Role of anti-inflammatory compounds in human immunodeficiency virus-1 glycoprotein120-mediated brain inflammation

Abstract

BackgroundNeuroinflammation is a common immune response associated with brain human immunodeficiency virus-1 (HIV-1) infection. Identifying therapeutic compounds that exhibit better brain permeability and can target signaling pathways involved in inflammation may benefit treatment of HIV-associated neurological complications. The objective of this study was to implement an in vivo model of brain inflammation by intracerebroventricular administration of the HIV-1 viral coat protein gp120 in rats and to examine anti-inflammatory properties of HIV adjuvant therapies such as minocycline, chloroquine and simvastatin.MethodsMale Wistar rats were administered a single dose of gp120ADA (500 ng) daily for seven consecutive days, intracerebroventricularly, with or without prior intraperitoneal administration of minocycline, chloroquine or simvastatin. Maraviroc, a CCR5 antagonist, was administered intracerebroventricularly prior to gp120 administration for seven days as control. Real-time qPCR was used to assess gene expression of inflammatory markers in the frontal cortex, hippocampus and striatum. Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) secretion in cerebrospinal fluid (CSF) was measured applying ELISA. Protein expression of mitogen-activated protein kinases (MAPKs) (extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinases (JNKs) and P38 kinases (P38Ks)) was detected using immunoblot analysis. Student’s t-test and ANOVA were applied to determine statistical significance.ResultsIn gp120ADA-injected rats, mRNA transcripts of interleukin-1β (IL-1β) and inducible nitric oxide synthase (iNOS) were significantly elevated in the frontal cortex, striatum and hippocampus compared to saline or heat-inactivated gp120-injected controls. In CSF, a significant increase in TNF-α and IL-1β was detected. Maraviroc reduced upregulation of these markers suggesting that the interaction of R5-tropic gp120 to CCR5 chemokine receptor is critical for induction of an inflammatory response. Minocycline, chloroquine or simvastatin attenuated upregulation of IL-1β and iNOS transcripts in different brain regions. In CSF, minocycline suppressed TNF-α and IL-1β secretion, whereas chloroquine attenuated IL-1β secretion. In gp120-injected animals, activation of ERK1/2 and JNKs was observed in the hippocampus and ERK1/2 activation was significantly reduced by the anti-inflammatory agents.ConclusionsOur data demonstrate that anti-inflammatory compounds can completely or partially reverse gp120-associated brain inflammation through an interaction with MAPK signaling pathways and suggest their potential role in contributing towards the prevention and treatment of HIV-associated neurological complications.

Acute effects of focused ultrasound-induced increases in blood-brain barrier permeability on rat microvascular transcriptome

“…Given the concurrent increase and decrease in pro-inflammatory cytokine and transporter gene expression, respectively, at 6 hrs following sonication reported here, it is plausible that there may be a causal link between the two observations5960. While these transporters are largely expressed in brain microvessel endothelial cells, changes in their expression have been reported in astrocytes and other parenchymal cells following the induction of seizures6162 or in HIV-1 infection of the brain5556. Thus, it is possible the changes detected in the current study are influenced by gene expression changes in cells beyond ECs.…”

“…At the protein level, HIV-1 associated brain inflammation has been shown to induce a downregulation in P-gp expression both in vitro , in primary cultures of rat astrocytes55, and in vivo , in rats56. Pro-inflammatory cytokines have also been shown to reduce protein expression and functionality of P-gp in the BB57.…”

HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition

“…These effects were further confirmed in vivo. For example, intracerebral administration of gp120 to rodents was also shown to trigger the release of IL-1␤, IL-6, TNF-␣, and inducible nitric oxide as well as the activation of ERK1/2 and JNK pathways in different brain regions (40). Involvement of similar signaling pathways was also reported for the gp120-mediated inflammatory response in cardiac myocytes (41,42).…”

Selective peroxisome proliferator‐activated receptor‐gamma modulator, INT131 exhibits anti‐inflammatory effects in an EcoHIV mouse model

“…Upon infection, these cells can secrete several pro‐inflammatory cytokines and chemokines (ie, tumor necrosis factor‐α [TNFα], interleukin‐1β [IL‐1β], interferon‐γ [IFNγ], C‐C motif chemokine ligand 2 [CCL2], C‐X‐C motif chemokine 10 [CXCL10]) and neurotoxins (ie, arachidonic/quinolinic acid and metabolites, platelet activating factor, neurotoxic amines, reactive oxygen species, nitric oxide and glutamate) . HIV‐1 viral proteins (ie, Transactivator of transcription [Tat], Viral protein R [Vpr], Negative Regulatory Factor [Nef]) can be released or shed from infected cells, and induce neurotoxic effects through interactions with neuronal chemokine receptors, excitotoxicity due to glutamate accumulation, caspase activation, loss of mitochondrial membrane potential, and DNA fragmentation . In the case of astrocytes, conflicting reports exist on the infection and involvement of this cell type in the neuropathogenesis of HAND.…”

“…3,4,9 HIV-1 viral proteins (ie, Transactivator of transcription [Tat], Viral protein R [Vpr], Negative Regulatory Factor [Nef]) can be released or shed from infected cells, and induce neurotoxic effects through interactions with neuronal chemokine receptors, excitotoxicity due to glutamate accumulation, caspase activation, loss of mitochondrial membrane potential, and DNA fragmentation. [9][10][11] In the case of astrocytes, conflicting reports exist on the infection and involvement of this cell type in the neuropathogenesis of HAND. Astrocytes lack expression of the critical CD4 molecule that permits the infection of lymphocytes, microglia, and macrophages; however, they have been shown to be susceptible to HIV, and viral DNA and protein have been detected in post-mortem brain tissue astrocytes from HIV+ patients.…”