PMID- 16541436
OWN - NLM
STAT- MEDLINE
DCOM- 20060622
LR  - 20151119
IS  - 0894-1491 (Print)
IS  - 0894-1491 (Linking)
VI  - 53
IP  - 8
DP  - 2006 Jun
TI  - Hypoxia-activated microglial mediators of neuronal survival are differentially 
      regulated by tetracyclines.
PG  - 809-16
AB  - The tetracycline derivatives minocycline (MINO) and doxycycline (DOXY) have been 
      shown to be neuroprotective in in vivo and in vitro models of stroke. This 
      neuroprotection is thought to be due to the suppression of microglial activation. 
      However, the specific molecular parameters in microglia of the tetracyclines' 
      effect are not understood. We subjected cultured rat microglial and neuronal 
      cells to in vitro hypoxia and examined the effects of MINO and DOXY 
      pre-treatments. Our data showed that MINO and DOXY protect against 
      hypoxia-induced neuronal death by a mechanism dependent on regulation of 
      microglial factors, but likely unrelated to regulation of microglial 
      proliferation/viability. Both MINO and DOXY suppressed the hypoxic activation of 
      ED-1, a marker for microglial activation. Morphological analyses of hypoxic 
      microglia using the microglial marker Iba1 revealed that treatment with MINO and 
      DOXY caused a higher percentage of microglia to remain in a non-activated state. 
      MINO suppressed the hypoxic upregulation of pro-inflammatory agents nitric oxide 
      (NO), interleukin-1 beta (IL-1beta), and tumor necrosis factor alpha (TNF-alpha), 
      while DOXY down-regulated only NO and IL-1beta. In contrast, the hypoxic 
      activation of pro-survival/neuroprotective microglial proteins, such as 
      brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic 
      factor (GDNF), were unaffected by tetracycline treatments. Taken together, these 
      results suggest that MINO and DOXY may provide neuroprotection against stroke by 
      selectively down-regulating microglial toxic factors while maintaining functional 
      pro-survival factors.
FAU - Lai, Aaron Y
AU  - Lai AY
AD  - Neurochemical Research Unit, Department of Psychiatry and Centre for 
      Neuroscience, University of Alberta, Edmonton, Alberta, Canada.
FAU - Todd, Kathryn G
AU  - Todd KG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Glia
JT  - Glia
JID - 8806785
RN  - 0 (Biomarkers)
RN  - 0 (Ectodysplasins)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Membrane Proteins)
RN  - 0 (Nerve Growth Factors)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Tetracyclines)
RN  - 0 (Tumor Necrosis Factors)
RN  - FYY3R43WGO (Minocycline)
RN  - N12000U13O (Doxycycline)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Biomarkers/metabolism
MH  - Brain/*metabolism/physiopathology
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects/physiology
MH  - Cells, Cultured
MH  - Coculture Techniques
MH  - Doxycycline/pharmacology
MH  - Ectodysplasins
MH  - Encephalitis/drug therapy/metabolism/prevention & control
MH  - Hypoxia-Ischemia, Brain/*metabolism/physiopathology
MH  - Inflammation Mediators/antagonists & inhibitors/metabolism
MH  - Membrane Proteins/drug effects/metabolism
MH  - Microglia/drug effects/*metabolism
MH  - Minocycline/pharmacology
MH  - Nerve Growth Factors/agonists/metabolism
MH  - Neuroprotective Agents/*pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Tetracyclines/*pharmacology
MH  - Tumor Necrosis Factors/metabolism
MH  - Up-Regulation/drug effects/physiology
EDAT- 2006/03/17 09:00
MHDA- 2006/06/23 09:00
CRDT- 2006/03/17 09:00
PHST- 2006/03/17 09:00 [pubmed]
PHST- 2006/06/23 09:00 [medline]
PHST- 2006/03/17 09:00 [entrez]
AID - 10.1002/glia.20335 [doi]
PST - ppublish
SO  - Glia. 2006 Jun;53(8):809-16. doi: 10.1002/glia.20335.