PMID- 25517826
OWN - NLM
STAT- MEDLINE
DCOM- 20160204
LR  - 20181202
IS  - 1557-7465 (Electronic)
IS  - 1079-9907 (Print)
IS  - 1079-9907 (Linking)
VI  - 35
IP  - 4
DP  - 2015 Apr
TI  - Interferon-alpha induces neurotoxicity through activation of the type I receptor and 
      the GluN2A subunit of the NMDA receptor.
PG  - 317-24
LID - 10.1089/jir.2014.0105 [doi]
AB  - Elevated levels of interferon-alpha (IFNalpha) in the central nervous system (CNS) 
      are linked to cognitive dysfunction in patients with inflammatory CNS diseases 
      such as HIV-associated neurocognitive disorders (HAND). Increased CNS IFNalpha has 
      also been found to be associated with cognitive dysfunction in a HAND mouse 
      model. Here, we corroborate previous studies showing a dose-dependent decrease in 
      dendritic branching and length caused by IFNalpha treatment and extend those studies. 
      Because both direct and indirect mechanisms of IFNalpha-induced neurotoxicity are 
      likely involved, the cell signaling pathway involving the IFNalpha receptor (IFNAR) 
      was initially evaluated. Rat neuronal cultures exposed to IFNalpha demonstrate 
      increased phosphorylation of STAT1 and increased interferon stimulating gene 15 
      (ISG15) expression, indicators of IFNAR engagement. However, specific blocking 
      antibodies to the IFNAR were found to only partially protect neurons from 
      IFNalpha-induced neurotoxicity. Additionally, inhibiting the GluN2A subunit of 
      N-methyl-D-asparate receptor (NMDAR) was also found to be partially protective 
      against IFNalpha-induced neurotoxicity compared with the GluN2B subunit. 
      Neurotoxicity is evident in neurons extracted from IFNAR KO mice treated with 
      IFNalpha as well, further indicating that IFNAR signaling is not required for IFNalpha 
      neurotoxicity. The neurotoxic actions of IFNalpha are mediated through both the IFNAR 
      as well as the GluN2A subunit of the NMDAR to reduce dendritic arborization in 
      neurons. Complete protection from IFNalpha-induced neurotoxicity was demonstrated 
      when both pathways were blocked. Blocking these pathways could lead to potential 
      therapies for cognitive dysfunction during neuroinflammation and specifically 
      lead to better treatments for HAND.
FAU - Kessing, Cari F
AU  - Kessing CF
AD  - 1 Department of Neurology, Emory University School of Medicine , Atlanta, Georgia 
      .
FAU - Tyor, William R
AU  - Tyor WR
LA  - eng
GR  - I01 BX001506/BX/BLRD VA/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20141217
PL  - United States
TA  - J Interferon Cytokine Res
JT  - Journal of interferon & cytokine research : the official journal of the 
      International Society for Interferon and Cytokine Research
JID - 9507088
RN  - 0 (Cytokines)
RN  - 0 (Interferon-alpha)
RN  - 0 (Receptors, AMPA)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (STAT1 Transcription Factor)
RN  - P6W5IXV8V9 (glutamate receptor ionotropic, AMPA 2)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - Cytokines/genetics
MH  - Gene Expression Regulation/drug effects
MH  - Interferon-alpha/metabolism/*pharmacology
MH  - Mice
MH  - Neurons/*drug effects
MH  - Phosphorylation/drug effects
MH  - Polymerase Chain Reaction
MH  - Rats
MH  - Receptors, AMPA/*metabolism
MH  - Receptors, N-Methyl-D-Aspartate/*metabolism
MH  - STAT1 Transcription Factor/metabolism
MH  - Signal Transduction/drug effects
PMC - PMC4389917
EDAT- 2014/12/18 06:00
MHDA- 2016/02/05 06:00
PMCR- 2016/04/01
CRDT- 2014/12/18 06:00
PHST- 2014/12/18 06:00 [entrez]
PHST- 2014/12/18 06:00 [pubmed]
PHST- 2016/02/05 06:00 [medline]
PHST- 2016/04/01 00:00 [pmc-release]
AID - 10.1089/jir.2014.0105 [pii]
AID - 10.1089/jir.2014.0105 [doi]
PST - ppublish
SO  - J Interferon Cytokine Res. 2015 Apr;35(4):317-24. doi: 10.1089/jir.2014.0105. 
      Epub 2014 Dec 17.