title: HIV protease inhibitors disrupt astrocytic glutamate transporter function and neurobehavioral performance.
abstract: OBJECTIVE
  The neurotoxic actions of the HIV protease inhibitors, amprenavir (APV) and lopinavir (LPV) were investigated.
  
  
  METHODS
  With combination antiretroviral therapy (cART), HIV-infected persons exhibit neurocognitive impairments, raising the possibility that cART might exert adverse central nervous system (CNS) effects. We examined the effects of LPV and APV using in-vitro and in-vivo assays of CNS function.
  
  
  METHODS
  Gene expression, cell viability and amino-acid levels were measured in human astrocytes, following exposure to APV or LPV. Neurobehavioral performance, amino-acid levels and neuropathology were examined in HIV-1 Vpr transgenic mice after treatment with APV or LPV.
  
  
  RESULTS
  Excitatory amino-acid transporter-2 (EAAT2) expression was reduced in astrocytes treated with LPV or APV, especially LPV (P < 0.05), which was accompanied by reduced intracellular L-glutamate levels in LPV-treated cells (P < 0.05). Treatment of astrocytes with APV or LPV reduced the expression of proliferating cell nuclear antigen (PCNA) and Ki-67 (P < 0.05) although cell survival was unaffected. Exposure of LPV to astrocytes augmented glutamate-evoked transient rises in [Cai] (P < 0.05). Vpr mice treated with LPV showed lower concentrations of L-glutamate, L-aspartate and L-serine in cortex compared with vehicle-treated mice (P < 0.05). Total errors in T-maze assessment were increased in LPV and APV-treated animals (P < 0.05). EAAT2 expression was reduced in the brains of protease inhibitor-treated animals, which was associated with gliosis (P < 0.05).
  
  
  CONCLUSIONS
  These results indicated that contemporary protease inhibitors disrupt astrocyte functions at therapeutic concentrations with enhanced sensitivity to glutamate, which can lead to neurobehavioral impairments. ART neurotoxicity should be considered in future therapeutic regimens for HIV/AIDS.
authors.affiliation: aDepartments of Medicine bDepartments of Psychiatry cNeuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada dDepartment of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand eDepartment of Physiology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Pornpun
authors.initials: P
authors.lastname: Vivithanaporn
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Asahchop
authors.forename: Shaona
authors.initials: S
authors.lastname: Acharjee
authors.forename: Glen B
authors.initials: GB
authors.lastname: Baker
authors.forename: Christopher
authors.initials: C
authors.lastname: Power
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology*; D001923:Brain Chemistry; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005663:Furans; D020869:Gene Expression Profiling; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D015497:HIV-1; D006801:Humans; D061466:Lopinavir / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008822:Mice, Transgenic; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology; D009460:Neurologic Examination; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D027322:Amino Acid Transport System X-AG; D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D061466:Lopinavir; C095108:amprenavir