title: Cocaine-mediated induction of platelet-derived growth factor: implication for increased vascular permeability.
abstract: Neuroinflammation associated with advanced HIV-1 infection is often exacerbated in cocaine-abusing, HIV-infected patients. The underlying mechanisms could, in part, be attributed to the increased impairment of blood brain barrier integrity in the presence of cocaine. Platelet-derived growth factor (PDGF) has been implicated in several pathologic conditions, specifically attributable to its potent mitogenic effects. Its modulation by drug abuse, however, has received very little attention. In the present study, we demonstrated cocaine-mediated induction of PDGF-BB in human brain microvascular endothelial cells through the binding to its cognate σ receptor. Furthermore, this effect was mediated, with subsequent activation of mitogen-activated protein kinases and Egr-1 pathways, culminating ultimately into increased expression of PDGF-BB. Cocaine exposure resulted in increased permeability of the endothelial barrier, and this effect was abrogated in mice exposed to PDGF-BB neutralizing antibody, thus underscoring its role as a vascular permeant. In vivo relevance of these findings was further corroborated in cocaine-treated mice that were administered neutralizing antibody specific for PDGF-BB as well as in Egr-1(-/-) mice. Understanding the regulation of PDGF-BB expression may provide insights into the development of potential therapeutic targets for neuroinflammation associated with HIV infection and drug abuse.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska MedicalCenter, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
authors.forename: Honghong
authors.initials: H
authors.lastname: Yao
authors.forename: Ming
authors.initials: M
authors.lastname: Duan
authors.forename: Shilpa
authors.initials: S
authors.lastname: Buch
mesh_terms: D043925:Angiogenesis Inducing Agents; D000818:Animals; D000077214:Becaplermin; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology; D001921:Brain / Q000473:pathology*; D002199:Capillary Permeability / Q000187:drug effects* / Q000235:genetics; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D015658:HIV Infections / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D051379:Mice; D010982:Platelet-Derived Growth Factor / Q000235:genetics*; D020574:Proto-Oncogene Proteins c-sis; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D043925:Angiogenesis Inducing Agents; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D003042:Cocaine