PMID- 29261743
OWN - NLM
STAT- MEDLINE
DCOM- 20180108
LR  - 20200730
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 12
DP  - 2017
TI  - A noradrenergic lesion aggravates the effects of systemic inflammation on the 
      hippocampus of aged rats.
PG  - e0189821
LID - 10.1371/journal.pone.0189821 [doi]
LID - e0189821
AB  - Neuroinflammation is potentiated by early degeneration of the locus coeruleus 
      noradrenergic pathway (LC-NE) commonly seen in aging-related neurodegenerative 
      diseases such as Alzheimer's disease and Parkinson's disease. In animal models, 
      lipopolysaccharide (LPS) induces strong peripheral immune responses that can 
      cause cognitive changes secondary to neuroinflammation. The influence of the 
      peripheral immune response on cognition might be exacerbated by LC-NE 
      degeneration, but this has not been well characterized previously. In this study, 
      we investigated how systemic inflammation affects neuroinflammation and cognition 
      in aged rats that have had either normal or damaged LC-NE transmitter systems. 
      Rats were first exposed to the selective noradrenergic (NE) neurotoxin 
      N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) to induce degeneration of 
      central NE pathways. Two weeks later, the rats received a low dose of LPS. This 
      resulted in 3 treatment groups (Control, LPS-, and DSP4+LPS-treated rats) studied 
      at 4 hours (short-term subgroup) and 7 days (long-term subgroup) following the 
      LPS injection. DSP4+LPS-treated rats exhibited increased serum levels of several 
      pro-inflammatory cytokines, increased astroglial and microglial activation in the 
      hippocampus, and poorer performance in the novel object recognition task (NORT) 
      compared to controls and LPS-treated rats. Additionally, serum and brain tissue 
      levels of brain-derived neurotrophic factor (BDNF) were modulated over time in 
      the DSP4+LPS group compared to the other two groups. Specifically, 
      DSP4+LPS-treated rats in the short-term subgroup had lower hippocampal BDNF 
      levels (~25%) than controls and LPS-treated rats, which negatively correlated 
      with hippocampal astrogliosis and positively correlated with hippocampal IL-1beta 
      levels. Serum and hippocampal BDNF levels in the DSP4+LPS-treated rats in the 
      long-term subgroup returned to levels similar to the control group. These results 
      show that systemic inflammation in LC-NE-lesioned aged rats promotes an 
      exacerbated systemic and central inflammatory response compared to LC-NE-intact 
      rats and alters BDNF levels, indicating the important role of this 
      neurotransmitter system in response to neuroinflammation.
FAU - Bharani, Krishna L
AU  - Bharani KL
AD  - Department of Neurosciences, Medical University of South Carolina, BSB, 
      Charleston, SC, United States of America.
FAU - Derex, Rebecca
AU  - Derex R
AD  - Department of Neurosciences, Medical University of South Carolina, BSB, 
      Charleston, SC, United States of America.
FAU - Granholm, Ann-Charlotte
AU  - Granholm AC
AD  - Department of Neurosciences, Medical University of South Carolina, BSB, 
      Charleston, SC, United States of America.
AD  - Knoebel Institute for Healthy Aging, University of Denver, Denver, CO, United 
      States of America.
FAU - Ledreux, Aurelie
AU  - Ledreux A
AUID- ORCID: 0000-0001-6232-7672
AD  - Knoebel Institute for Healthy Aging, University of Denver, Denver, CO, United 
      States of America.
LA  - eng
GR  - R01 AG012122/AG/NIA NIH HHS/United States
GR  - R01 AG044920/AG/NIA NIH HHS/United States
PT  - Journal Article
DEP - 20171219
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Aif1 protein, rat)
RN  - 0 (Benzylamines)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (Chemokines)
RN  - 0 (Glial Fibrillary Acidic Protein)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Microfilament Proteins)
RN  - EC 1.14.16.2 (Tyrosine 3-Monooxygenase)
RN  - PQ1P7JP5C1 (DSP 4)
RN  - X4W3ENH1CV (Norepinephrine)
SB  - IM
MH  - Aging/*pathology
MH  - Analysis of Variance
MH  - Animals
MH  - Astrocytes/pathology
MH  - Benzylamines
MH  - Brain-Derived Neurotrophic Factor/blood/metabolism
MH  - Calcium-Binding Proteins/metabolism
MH  - Chemokines/blood
MH  - Discrimination, Psychological
MH  - Fluorescent Antibody Technique
MH  - Glial Fibrillary Acidic Protein/metabolism
MH  - Hippocampus/*pathology/physiopathology
MH  - Inflammation/blood/*pathology
MH  - Interleukin-1beta/metabolism
MH  - Lipopolysaccharides
MH  - Locomotion
MH  - Male
MH  - Microfilament Proteins/metabolism
MH  - Microglia/pathology
MH  - Nerve Degeneration/pathology
MH  - Norepinephrine/*metabolism
MH  - Rats, Inbred F344
MH  - Task Performance and Analysis
MH  - Tyrosine 3-Monooxygenase/metabolism
PMC - PMC5736222
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2017/12/21 06:00
MHDA- 2018/01/09 06:00
PMCR- 2017/12/19
CRDT- 2017/12/21 06:00
PHST- 2017/09/18 00:00 [received]
PHST- 2017/12/02 00:00 [accepted]
PHST- 2017/12/21 06:00 [entrez]
PHST- 2017/12/21 06:00 [pubmed]
PHST- 2018/01/09 06:00 [medline]
PHST- 2017/12/19 00:00 [pmc-release]
AID - PONE-D-17-33964 [pii]
AID - 10.1371/journal.pone.0189821 [doi]
PST - epublish
SO  - PLoS One. 2017 Dec 19;12(12):e0189821. doi: 10.1371/journal.pone.0189821. 
      eCollection 2017.