DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 434

has been reported in gliomas 312 , 313 as well as along the tumor microvasculature in
both gliomas and glioblastomas. 314 , 315 In addition, Abe et al. reported MRP1 expres-
sion in gliomas isolated from chemotherapy-naive patients. 316 Interestingly, this same
study reported that MRP1 expression increased in patients who received aggressive
chemotherapy, 316 suggesting that drug treatment may up-regulate the expression of
this transporter in brain cancer. Gene and protein expression of several MRP isoforms,
including MRP3, MRP4, and MRP5, have been identified in cell lines derived from
brain neoplasms. 317 Up-regulation of ABCG2 in brain cancer has also been reported,
and it appears to be localized exclusively to the tumor microvasculature. 318 As de-
scribed earlier in the chapter, many ABC transporter substrates are also commonly
used chemotherapeutic agents. 319 - 321 The expression of ABC transporters in brain
tumors may explain, in part, the limited efficacy of pharmacotherapeutic approaches
in the treatment of brain cancer.
To date, little is known about the expression of uptake transporters in various
types of brain cancer. A recent manuscript has described the mRNA expression of
various OATP isoforms, including OATP-A, OATP-B, and OATP-C in isolated hu-
man gliomas. 322 The role of these transporters in regulating chemotherapeutic drug
distribution in the brain remains to be determined.

14.4.2. HIV-1 Encephalitis

Human immunodeficiency virus type-1 (HIV-1) infection of the brain may lead
to HIV-1 encephalitis (HIVE), a chronic neurodegenerative condition character-
ized by productive viral replication in brain mononuclear phagocytes. 323 , 324 HIVE
may lead to various neurocognitive disorders, including HIV-1-associated dementia
(HAD), which is characterized by cognitive and motor dysfunction as well as be-
havioral abnormalities. 325 The implementation of highly active antiretroviral therapy
(HAART) to treat HIV-1 infection has led to a 40 to 50% decrease in the incidence of
HAD. 326 - 328 However, HIV-1-associated neurocognitive disorders, including HAD-
and HIV-related sensory neuropathies, continue to be a major cause of morbidity and
mortality. In fact, the combined prevalence of HAD-and HIV-related sensory neu-
ropathy is approximately 30 to 50% in patients with advanced HIV-1 infection. 328
Taken together, these observations suggest that HAART may not provide complete
protection against the progression of HAD/HIVE.
HIV-1 enters the brain early during the course of infection and infects primarily
microglia and to a lesser extent, astrocytes. 324 Once they are infected, these cells may
become activated and secrete cytokines (e.g., TNF , IL-6) and neurotoxins

(e.g., arachidonic acid, glutamate, nitric oxide, platelet activating factor, quinolinic
acid). 324 Release of these substances may be induced by the binding of HIV-1 viral
proteins HIV-1 viral envelope glycoprotein gp120 or HIV-1 transactivator protein
(Tat) to chemokine receptors (e.g., CXCR4, CCR5) on the microglia/astrocyte cell
surface. 323 , 324 , 329 When high concentrations of these substances are present in the
brain, neurotoxicity may result due to overactivation of neuronal receptors [e.g.,
N -methyl-D-aspartate receptors (NMDARs)].

, IL-1