PMID- 12843275
OWN - NLM
STAT- MEDLINE
DCOM- 20030814
LR  - 20211203
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 23
IP  - 13
DP  - 2003 Jul 2
TI  - Brain-derived neurotrophic factor inhibits human immunodeficiency 
      virus-1/gp120-mediated cerebellar granule cell death by preventing gp120 
      internalization.
PG  - 5715-22
AB  - The human immunodeficiency virus type 1 (HIV-1) envelope protein gp120 has been 
      implicated in the pathogenesis of HIV-1 dementia. Thus, inhibition of gp120 
      activity could reduce HIV toxicity in the brain. We have used primary cultures of 
      rat cerebellar granule cells to examine mechanisms whereby gp120 causes cell 
      death and to characterize neuroprotective agents. gp120 induced a time- and 
      concentration-dependent apoptotic cell death, which was caspase-3-mediated but 
      caspase-1 independent, and was totally blocked by the irreversible caspase-3-like 
      protease inhibitor N-acetyl-Asp-Glu-Val-Asp-chloromethylketone. Caspase-3 
      activation was observed only in neurons that internalize gp120, indicating that 
      internalization is key to gp120 toxicity. Because brain-derived neurotrophic 
      factor (BDNF) prevents caspase-3-mediated neuronal cell death, we examined 
      whether BDNF could prevent gp120-mediated apoptosis. Preincubation of neurons 
      with BDNF before the addition of gp120 reduced caspase-3 activation, and 
      consequently rescued 80% of neurons from apoptosis. Most importantly, BDNF 
      reduced the levels of CXC chemokine receptor-4 (CXCR4), a receptor that mediates 
      HIV-1 gp120-induced apoptosis. This effect correlated with the ability of BDNF to 
      reduce gp120 internalization and apoptosis. Moreover, BDNF blocked the neurotoxic 
      effect of stromal-derived factor-1alpha, a natural ligand for CXCR4, further 
      establishing a correlation between neuroprotection and downregulation of CXCR4. 
      We propose that BDNF may be a valid therapy to slow down the progression of 
      HIV/gp120-mediated neurotoxicity.
FAU - Bachis, Alessia
AU  - Bachis A
AD  - Department of Neuroscience, Georgetown University Medical Center, Washington, DC 
      20057, USA.
FAU - Major, Eugene O
AU  - Major EO
FAU - Mocchetti, Italo
AU  - Mocchetti I
LA  - eng
GR  - R01 NS040670/NS/NINDS NIH HHS/United States
GR  - NS40670/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Anti-HIV Agents)
RN  - 0 (Benzylamines)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (CXCL12 protein, human)
RN  - 0 (Caspase Inhibitors)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Chemokines, CXC)
RN  - 0 (Cyclams)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (HIV Envelope Protein gp120)
RN  - 0 (Heterocyclic Compounds)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Receptors, CXCR4)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (Casp3 protein, rat)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspases)
RN  - S915P5499N (plerixafor)
SB  - IM
MH  - Animals
MH  - Anti-HIV Agents/pharmacology
MH  - Apoptosis/drug effects
MH  - Benzylamines
MH  - Brain-Derived Neurotrophic Factor/*pharmacology
MH  - Caspase 3
MH  - Caspase Inhibitors
MH  - Caspases/metabolism
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Cerebellum/*cytology
MH  - Chemokine CXCL12
MH  - Chemokines, CXC/antagonists & inhibitors/toxicity
MH  - Cyclams
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Activation/drug effects
MH  - Enzyme Inhibitors/pharmacology
MH  - HIV Envelope Protein gp120/*metabolism/toxicity
MH  - *HIV-1
MH  - Heterocyclic Compounds/pharmacology
MH  - Neurons/*drug effects/metabolism
MH  - Neuroprotective Agents/pharmacology
MH  - Protein Transport/drug effects
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, CXCR4/antagonists & inhibitors/metabolism
PMC - PMC6741234
EDAT- 2003/07/05 05:00
MHDA- 2003/08/15 05:00
PMCR- 2004/01/02
CRDT- 2003/07/05 05:00
PHST- 2003/07/05 05:00 [pubmed]
PHST- 2003/08/15 05:00 [medline]
PHST- 2003/07/05 05:00 [entrez]
PHST- 2004/01/02 00:00 [pmc-release]
AID - 23/13/5715 [pii]
AID - 10.1523/JNEUROSCI.23-13-05715.2003 [doi]
PST - ppublish
SO  - J Neurosci. 2003 Jul 2;23(13):5715-22. doi: 10.1523/JNEUROSCI.23-13-05715.2003.