Document Detail

The effects of doxycycline administration on amino acid neurotransmitters in an animal model of neonatal hypoxia-ischemia.
MedLine Citation:
PMID:  16919849     Owner:  NLM     Status:  MEDLINE    
Neonatal hypoxia-ischemia (HI) is a major contributor to many neurological, psychiatric and behavioral disorders. Previous studies in our laboratory have shown that a one-time dose of doxycycline (DOXY), even when given 3h after HI insult, was neuroprotective and significantly reduced microglial activation and cleaved caspase-3 protein expression in the immature brain. In light of these data, the goal of this study was to investigate the effects of DOXY administration on amino acid neurotransmitters. Post-natal-day 7 rats received DOXY (10mg/kg) or vehicle (VEH) concomitant with the onset of HI, and were euthanized 30 min, 1, 2 or 4h post-HI (n>or=6). Extracted brains were either immediately dissected for frontal cortex, striatum and hippocampal regions, or removed in their entirety and flash frozen in isopentane for histological analyses. Dissected regions were homogenized and aliquots were prepared for high performance liquid chromatography (HPLC) analyses of amino acid levels and brain levels of DOXY. HPLC extraction revealed that systemic administration of DOXY resulted in mean drug levels of 867.1+/-376.1 ng/g of brain tissue. Histological analyses revealed microglial activation, caspase-3 activation and neuronal degeneration consistent with a mild injury in the regions most vulnerable to HI. We found that HI caused significant, time-dependent, regional changes in brain amino acids including glutamate, GABA, alanine, aspartate, asparagine, serine, glutamine, glycine and taurine. HI significantly increased glutamate levels in the hippocampus (HI+VEH=15.8+/-3.1 ng/microg versus control=11.8+/-1.4 ng/microg protein) 4h post-HI (p<0.05). Pups treated with DOXY had lower glutamate levels (13.1+/-2.4 ng/microg) when compared to VEH-treated pups (15.8+/-3.1 ng/microg), however these values failed to reach significance. In addition, DOXY-treated pups had significantly lower alanine (HI+VEH=1.1+/-0.2 ng/microg versus HI+DOXY=0.5+0.1 ng/microg) and serine (HI+VEH=1.4+/-0.4 ng/microg versus HI+DOXY=0.7+0.1 ng/microg) levels in the hippocampus, 4h post-HI. Similar normalizations and significant reductions in alanine and serine were seen in the cortex and striatum. These results show that in addition to its previously reported and well-documented anti-inflammatory and anti-apoptotic properties, DOXY has significant effects on amino acid neurotransmitters.
Lauren L Jantzie; Gail A Rauw; Kathryn G Todd
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-08-17
Journal Detail:
Title:  Neurochemistry international     Volume:  49     ISSN:  0197-0186     ISO Abbreviation:  Neurochem. Int.     Publication Date:  2006 Dec 
Date Detail:
Created Date:  2006-11-06     Completed Date:  2007-01-26     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8006959     Medline TA:  Neurochem Int     Country:  England    
Other Details:
Languages:  eng     Pagination:  717-28     Citation Subset:  IM    
Neurochemical Research Unit, Department of Psychiatry, 1E7 WMC, University of Alberta, Edmonton, Alberta, Canada T6G 2R7.
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MeSH Terms
Amino Acids / metabolism*
Animals, Newborn
Brain / drug effects,  metabolism
Chromatography, High Pressure Liquid
Disease Models, Animal
Doxycycline / administration & dosage*
Hypoxia-Ischemia, Brain / metabolism*
Neurotransmitter Agents / metabolism*
Rats, Sprague-Dawley
Reg. No./Substance:
0/Amino Acids; 0/Neurotransmitter Agents; 564-25-0/Doxycycline

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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