-ATPase activity. Furthermore, mechanisms of D1 receptor toxicity may involve DARPP-32-dependent phosphorylation of NMDA receptor NR1 and Na(+),K(+)-ATPase.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Zeng-Jin
authors.initials: ZJ
authors.lastname: Yang
authors.forename: Michel
authors.initials: M
authors.lastname: Torbey
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bernardy
authors.forename: W Christopher
authors.initials: WC
authors.lastname: Golden
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Martin
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Koehler
mesh_terms: D000251:Adenosine Triphosphatases / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D003342:Corpus Striatum / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000187:drug effects / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D017551:Microdialysis; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010766:Phosphorylation; D011954:Receptors, Dopamine / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D013552:Swine; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D018492:Dopamine Antagonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C409466:NR1 NMDA receptor; D018696:Neuroprotective Agents; D011954:Receptors, Dopamine; D016194:Receptors, N-Methyl-D-Aspartate; C002744:3-nitrotyrosine; D014443:Tyrosine; D000251:Adenosine Triphosphatases; D004298:Dopamine