TY - JOUR
T1 - Pituitary adenylate cyclase-activating polypeptide (PACAP) 38 and PACAP4-6 are neuroprotective through inhibition of NADPH oxidase
T2 - Potent regulators of microglia-mediated oxidative stress
AU - Yang, Sufen
AU - Yang, Jun
AU - Yang, Zhengqin
AU - Chen, Posee
AU - Fraser, Alison
AU - Zhang, Wei
AU - Pang, Hao
AU - Gao, Xi
AU - Wilson, Belinda
AU - Hong, Jau Shyong
AU - Block, Michelle L.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2006
Y1 - 2006
N2 - Microglial activation is implicated in the progressive nature of numerous neurodegenerative diseases, including Parkinson's disease. Using primary rat mesencephalic neuron-glia cultures, we found that pituitary adenylate cyclase-activating polypeptide (PACAP) 38, PACAP27, and its internal peptide, Gly-Ile-Phe (GIF; PACAP4-6), are neuroprotective at 10-13 M against lipopolysaccharide (LPS)-induced dopaminergic (DA) neurotoxicity, as determined by [3H]DA uptake and the number of tyrosine hydroxylase- immunoreactive neurons. PACAP38 and GIF also protected against 1-methyl-4-phenylpyridinium+-induced neurotoxicity but only in cultures containing microglia. PACAP38 and GIF ameliorated the production of microglia-derived reactive oxygen species (ROS), where both LPS- and phorbol 12-myristate 13-acetate-induced superoxide and intracellular ROS were inhibited. The critical role of NADPH oxidase for GIF and PACAP38 neuroprotection against LPS-induced DA neurotoxicity was demonstrated using neuron-glia cultures from mice deficient in NADPH oxidase (PHOX-/-), where PACAP38 and GIF reduced tumor necrosis factor α production and were neuroprotective only in PHOX+/+ cultures and not in PHOX-/- cultures. Pretreatment with PACAP6-38 (3 μM; PACAP-specific receptor antagonist) was unable to attenuate PACAP38, PACAP27, or GIF (10-13 M) neuroprotection. PACAP38 and GIF (10-13 M) failed to induce cAMP in neuronglia cultures, supporting that the neuroprotective effect was independent of traditional high-affinity PACAP receptors. Pharmacophore analysis revealed that GIF shares common chemical properties (hydrogen bond acceptor, positive ionizable, and hydrophobic regions) with other subpicomolar-acting compounds known to inhibit NADPH oxidase: naloxone, dextromethorphan, and Gly-Gly-Phe. These results indicate a common high-affinity site of action across numerous diverse peptides and compounds, revealing a basic neuropeptide regulatory mechanism that inhibits microglia-derived oxidative stress and promotes neuron survival.
AB - Microglial activation is implicated in the progressive nature of numerous neurodegenerative diseases, including Parkinson's disease. Using primary rat mesencephalic neuron-glia cultures, we found that pituitary adenylate cyclase-activating polypeptide (PACAP) 38, PACAP27, and its internal peptide, Gly-Ile-Phe (GIF; PACAP4-6), are neuroprotective at 10-13 M against lipopolysaccharide (LPS)-induced dopaminergic (DA) neurotoxicity, as determined by [3H]DA uptake and the number of tyrosine hydroxylase- immunoreactive neurons. PACAP38 and GIF also protected against 1-methyl-4-phenylpyridinium+-induced neurotoxicity but only in cultures containing microglia. PACAP38 and GIF ameliorated the production of microglia-derived reactive oxygen species (ROS), where both LPS- and phorbol 12-myristate 13-acetate-induced superoxide and intracellular ROS were inhibited. The critical role of NADPH oxidase for GIF and PACAP38 neuroprotection against LPS-induced DA neurotoxicity was demonstrated using neuron-glia cultures from mice deficient in NADPH oxidase (PHOX-/-), where PACAP38 and GIF reduced tumor necrosis factor α production and were neuroprotective only in PHOX+/+ cultures and not in PHOX-/- cultures. Pretreatment with PACAP6-38 (3 μM; PACAP-specific receptor antagonist) was unable to attenuate PACAP38, PACAP27, or GIF (10-13 M) neuroprotection. PACAP38 and GIF (10-13 M) failed to induce cAMP in neuronglia cultures, supporting that the neuroprotective effect was independent of traditional high-affinity PACAP receptors. Pharmacophore analysis revealed that GIF shares common chemical properties (hydrogen bond acceptor, positive ionizable, and hydrophobic regions) with other subpicomolar-acting compounds known to inhibit NADPH oxidase: naloxone, dextromethorphan, and Gly-Gly-Phe. These results indicate a common high-affinity site of action across numerous diverse peptides and compounds, revealing a basic neuropeptide regulatory mechanism that inhibits microglia-derived oxidative stress and promotes neuron survival.
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U2 - 10.1124/jpet.106.102236
DO - 10.1124/jpet.106.102236
M3 - Article
C2 - 16891616
AN - SCOPUS:33751166602
VL - 319
SP - 595
EP - 603
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 2
ER -