Platelet-derived growth factor protects neurons against gp120-mediated toxicity.
The human immunodeficiency virus (HIV)-1 envelope glycoprotein gp120 has been implicated in mediating neuronal apoptosis, a hallmark feature of HIV-associated dementia (HAD). Mitigation of the toxic effects of gp120 could thus be a potential mechanism for reducing HIV toxicity in the brain. In this study the authors hypothesized that neurotrophic factor, such as platelet-derived growth factor (PDGF), could protect the neurons against gp120-mediated apoptosis. SH-SY5Y cells treated with gp120 exhibited increased cell death when measured by lactate dehydrogenase (LDH) and deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) assay, with concomitant loss of neurites and increased cell rounding. Pretreatment with PDGF-BB, however, reduced gp120-associated neurotoxicity and rescued the neurite outgrowth. Additionally, gp120-mediated activation of caspase-3 was also significantly reduced in cells pretreated with PDGF-BB. Antiapoptotic effects of PDGF-BB were also confirmed by monitoring levels of anti- and proapoptotic genes, Bcl-xL and Bax, respectively. Furthermore, PDGF-mediated protection against gp120 involved the phosphoinositide (PI) 3-kinase/Akt pathway. Taken together these findings lead us to suggest that PDGF-BB could be considered as a therapeutic agent that can mitigate gp120-mediated neurotoxicity in HAD.
Peng
Fuwang
F
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Dhillon
Navneet
N
Callen
Shannon
S
Yao
Honghong
H
Bokhari
Sirosh
S
Zhu
Xuhui
X
Baydoun
Hicham H
HH
Buch
Shilpa
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000077214:Becaplermin; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D048430:Cell Shape / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D006801:Humans; D016501:Neurites / Q000187:drug effects / Q000648:ultrastructure; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000235:genetics; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics
C494826:BAX protein, human; C494811:BCL2L1 protein, human; D015699:HIV Envelope Protein gp120; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C514793:gp120 protein, Human immunodeficiency virus 1; D000077214:Becaplermin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; D053148:Caspase 3