Molecular mechanisms involving sigma receptor-mediated induction of MCP-1: implication for increased monocyte transmigration.

Cocaine abuse hastens the neurodegeneration often associated with advanced HIV-1 infection. The mechanisms, in part, revolve around the neuroinflammatory processes mediated by the chemokine monocyte chemotactic protein-1 (MCP-1/CCL2). Understanding factors that modulate MCP-1 and, in turn, facilitate monocyte extravasation in the brain is thus of paramount importance.

Nanoformulated antiretroviral drug combinations extend drug release and antiretroviral responses in HIV-1-infected macrophages: implications for neuroAIDS therapeutics.

We posit that improvements in pharmacokinetics and biodistributions of antiretroviral therapies (ART) for human immunodeficiency virus type one-infected people can be achieved through nanoformulationed drug delivery systems. To this end, we manufactured nanoparticles of atazanavir, efavirenz, and ritonavir (termed nanoART) and treated human monocyte-derived macrophages (MDM) in combination therapies to assess antiretroviral responses. This resulted in improved drug uptake, release, and antiretroviral efficacy over monotherapy.

Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease.

Nitrated alpha-synuclein (N-alpha-syn) immunization elicits adaptive immune responses to novel antigenic epitopes that exacerbate neuroinflammation and nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. We show that such neuroimmune degenerative activities, in significant measure, are Th17 cell-mediated, with CD4(+)CD25(+) regulatory T cell (Treg) dysfunction seen among populations of N-alpha-syn-induced T cells. In contrast, purified vasoactive intestinal peptide induced and natural Tregs reversed N-alpha-syn T cell nigrostriatal degeneration.

Effects of pluronic and doxorubicin on drug uptake, cellular metabolism, apoptosis and tumor inhibition in animal models of MDR cancers.

Cancer chemotherapy is believed to be impeded by multidrug resistance (MDR). Pluronic (triblock copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), PEO-b-PPO-b-PEO) were previously shown to sensitize MDR tumors to antineoplastic agents. This study uses animal models of Lewis lung carcinoma (3LL-M27) and T-lymphocytic leukemia (P388/ADR and P388) derived solid tumors to delineate mechanisms of sensitization of MDR tumors by Pluronic P85 (P85) in vivo.

Control of neuroinflammation as a therapeutic strategy for amyotrophic lateral sclerosis and other neurodegenerative disorders.

Neurodegenerative diseases, Alzheimer's and Parkinson's diseases, and amyotrophic lateral sclerosis (ALS) are progressive and devastating disorders of the nervous system without cure. Although a number of distinct, but not mutually exclusive, mechanisms can affect disease pathogenesis, neuroinflammation stands in common. Neuroinflammatory responses occur as a consequence of oxidative and excitotoxic neuronal damage, mitochondrial dysfunction, and protein aggregation.

HIV-1 neuroimmunity in the era of antiretroviral therapy.

Human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) can affect up to 50% of infected people during the disease course. While antiretroviral therapies have substantively increased the quality of life and reduced HIV-1-associated dementia, less severe minor cognitive and motor deficits continue. Trafficking of HIV-1 into the central nervous system (CNS), peripheral immune activation, dysregulated glial immunity, and diminished homeostatic responses are the disease-linked pathobiologic events.

Neuroprotective activities of CEP-1347 in models of neuroAIDS.

When the nervous system is infected with HIV-1, it commonly results in neuroinflammation leading to overt neuronal dysfunction and subsequent cognitive and behavioral impairments. The multifaceted disease process, now referred to as HIV-1-associated neurocognitive disorders (HAND), provides a range of molecular targets for adjunctive therapies. One is CEP-1347, an inhibitor of mixed lineage kinases that elicits neuroprotective and anti-inflammatory responses in models of neurodegenerative diseases.

NanoART synthesis, characterization, uptake, release and toxicology for human monocyte-macrophage drug delivery.

Background: Factors limiting the efficacy of conventional antiretroviral therapy for HIV-1 infection include treatment adherence, pharmacokinetics and penetration into viral sanctuaries. These affect the rate of viral mutation and drug resistance. In attempts to bypass such limitations, nanoparticles containing ritonavir, indinavir and efavirenz (described as nanoART) were manufactured to assess macrophage-based drug delivery.

Simvastatin inhibits the activation of p21ras and prevents the loss of dopaminergic neurons in a mouse model of Parkinson's disease.

Parkinson's disease (PD) is second only to Alzheimer's disease as the most common devastating human neurodegenerative disorder. Despite intense investigation, no interdictive therapy is available for PD. We investigated whether simvastatin, a Food and Drug Administration-approved cholesterol-lowering drug, could protect against nigrostriatal degeneration after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication to model PD in mice.

A coat of many colors: neuroimmune crosstalk in human immunodeficiency virus infection.

The use of antiretroviral therapy has reduced mortality and increased the quality of life of HIV-1-infected people, particularly in more developed countries where access to treatment is more widespread. However, morbidities continue, which include HIV-1-associated neurocognitive disorders (HAND). Subtle cognitive abnormalities and low-level viral replication underlie disease.

CCL2 accelerates microglia-mediated Abeta oligomer formation and progression of neurocognitive dysfunction.

Background: The linkages between neuroinflammation and Alzheimer's disease (AD) pathogenesis are well established. What is not, however, is how specific immune pathways and proteins affect the disease. To this end, we previously demonstrated that transgenic over-expression of CCL2 enhanced microgliosis and induced diffuse amyloid plaque deposition in Tg2576 mice.

NanoART, neuroAIDS and CNS drug delivery.

A broad range of nanomedicines is being developed to improve drug delivery for CNS disorders. The structure of the blood-brain barrier (BBB), the presence of efflux pumps and the expression of metabolic enzymes pose hurdles for drug-brain entry. Nanoformulations can circumvent the BBB to improve CNS-directed drug delivery by affecting such pumps and enzymes.

Neurodegenerative disorders and nanoformulated drug development.

Degenerative and inflammatory diseases of the CNS include, but are not limited to, Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis and HIV-1-associated neurocognitive disorders. These are common, debilitating and, unfortunately, hold few therapeutic options. In recent years, the application of nanotechnologies as commonly used or developing medicines has served to improve pharmacokinetics and drug delivery specifically to CNS-diseased areas.

Development of a platelet-activating factor antagonist for HIV-1 associated neurocognitive disorders.

The neuroregulatory activities of PMS-601, a platelet activating factor antagonist, were investigated in laboratory and animal models of HIV-1 encephalitis (HIVE). For the former, PMS-601 reduced monocyte-derived macrophage pro-inflammatory secretions, multinucleated giant cell (MGC) formation, and neuronal loss independent of antiretroviral responses. PMS-601 treatment of HIVE severe combined immunodeficient mice showed reduced microgliosis, MGCs and neurodegeneration.

Macrophage delivery of nanoformulated antiretroviral drug to the brain in a murine model of neuroAIDS.

Antiretroviral therapy (ART) shows variable blood-brain barrier penetration. This may affect the development of neurological complications of HIV infection. In attempts to attenuate viral growth for the nervous system, cell-based nanoformulations were developed with the focus on improving drug pharmacokinetics.

4-Aminopyridine improves spatial memory in a murine model of HIV-1 encephalitis.

HIV-1-associated neurocognitive disorders (HAND) remains a significant source of morbidity in the era of wide spread use of highly active antiretroviral therapy. Disease is precipitated by low levels of viral growth and glial immune activation within the central nervous system. Blood borne macrophage and microglia affect a proinflammatory response and release viral proteins that affects neuronal viability and leads to death of nerve cells.

Planning Future Strategies for Domestic and International NeuroAIDS Research, July 24-25, 2008.

The National Institute of Mental Health in cooperation with the National Institute on Drug Abuse and the National Institute of Neurological Disorders and Stroke organized a meeting on July 24-25, 2008 to develop novel research directions for neuroAIDS research. The deliberations of this meeting are outlined in this brief report. Several critical research areas in neuroAIDS were identified as areas of emphasis.

CD 4+ T cells in the pathobiology of neurodegenerative disorders.

CD4+ T cells orchestrate innate and adaptive immunity. In the central nervous system they modulate immune responses including cell trafficking and glial neuroregulatory functions through an array of soluble molecules cell-cell interactions affecting tissue homeostasis. During disease their roles evolve to an auto-aggressive or, alternatively, protective phenotype.

Proteomic studies of nitrated alpha-synuclein microglia regulation by CD4+CD25+ T cells.

Microglial inflammatory responses affect Parkinson's disease (PD) associated nigrostriatal degeneration. This is triggered, in measure, by misfolded, nitrated alpha-synuclein (N-alpha-syn) contained within Lewy bodies that are released from dying or dead dopaminergic neurons into the extravascular space. N-alpha-syn-stimulated microglial immunity is regulated by CD4+ T cell subset.

HIV-1 transforms the monocyte plasma membrane proteome.

How HIV-1 affects the monocyte proteome is incompletely understood. We posit that one functional consequence of virus-exposure to the monocyte is the facilitation of protein transformation from the cytosol to the plasma membrane (PM). To test this, cell surface labeling with CyDye fluorophores followed by 2 dimensional differential in-gel electrophoresis (2D DIGE) and liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed.

Lithium therapy for human immunodeficiency virus type 1-associated neurocognitive impairment.

The objective of this study was to assess lithium safety and tolerability and to explore its impact on cognition, function, and neuroimaging biomarkers in human immunodeficiency virus (HIV)-infected subjects with cognitive impairment. Fifteen cognitively impaired HIV-infected subjects were enrolled in this 10-week open-label study of lithium 300 mg twice daily. Neuroimaging was performed at baseline and following 10 weeks of treatment and included magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and functional MRI (fMRI).

Nitrated {alpha}-synuclein-induced alterations in microglial immunity are regulated by CD4+ T cell subsets.

Microglial inflammatory neuroregulatory activities affect the tempo of nigrostriatal degeneration during Parkinson's disease (PD). Such activities are induced, in part, by misfolded, nitrated alpha-synuclein (N-alpha-syn) within Lewy bodies released from dying or dead dopaminergic neurons. Such pathobiological events initiate innate and adaptive immune responses affecting neurodegeneration.

AAV1/2-mediated CNS gene delivery of dominant-negative CCL2 mutant suppresses gliosis, beta-amyloidosis, and learning impairment of APP/PS1 mice.

Accumulation of aggregated amyloid-beta (Abeta) peptide was studied as an initial step for Alzheimer's disease (AD) pathogenesis. Following amyloid plaque formation, reactive microglia and astrocytes accumulate around plaques and cause neuroinflammation. Here brain chemokines play a major role for the glial accumulation.

Neuromodulatory activities of CD4+CD25+ regulatory T cells in a murine model of HIV-1-associated neurodegeneration.

HIV-1-associated neurocognitive impairments are intrinsically linked to microglial immune activation, persistent viral infection, and inflammation. In the era of antiretroviral therapy, more subtle cognitive impairments occur without adaptive immune compromise. We posit that adaptive immunity is neuroprotective, serving in both the elimination of infected cells through CD8(+) cytotoxic T cell activities and the regulation of neuroinflammatory responses of activated microglia.

Innate and adaptive immunity for the pathobiology of Parkinson's disease.

Innate and adaptive immunity affect the pathogenesis of Parkinson's disease (PD). In particular, activation of microglia influences degeneration of dopaminergic neurons. Cell-to-cell interactions and immune regulation critical for neuronal homeostasis also influence immune responses.