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NEUROPHARMACOLOGY

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) 38 and PACAP4–6 Are Neuroprotective through Inhibition of NADPH Oxidase: Potent Regulators of Microglia-Mediated Oxidative Stress

Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (S.Y., J.Y., Z.Y., A.F., W.Z., H.P., X.G., B.W., J.-S.H., M.L.B.); and Institute of Basic Medical Sciences and Department of Psychiatry, College of Medicine, National Cheng Kung University, Tainan, Taiwan (P.C.)

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 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.

Address correspondence to: Dr. Michelle L. Block, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, MD F1-01, P.O. Box 12233, Research Triangle Park, NC 27709. E-mail: block{at}niehs.nih.gov

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