Neuronal pentraxin 1: a novel mediator of hypoxic-ischemic injury in neonatal brain.
Neonatal hypoxic-ischemic brain injury is a major cause of neurological disability and mortality. Its therapy will likely require a greater understanding of the discrete neurotoxic molecular mechanism(s) triggered by hypoxia-ischemia (HI). Here, we investigated the role of neuronal pentraxin 1 (NP1), a member of a newly recognized subfamily of "long pentraxins," in the HI injury cascade. Neonatal brains developed marked infarcts in the ipsilateral cerebral hemisphere at 24 hr and showed significant loss of ipsilateral striatal, cortical, and hippocampal volumes at 7 d after HI compared with the contralateral hemisphere and sham controls. Immunofluorescence analyses revealed elevated neuronal expression of NP1 in the ipsilateral cerebral cortex from 6 hr to 7 d and in the hippocampal CA1 and CA3 regions from 24 hr to 7 d after HI. These same brain areas developed infarcts and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive cells within 24-48 hr of HI. In primary cortical neurons, NP1 protein was induced >2.5-fold (p < 0.001) after their exposure to hypoxia that caused approximately 30-40% neuronal death. Transfecting cortical neurons with antisense oligodeoxyribonucleotides directed against NP1 mRNA (NP1AS) significantly inhibited (p < 0.01) hypoxia-induced NP1 protein induction and neuronal death (p < 0.001), demonstrating a specific requirement of NP1 in hypoxic neuronal injury. NP1 protein colocalized and coimmunoprecipitated with the fast excitatory AMPA glutamate receptor subunit (GluR1) in primary cortical neurons, and hypoxia induced a time-dependent increase in NP1-GluR1 interactions. NPIAS also protected against AMPA-induced neuronal death (p < 0.05), implicating a role for NP1 in the excitotoxic cascade. Our results show that NP1 induction mediates hypoxic-ischemic injury probably by interacting with and modulating GluR1 and potentially other excitatory glutamate receptors.
Hossain
Mir Ahamed
MA
Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. hossain@kennedykrieger.org
Russell
Juliet C
JC
O'Brien
Richard
R
Laterra
John
J
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D020287:In Situ Nick-End Labeling; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D018091:Receptors, AMPA / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity; D000099153:Pentraxins
D002097:C-Reactive Protein; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D000099153:Pentraxins