Depletion of neutrophils reduces neuronal degeneration and inflammatory responses induced by quinolinic acid in vivo.
The use of anti-neutrophil serum (anti-PMN) to induce neutropenia has been assessed for neuroprotection, modulation of microgliosis and astrogliosis, effects on oxidative stress, and intactness of blood-brain barrier (BBB) following injection of the excitotoxin quinolinic acid (QUIN) into rat striatum. At 1 day following QUIN injection, considerable striatal neurodegeneration was measured (Fluoro-Jade B marker). At this time, marked microgliosis (OX-42 marker) and astrogliosis (GFAP marker) were evident in QUIN-injected striatum. Treatment of QUIN-injected animals with anti-PMN protected neurons (48% reduction of striatal neuron loss) and inhibited microgliosis (61% reduction) and astrogliosis (43% reduction) compared with QUIN injection alone. Anti-PMN treatment was effective in decreasing levels of superoxide anions (by 42%) compared with QUIN alone; in addition, expressions of the neutrophil enzyme myeloperoxidase and the neutrophil oxidant 3-chlorotyrosine were markedly reduced (by 79 and 72%, respectively) with neutrophil depletion. QUIN-induced leakiness in BBB was indicated by elevated striatal levels of the blood protein fibrinogen, a result confirmed using Evans blue dye; anti-PMN was effective in reducing BBB permeability. Measurements from QUIN-injected animals directly confirmed anti-PMN efficacy in diminishing numbers of circulating neutrophils. Longer term neuroprotection and reduced microgliosis were also observed at 7 days post-injection of anti-PMN; at this time, anti-PMN-treated rats also demonstrated an improved apomorphine-induced rotational performance. We conclude that anti-PMN treatment could serve as a novel strategy to prevent leakiness to BBB, reduce gliosis, and protect striatal neurons in excitotoxin-injected brain.
Ryu
Jae K
JK
Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Tran
Karen C
KC
McLarnon
James G
JG
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005911:Gliosis / Q000473:pathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology*; D008297:Male; D017628:Microglia / Q000187:drug effects; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects; D009410:Nerve Degeneration / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D009504:Neutrophils / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects; D017378:Quinolinic Acid / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism
D013481:Superoxides; D017378:Quinolinic Acid; D001058:Apomorphine