Showing papers in "Journal of Neuroimmune Pharmacology in 2007"
TL;DR: The differential role of TNF-α in response to brain injury, with emphasis on neurodegeneration, is reviewed, and the possible mechanisms for such diverse and region-specific effects are discussed.
Abstract: Proinflammatory cytokines and chemokines have been implicated in the pathogenesis of several neurological and neurodegenerative disorders. Prominent among such factors is the pleiotropic cytokine, tumor necrosis factor (TNF)-α. Under normal physiological conditions, TNF-α orchestrates a diverse array of functions involved in immune surveillance and defense, cellular homeostasis, and protection against certain neurological insults. However, paradoxical effects of this cytokine have been observed. TNF-α is elicited in the brain following injury (ischemia, trauma), infection (HIV, meningitis), neurodegeneration (Alzheimer’s, Parkinson’s), and chemically induced neurotoxicity. The multifarious identity for this cytokine appears to be influenced by several mechanisms. Among the most prominent are the regulation of TNFα-induced NF-κB activation by adapter proteins such as TRADD and TRAF, and second, the heterogeneity of microglia and their distribution pattern across brain regions. Here, we review the differential role of TNF-α in response to brain injury, with emphasis on neurodegeneration, and discuss the possible mechanisms for such diverse and region-specific effects.
217 citations
TL;DR: Understanding the basis of TLR signaling in producing responses may provide insights into how activated microglia attempt to strike a balance between defense against invading pathogens and inflicting irreparable brain damage and may lead to innovative therapies for CNS infections and neuroinflammatory diseases.
Abstract: Members of the Toll-like receptor (TLR) family play critical roles as regulators of innate and adaptive immune responses. TLRs function by recognizing diverse molecular patterns on the surface of invading pathogens. In the brain, microglial cells generate neuroimmune responses through production of proinflammatory mediators. The upregulation of cytokines and chemokines in response to microbial products and other stimuli has both beneficial and deleterious effects. Emerging evidence demonstrates a central role for TLRs expressed on microglia as a pivotal factor in generating these neuroimmune responses. Therefore, understanding the basis of TLR signaling in producing these responses may provide insights into how activated microglia attempt to strike a balance between defense against invading pathogens and inflicting irreparable brain damage. These insights may lead to innovative therapies for CNS infections and neuroinflammatory diseases based on the modulation of microglial cell activation through TLR signaling.
155 citations
TL;DR: Results indicate a complex response by microglia to acute LPS treatment, with only some responses sensitive to steroidal anti-inflammatory drug treatment, Nonetheless, microglial activation was necessary to remove Aβ in this model of neuroinflammation.
Abstract: Inflammation has been argued to play a fundamental role in the pathogenesis of Alzheimer’s disease. Mice transgenic for mutant human amyloid precursor protein (APP) develop progressive amyloid deposition, gliosis, and cognitive impairment. Paradoxically, intracranial administration of lipopolysaccharide (LPS) to promote neuroinflammation results in a reduction in amyloid-β peptide (Aβ) burden concurrent with the inflammatory response. To determine whether microglia mediate Aβ clearance after LPS, we used dexamethasone to inhibit the microglial response. Amyloid precursor protein mice were injected intrahippocampally with either LPS or saline and were allowed to survive for 7 days with or without dexamethasone cotreatment. Brain tissue was then analyzed by immunohistochemistry. Hippocampal Aβ burden was reduced 7 days after LPS injection, and this was prevented by cotreatment with dexamethasone. Markers of microglial activation [CD45, complement receptor 3 (CR3), and macrosialin (CD68)] were increased by LPS, and these increases were attenuated by dexamethasone. Dexamethasone failed to block LPS-induced increases in all microglial markers, and Fcγ receptors II/III and scavenger receptor A were increased by LPS but were unaffected by dexamethasone cotreatment. These results indicate a complex response by microglia to acute LPS treatment, with only some responses sensitive to steroidal anti-inflammatory drug treatment. Nonetheless, microglial activation was necessary to remove Aβ in this model of neuroinflammation.
138 citations
TL;DR: Using this intranasal method in animal models, researchers have successfully reduced stroke damage, reversed Alzheimer’s neurodegeneration, reduced anxiety, improved memory, stimulated cerebral neurogenesis, and treated brain tumors.
Abstract: Intranasal drug administration is a noninvasive method of bypassing the blood-brain barrier (BBB) to deliver neurotrophins and other therapeutic agents to the brain and spinal cord. This method allows drugs that do not cross the BBB to be delivered to the central nervous system (CNS) and eliminates the need for systemic delivery, thereby reducing unwanted systemic side effects. Delivery from the nose to the CNS occurs within minutes along both the olfactory and trigeminal neural pathways. Intranasal delivery occurs by an extracellular route and does not require that drugs bind to any receptor or undergo axonal transport. Intranasal delivery also targets the nasal associated lymphatic tissues (NALT) and deep cervical lymph nodes. In addition, intranasally administered therapeutics are observed at high levels in the blood vessel walls and perivascular spaces of the cerebrovasculature. Using this intranasal method in animal models, researchers have successfully reduced stroke damage, reversed Alzheimer's neurodegeneration, reduced anxiety, improved memory, stimulated cerebral neurogenesis, and treated brain tumors. In humans, intranasal insulin has been shown to improve memory in normal adults and patients with Alzheimer's disease. Intranasal delivery strategies that can be employed to treat and prevent NeuroAIDS include: (1) target antiretrovirals to reach HIV that harbors in the CNS; (2) target therapeutics to protect neurons in the CNS; (3) modulate the neuroimmune function of moncyte/macrophages by targeting the lymphatics, perivascular spaces of the cerebrovasculature, and the CNS; and (4) improve memory and cognitive function by targeting therapeutics to the CNS.
110 citations
TL;DR: Underlines the importance of neutral sphingomyelinase–ceramide pathway in mediating oxidative stress-induced apoptosis and cell death of human primary oligodendrocytes and identifies neutral but not acidic sphingomeelinase as a target for possible therapeutic intervention in MS.
Abstract: Multiple sclerosis (MS) is the most common human demyelinating disease of the central nervous system where oxidative stress has been proposed to play an important role in oligodendroglial death. However, molecular mechanisms that couple oxidative stress to the loss of oligodendrocytes are poorly understood. This study underlines the importance of neutral sphingomyelinase–ceramide pathway in mediating oxidative stress-induced apoptosis and cell death of human primary oligodendrocytes. Various oxidative stress-inducing agents, such as, superoxide radical produced by hypoxanthine and xanthine oxidase, hydrogen peroxide, aminotriazole capable of inhibiting catalase and increasing intracellular level of H2O2, or reduced glutathione-depleting diamide induced the activation of neutral sphingomyelinase and the production of ceramide. It is interesting to note that antisense knockdown of neutral but not acidic sphingomyelinase ablated oxidative stress-induced apoptosis and cell death in human primary oligodendrocytes. This study identifies neutral but not acidic sphingomyelinase as a target for possible therapeutic intervention in MS.
105 citations
TL;DR: It is demonstrated that neurologically intact rats can effectively learn the water maze in the absence of visual cues and in the presence of non-visual navigation cues and suggest that the noninfectious HIV-1Tg rat can be a valid model for the behavioral studies of HIV-related neurological dysfunction.
Abstract: HIV-1 infection of the central nervous system impairs neural, cognitive, and behavioral functioning in patients despite antiretroviral therapy. However, studying mechanisms underlying HIV-1-related neurological and cognitive dysfunction has been limited without an adequate animal model. A novel, noninfectious HIV-1 transgenic (HIV-1Tg) rat model was recently created that expresses an HIV-1 provirus with a deletion of functional gag and pol genes. This HIV-1Tg rat reportedly develops clinical manifestations of human HIV disease and thus appears to mimic the persistent infection that results from the presence of HIV viral proteins in the host. We evaluated the HIV-1Tg rat model using the Morris water maze, a popular paradigm for testing learning and memory deficits in rodents. Because of congenital cataracts in HIV-1Tg rats, however, the traditional use of visual navigational cues in this paradigm were precluded. We first designed a modified Morris water maze and demonstrated that neurologically intact rats can effectively learn the water maze in the absence of visual cues and in the presence of non-visual navigation cues. We then tested HIV-1Tg rats in this modified Morris water maze. These HIV-1Tg rats showed a deficit in learning how to swim to the location of the hidden platform but did not show a deficit in their memory of the general location of the hidden platform. These results suggest that the noninfectious HIV-1Tg rat can be a valid model for the behavioral studies of HIV-related neurological dysfunction.
84 citations
TL;DR: The literature for Ran Binding Protein in the Microtubule-Organizing Center (RanBPM; RanBP9), a 90-kDa protein that possesses many characteristics of a scaffolding protein, is reviewed to suggest that it provides a platform for the interaction of a variety of signaling proteins.
Abstract: We review the literature for Ran Binding Protein in the Microtubule-Organizing Center (RanBPM; RanBP9), a 90-kDa protein that possesses many characteristics of a scaffolding protein, including protein-interaction motifs, a cytoskeletal-binding domain, and multiple canonical docking sites for signaling intermediates. We focus on studies that have examined functional interactions between RanBPM and other proteins. These studies suggest that RanBPM provides a platform for the interaction of a variety of signaling proteins, including cell surface receptors, nuclear receptors, nuclear transcription factors, and cytosolic kinases. These studies indicate that RanBPM acts as a scaffolding protein and is important in regulating cellular function in both the immune system and the nervous system.
83 citations
TL;DR: The major angiogenic factors in the brain are summarized, the significant changes of angiogenesis factors and endothelial progenitor cells (EPCs) in response to brain ischemia are discussed, and the therapeutic potential is reviewed based on the concept of neurovascular unit.
Abstract: In the normal mature brain, blood vessel formation is tightly downregulated. However, pathologic processes such as ischemia can induce cerebral vascular regeneration. Angiogenesis is one of the major styles of new vessel formation. In this article, we summarize the major angiogenic factors in the brain, discuss the significant changes of angiogenic factors and endothelial progenitor cells (EPCs) in response to brain ischemia, and finally, review the therapeutic potential of angiogenic factors and EPCs in experimental cerebral ischemia based on the concept of neurovascular unit.
80 citations
TL;DR: Recommendations are that future studies should further identify parameters that generate the strongest protection for postconditioning against cerebral ischemia and should study whether post conditioning provides long-term protection, and clarification of the underlying protective mechanisms should be pursued.
Abstract: Postconditioning, a series of mechanical interruptions of reperfusion after ischemia, prevents ischemia/reperfusion injury in myocardial infarction. The extensive studies of postconditioning in myocardial infarction have led to clinical trials. This article reviews the protective effects of postconditioning against ischemia from the heart to the brain and provides insights on how studies of postconditioning in the field of heart ischemia have shed light on postconditioning of the brain. Because brain ischemia has many mechanisms in common with heart ischemia, it is logical to test whether postconditioning protects against brain ischemia as well. A few groups have reported that postconditioning reduces infarct size in focal cerebral ischemia and improves deficits of short-term memory and motor coordination after global cerebral ischemia. However, many outstanding issues remain elusive regarding the protective effects of postconditioning against cerebral ischemia. Future studies should further identify parameters that generate the strongest protection for postconditioning against cerebral ischemia and should study whether postconditioning provides long-term protection. In addition, clarification of the underlying protective mechanisms should be pursued. This will certainly enhance our understanding of this novel phenomenon and may provide important clues for developing pharmacological analogues for stroke treatment.
69 citations
TL;DR: It is strongly suggested that it is very promising to regulate microglia activation in PD via targeting CD200–CD200R signaling pathways.
Abstract: The role of CD200–CD200R signaling in immune regulation of the central nervous system has become a popular field of research in recent years. Many studies have shown that there is a close correlation between CD200–CD200R, microglia activation, and Parkinson’s disease (PD). This review discusses the above relationship, highlighting (1) the gene mapping and molecular structure of CD200 and CD200R, (2) the distribution and expression of CD200 and CD200R in the nervous system, (3) the effect of CD200–CD200R signaling on microglia activation, and (4) the role of microglia activation in the pathogenesis and progression of PD. Finally, we discuss the status of current studies on the regulation of microglia activation in PD and strongly suggest that it is very promising to regulate microglia activation in PD via targeting CD200–CD200R signaling pathways.
66 citations
TL;DR: 3-D models established in the lab have shown that they respond to infection with bacterial and viral pathogens in ways that reflect the infection process in vivo, and may have important implications for the design and development of drugs with which to effectively treat neurological complications of HIV infection.
Abstract: Representative, reproducible, and high-throughput models of human cells and tissues are critical for a meaningful evaluation of host–pathogen interactions and are an essential component of the research developmental pipeline. The most informative infection models—animals, organ explants, and human trials—are not suited for extensive evaluation of pathogenesis mechanisms and screening of candidate drugs. At the other extreme, more cost-effective and accessible infection models such as conventional cell culture and static coculture may not capture physiological and three-dimensional (3-D) aspects of tissue biology that are important in assessing pathogenesis, effectiveness, and cytotoxicity of therapeutics. Our lab has used innovative bioengineering technology to establish biologically meaningful 3-D models of human tissues that recapitulate many aspects of the differentiated structure and function of the parental tissue in vivo, and we have applied these models to study infectious disease. We have established a variety of different 3-D models that are currently being used in infection studies—including small intestine, colon, lung, placenta, bladder, periodontal ligament, and neuronal models. Published work from our lab has shown that our 3-D models respond to infection with bacterial and viral pathogens in ways that reflect the infection process in vivo. By virtue of their physiological relevance, 3-D cell cultures may also hold significant potential as models to provide insight into the neuropathogenesis of HIV infection. Furthermore, the experimental flexibility, reproducibility, cost efficiency, and high-throughput platform afforded by these 3-D models may have important implications for the design and development of drugs with which to effectively treat neurological complications of HIV infection.
TL;DR: This study investigated the expression of CXCL12 and CXCR4 during neural progenitor cells (NPC) differentiation by microarray analysis and reverse transcriptase-polymerase chain reaction (RT-PCR) using human fetal NPC as a model system and demonstrated that CxCR4 expression is significantly upregulated when NPC are differentiated into neuronal precursors, whereas CxCL12 is up regulated when differentiated into astrocytes.
Abstract: Stromal cell-derived factor 1 alpha (SDF-1α, CXCL12) and its receptor CXCR4 play an important role in the central nervous system (CNS) development and adulthood by mediating cell migration, enhancing precursor cell proliferation, assisting in neuronal circuit formation, and possibly regulating migration during repair. The expression pattern of CXCR4 and CXCL12 during neurogenesis has not been thoroughly elucidated. In this study, we investigated the expression of CXCL12 and CXCR4 during neural progenitor cells (NPC) differentiation by microarray analysis and reverse transcriptase-polymerase chain reaction (RT-PCR) using human fetal NPC as a model system. The production of CXCL12 was measured by enzyme-linked immunosorbent assay (ELISA). CXCR4 expression was determined by florescence-activated cell sorting (FACS) analysis, immunocytochemical staining, and CXCR4-mediated inhibition of cyclic AMP (cAMP) accumulation. Our data demonstrated that CXCR4 expression is significantly upregulated when NPC are differentiated into neuronal precursors, whereas CXCL12 is upregulated when differentiated into astrocytes. We also provide evidence that CXCR4 localization changes as neurons mature. In neuronal precursors, CXCR4 is localized in both neuronal processes and the cell body, whereas in mature neurons, it is primarily expressed on axons and dendrites. This differential expression of CXCR4 and CXCL12 may be important for the temporal regulation of neuronal migration and circuit formation during development and possibly in adult neurogenesis and repair.
TL;DR: The stem cell transplantation in the animal model of Parkinson’s disease proves that it is capable of relieving symptoms and restoring damaged brain function and future stem cell research should focus on neuroprotection or neurorescue that can favorably modify the natural course and slow the progression of the disease.
Abstract: Parkinson's disease is one of the most common neurodegenerative diseases caused by the loss of dopaminergic neurons in the substantia nigra pars compacta Pharmacological therapies are valuable but suffer from two main drawbacks: side effects and loss of efficacy with disease progression Surgical treatment is no better than drugs Transplantation of embryonic mesencephalic tissue has emerged as a therapeutic alternative, but the unstable efficiency and the shortage of embryonic donors limit its clinical application Recent advances in stem cell research inspire our hope that stem cell transplantation to replace degenerated neurons may be a promising therapy for Parkinson's disease There are three sources of stem cells currently in testing: embryonic stem cells, neural stem cells, and mesenchymal stem cells The stem cell transplantation in the animal model of Parkinson's disease proves that it is capable of relieving symptoms and restoring damaged brain function Future stem cell research should focus not only on ameliorating the symptoms of Parkinson's disease but also on neuroprotection or neurorescue that can favorably modify the natural course and slow the progression of the disease
TL;DR: Proliferation, migration, and neuronal differentiation of endogenous NSCs could be manipulated by pharmaceutical tools to reach the adequate benefits for the treatment of CNS diseases.
Abstract: Despite progress in our understanding molecular mechanisms of neuronal cell death in many central nervous system (CNS) diseases, widely effective treatments remain elusive. Recent studies have shown that neural stem cells (NSCs) are present in the subventricular zone (SVZ) lining the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) in adult mouse, rat, nonhuman primate, and human brain. Newly generated cells in the SGZ can differentiate into mature, functional neurons and integrate into the DG as granule cells, which are involved in memory formation. In addition, many CNS diseases can stimulate the proliferation of neuronal stem/progenitor cells located in the SVZ and SGZ of the adult rodent brain, and the resulting newborn cells migrate into damaged brain regions, where they express mature neuronal markers. Therefore, it might be possible for damaged cells to be replaced from endogenous neural stem cell pools. However, the capacity of self-repair is obviously not enough. Proliferation, migration, and neuronal differentiation of endogenous NSCs could be manipulated by pharmaceutical tools to reach the adequate benefits for the treatment of CNS diseases.
TL;DR: It is found that CB2 receptors are involved in WIN55,212-2’s antiviral activity and surprisingly that the CB1 receptor-selective antagonist SR141716A behaved as an agonist in these brain macrophages.
Abstract: Cannabinoid receptors CB1 and CB2 are primarily expressed in cells of the nervous and immune systems, respectively. Recently, the synthetic CB1/CB2 agonist WIN55,212-2 was found to suppress replication of HIV-1 in microglial cell cultures. The present study was undertaken to test the hypothesis that WIN55,212-2’s antiviral effect is mediated via CB2 receptors. By reverse transcription-polymerase chain reaction, microglia were found to express both CB1 and CB2 receptors. Using additional CB1/CB2 receptor agonists and selective antagonists, we found that CB2 receptors are involved in WIN55,212-2’s antiviral activity and surprisingly that the CB1 receptor-selective antagonist SR141716A behaved as an agonist in these brain macrophages.
TL;DR: In a series of studies initiated using in vitro, then in vivo models of HIV-1-associated dementia (HAD), the ability of the mood stabilizing and anticonvulsant drug, sodium valproate (VPA), that inhibits GSK-3β activity and other downstream mediators, to reverse HIV- 1-induced damage to synaptic pathways in the CNS is demonstrated.
Abstract: Highly active antiretroviral therapy (HAART) has made a significant impact on the lives of people living with HIV-1 infection. The incidence of neurologic disease associated with HIV-1 infection of the CNS plummeted between 1996–2000, but unfortunately the number of people currently HIV-1 infected (i.e., prevalence) with associated cognitive impairment has been steadily rising. While the reasons for this may be multifactorial, the implication is clear: there is a pressing need for adjunctive therapy directed at reversing or preventing damage to vulnerable pathways in the central nervous system (CNS) from HIV-1 infection. Using a team of preclinical and clinical investigators, we have focused our efforts on defining how proinflammatory mediators and secretory neurotoxins from HIV-1 disrupt signaling of the survival-regulating enzyme, glycogen synthase kinase 3 beta (GSK-3β). In a series of studies initiated using in vitro, then in vivo models of HIV-1-associated dementia (HAD), we have demonstrated the ability of the mood stabilizing and anticonvulsant drug, sodium valproate (VPA), that inhibits GSK-3β activity and other downstream mediators, to reverse HIV-1-induced damage to synaptic pathways in the CNS. Based on these results, we successfully performed pharmacokinetic and safety and tolerability trials with VPA in a cohort of HIV-1-infected patients with neurologic disease. VPA was well tolerated in this population and secondary measures of brain metabolism, as evidenced by an increase in N-acetyl aspartate/creatine (NAA/Cr), further suggested that VPA may improve gray matter integrity in brain regions damaged by HIV-1. These findings highlight the therapeutic potential of GSK-3β blockade.
TL;DR: Using a simple model of pathogenesis, an approach to characterizing patients, selecting treatment targets, and evaluating outcomes that emphasize a combination of cerebrospinal fluid (CSF) markers is proposed.
Abstract: There are a number of reasons that the accomplishments of clinical trials related to HIV-related neurodegenerative disease (HRND) and the AIDS dementia complex (ADC) have had such limited impact on clinical practice. These include: rapid evolution and progress in the treatment of systemic HIV infection that has quickly outpaced neurological efforts and has markedly reduced disease incidence; ethical constraints that (rightly) demand neurologically compromised patients receive the best available treatment before experimental therapeutics; complicated backgrounds and comorbidities of patients now most susceptible to HRND; and reluctance of general AIDS clinicians and drug companies to look beyond systemic or pivotal outcomes. However, the field has also been slow to adopt methods that better exploit advances in understanding of the pathogenesis of central nervous system (CNS) infection and brain injury, and that might circumvent some of these constraints. Using a simple model of pathogenesis, we propose an approach to characterizing patients, selecting treatment targets, and evaluating outcomes that emphasize a combination of cerebrospinal fluid (CSF) markers. This model begins by using three markers related to cardinal components of HRND: CNS HIV infection (measurement of CSF HIV RNA), intrathecal immunoactivation (CSF neopterin), and brain injury [CSF light chain neurofilament (NFL)]. Careful analysis of this and other marker combinations promises more rational trial design and more rapid progress in managing CNS HIV infection and HRND using both antiviral and adjuvant treatment approaches.
TL;DR: Variation in R5 macrophage tropism may also have implications for transmission, depending on what role macrophages or cells that express low CD4 and/or CCR5 play in the establishment of infection in a new host, and for pathogenesis and depletion of CD4+ T cells (i.e., do highly macophage-tropic variants confer a broader tropism among CD4- T-cell populations late in disease and contribute to their depletion?).
Abstract: Human immunodeficiency virus (HIV)-positive individuals frequently suffer from progressive encephelopathy, which is characterized by sensory neuropathy, sensory myelopathy, and dementia. Our group and others have reported the presence of highly macrophage-tropic R5 variants of HIV-1 in brain tissue of patients with neurological complications. These variants are able to exploit low amounts of CD4 and/or CCR5 for infection and potentially confer an expanded tropism for any cell types that express low CD4 and/or CCR5. In contrast to the brain-derived envelopes, we found that envelopes from lymph node tissue, blood, or semen were predominantly non-macrophage-tropic and required high amounts of CD4 for infection. Nevertheless, where tested, the non-macrophage-tropic envelopes conferred efficient replication in primary CD4+ T-cell cultures. Determinants of R5 macrophage tropism appear to involve changes in the CD4 binding site, although further unknown determinants are also involved. The variation of R5 envelopes also affects their sensitivity to inhibition by ligands and entry inhibitors that target CD4 and CCR5. In summary, HIV-1 R5 viruses vary extensively in macrophage tropism. In the brain, highly macrophage-tropic variants may represent neurotropic or neurovirulent viruses. In addition, variation in R5 macrophage tropism may also have implications (1) for transmission, depending on what role macrophages or cells that express low CD4 and/or CCR5 play in the establishment of infection in a new host, and (2) for pathogenesis and depletion of CD4+ T cells (i.e., do highly macrophage-tropic variants confer a broader tropism among CD4+ T-cell populations late in disease and contribute to their depletion?).
TL;DR: Multivariate analyses indicated that the use of “antiviral” SRIs—but not statins—was associated with undetectable HIV RNA levels in CSF and better NP performance, which supports the value of large observational cohort studies in identifying FDA-approved drugs that may be worth further investigation.
Abstract: Effective antiretroviral therapy (ART) has reduced the incidence of HIV-associated neurocognitive impairment (HNCI) but its prevalence remains high. Clinical trials have yet to identify a consistently effective treatment for HNCI, other than ART, but in vitro data support that some drugs approved by the Food and Drug Administration (FDA) for other indications might benefit individuals with HNCI. Some of these drugs, such as serotonin reuptake inhibitors (SRIs) and HMG-CoA reductase inhibitors (statins), may do so by reducing HIV replication in the CNS and are already widely used by HIV-infected individuals. Six-hundred fifty-eight HIV-infected participants of the CHARTER cohort had a baseline assessment, which included comprehensive neuropsychological (NP) testing and HIV RNA measurements in plasma and cerebrospinal fluid (CSF). Four-hundred sixty-seven (71%) subjects used ART, 195 (30%) used SRIs, and 63 (10%) used statins. SRI users were less likely to have HIV RNA levels in CSF above 50 copies (c)/mL (29 vs. 37% in non-SRI users, OR 0.69, p = 0.05). This association was most evident for three of the seven SRIs (citalopram, sertraline, and trazodone, or “antiviral” SRIs, combined 25 vs. 38% in non-SRI users, OR 0.56, p = 0.01) and was strongest in those not taking concomitant ART (61 vs. 83%, OR 0.31, p = 0.01). “Antiviral” SRI users also performed better on NP tests (median global deficit score 0.37 vs. 0.47, p = 0.04). Statin users were also less likely to have HIV RNA levels in CSF above 50 c/mL (16 vs. 37%, p < 0.001) but, in contrast to SRIs, the association was strongest in those taking ART (2 vs. 18%, p < 0.001). Statin use was not associated with better NP performance. Multivariate analyses indicated that the use of “antiviral” SRIs—but not statins—was associated with undetectable HIV RNA levels in CSF and better NP performance. SRIs may reduce HIV replication in CSF and improve NP performance. This was particularly true for three SRIs—supporting differences in antiviral efficacy between drugs—in individuals who were not taking ART. In contrast, statins were not associated with lower HIV replication in CSF in multivariate analyses and were not associated with better NP performance. These analyses support the value of large observational cohort studies in identifying FDA-approved drugs that may be worth further investigation.
TL;DR: Aprepitant is active against HIV drug-resistant isolates and enhances the anti-HIV activity of the antiretrovirals and NK-1R antagonists merit further investigation as potential HIV therapeutic and immunomodulatory agents.
Abstract: Despite the success of antiretroviral therapy in controlling HIV replication, treatment failure may ultimately occur in more than 50% of the individuals on antiretroviral therapy. Cellular targets offer an attractive alternative, as it may be more difficult for HIV to develop resistance to alternative cellular inhibitory pathways. We have previously shown that CP-96,345, a neurokinin-1 receptor (NK-1R) antagonist, inhibits HIV-1 infection of macrophages in vitro by downregulating CCR5 expression (Lai JP, Ho WZ, Zhan GX, Yi Y, Collman RG, Douglas SD 2001). We have now investigated the effects of a Food and Drug Administration (FDA)-approved NK-1R antagonist, aprepitant (Emend®), on HIV infection of macrophages in an in vitro system. Aprepitant is in clinical use for the prevention of nausea and vomiting associated with cancer chemotherapy or following surgical procedures. Monocytes isolated from healthy donors were cultured for 7 days and then treated with or without aprepitant (10−6 M) for 2 h, followed by HIV infection with drug-resistant strains for 2 h. Untreated and HIV-infected macrophages were used as controls. Culture supernatants were harvested for p24 enzyme-linked immunosorbent assay (ELISA) or HIV reverse transcriptase (RT) activity at different time points after infection. R5X4 tropic and AZT-resistant strains (R5X4 tropic: A012 and A018) and RT inhibitor-resistant HIV strains (R5 tropic: TC60 and TC49) were used for infection. Aprepitant suppressed HIV Bal infection of macrophages. Treatment with aprepitant (10−6 M) inhibited infection of macrophages with the AZT-resistant viruses (A018, A012) by 0.7 log10. Aprepitant also suppressed infection of macrophages with RT inhibitor-resistant virus (TC 49 and TC 60) by 0.5 log10. Furthermore, aprepitant significantly enhanced the anti-HIV activity of antiretrovirals (AZT, Efavirenz, and Indinavir) in HIV Bal-infected macrophages, and aprepitant inhibited CCR5 expression on macrophages, ranging from 50.5 to 29.6%. Donor heterogeneity was observed in antiviral activity and CCR5 receptor expression. Aprepitant is active against HIV drug-resistant isolates and enhances the anti-HIV activity of the antiretrovirals. Aprepitant downregulates CCR5 expression on macrophages. NK-1R antagonists merit further investigation as potential HIV therapeutic and immunomodulatory agents.
TL;DR: It is demonstrated that widespread increased p53 expression is present in HAD, and activation of p53 mediated pathways in the glia of HAD patients may contribute to the neuroinflammatory processes that promote neurodegeneration by inhibiting glial proliferation and/or promoting glial cell dysfunction.
Abstract: HIV-associated dementia (HAD) is a chronic neuroinflammatory disease that remains an important clinical problem without available rational treatment. As HIV does not infect neurons, the pathogenesis of HAD is thought to be secondary to the impact of infected leukocytes, including parenchymal microglia, which can secrete inflammatory mediators and viral products that alter the function of surrounding uninfected cells. We previously reported that the transcription factor p53 accumulates in neurons, microglia, and astrocytes of HAD patients. We have also shown that microglia from p53-deficient mice fail to induce neurotoxicity in response to the HIV coat protein gp120 in a coculture system, supporting the hypothesis that p53 plays a pathogenic role in the chronic neuroinflammatory component of HIV-associated neurodegeneration. We analyzed the extent and cell type specificity of p53 accumulation in subcortical white matter of ten AIDS patients that had previously been shown to demonstrate white matter p53 accumulation. To determine if p53 activation functioned to alter gene expression in HAD, cortical tissue sections were also immunolabeled for the p53 target genes Bax and p21(WAF1). These studies reveal that microglia, astrocytes, and oligodendrocytes all demonstrate p53 activation in response to HIV infection. We observed immunoreactivity for both Bax and p21(WAF1) in neurons and glia from patients demonstrating elevated p53 immunoreactivity. Our findings demonstrate that widespread increased p53 expression is present in HAD. Activation of p53 mediated pathways in the glia of HAD patients may contribute to the neuroinflammatory processes that promote neurodegeneration by inhibiting glial proliferation and/or promoting glial cell dysfunction.
TL;DR: This review of metabolomics research highlights the identification of reliable biomarkers with emphasis on neuroAIDS, which will be advantageous for tracking the progression of human immunodeficiency virus/central nervous system (HIV/CNS) disease to gain maximal benefit from antiretroviral treatment.
Abstract: "Metabolomics", the measurement of metabolite concentrations and fluxes in cell systems, is an emerging science that has enormous potential and several unique characteristics. The current applications for this field are, primarily, toxicological profiling and biomarker studies. This review of metabolomics research highlights the identification of reliable biomarkers with emphasis on neuroAIDS. Such identification of candidate markers will be advantageous for tracking the progression of human immunodeficiency virus/central nervous system (HIV/CNS) disease to gain maximal benefit from antiretroviral treatment and to provide insight into the mechanism of related neuropathogenesis.
TL;DR: The results indicate that downregulation of Parkin may damage the antioxidation defenses of dopaminergic cells and increase their susceptibility to proteasome inhibitor-induced toxicity.
Abstract: Loss-of-function mutations in the parkin gene have recently been shown to be responsible for autosomal recessive juvenile Parkinsonism. However, the exact mechanism of pathogenesis remains unclear. This study explores the effect of Parkin downregulation on dopaminergic cells in Parkinson’s disease. We generated small interfering RNA plasmids that target the parkin gene and transfected them into PC12 cells to mimic in vivo loss-of-function. We found that these small plasmids were able to effectively inhibit endogenous Parkin expression in PC12 cells. Downregulation of Parkin decreased the amount of glutathione and superoxide dismutase activity without affecting the amount of malondialdehyde. Moreover, Parkin knockdown rendered PC12 cells more susceptible to cell death induced by the proteasome inhibitor lactacystin. These results indicate that downregulation of Parkin may damage the antioxidation defenses of dopaminergic cells and increase their susceptibility to proteasome inhibitor-induced toxicity.
TL;DR: This review summarizes contributions made from in vitro and in vivo studies on the infectious and pathological interactions of feline immunodeficiency virus (FIV) with the nervous system and offers enormous potential to explore neuropathogenic mechanisms and generate information necessary for the development of effective therapeutic interventions.
Abstract: Invasion of human immunodeficiency virus (HIV) into the central and peripheral nervous system produces a wide range of neurological symptoms, which continue to persist even with adequate therapeutic suppression of the systemic viremia. The development of therapies designed to prevent the neurological complications of HIV require a detailed understanding of the mechanisms of virus penetration into the nervous system, infection, and subsequent neuropathogenesis. These processes, however, are difficult to study in humans. The identification of animal lentiviruses similar to HIV has provided useful models of HIV infection that have greatly facilitated these efforts. This review summarizes contributions made from in vitro and in vivo studies on the infectious and pathological interactions of feline immunodeficiency virus (FIV) with the nervous system. In vivo studies on FIV have provided insights into the natural progression of CNS disease as well as the contribution of various risk factors. In vitro studies have contributed to our understanding of immune cell trafficking, CNS infection and neuropathogenesis. Together, these studies have made unique contributions to our understanding of (1) lentiviral interactions at the blood–cerebrospinal fluid (CSF) barrier within the choroid plexus, (2) early FIV invasion and pathogenesis in the brain, and (3) lentiviral effects on intracellular calcium deregulation and neuronal dysfunction. The ability to combine in vitro and in vivo studies on FIV offers enormous potential to explore neuropathogenic mechanisms and generate information necessary for the development of effective therapeutic interventions.
TL;DR: The results demonstrate the implications of opiate abuse on the efficacy assessment of antileishmanial drugs and vaccines, and on the reactivation of latent VL in areas where both drug abuse and VL are rampant.
Abstract: Opioid modulation of host resistance to infectious diseases is well documented; however, not much is known during visceral leishmaniasis (VL). Low doses of morphine, administered subcutaneously in Leishmania donovani-infected BALB/c mice, on days 0 and +15, significantly (p < 0.05) suppressed (1 mg/kg/day) or even sterile-cleared (2 mg/kg/day) the infection; paradoxically, high doses (10 and 30 mg/kg/day) exacerbated the infection. In vitro, low concentration (1 × 10−9 and 1 × 10−11 M) morphine treatment of L. donovani-infected mouse peritoneal macrophages (PM), endowed them with significant (p < 0.05) leishmanicidal activity, whereas a high-concentration (1 × 10−5 M) treatment augmented intramacrophage parasite growth. Naloxone pre-treatment of infected-mice (4 mg/kg × 2) and of infected-PM (1 × 10−5 M), blocked only the morphine low dose/concentration-induced protective effect. The splenocytes from protected mice and morphine low concentration-treated infected-PM, elaborated significantly (p < 0.05) enhanced levels of interleukin-12, interferon-γ, tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor and nitrite in the culture medium; a high dose/concentration suppressed their elaboration. Curiously, only morphine high dose/concentration-treated infected mice splenocytes and infected PM, produced significantly (p < 0.05) increased quantity of transforming growth factor-β1. Aminoguanidine, significantly (p < 0.05) blocked the morphine low dose/concentration-induced protective effect, in vivo and in vitro. This first study demonstrates dose-dependent biphasic modulatory effects of morphine in L. donovani-infected mice and PM, in vitro, apparently via nitric oxide-dependent mechanisms. These results thus demonstrate the implications of opiate abuse on the efficacy assessment of antileishmanial drugs and vaccines, and on the reactivation of latent VL in areas where both drug abuse and VL are rampant.
TL;DR: The latest studies have suggested that intranasal administration with NAD+ can profoundly decrease ischemic brain damage, and these observations suggest that NAD+ administration may be a novel therapeutic strategy for some neurological diseases.
Abstract: Neuronal death is a key pathological event in multiple neurological diseases. Increasing evidence has suggested that NAD+ and NADH mediate not only energy metabolism and mitochondrial functions, but also calcium homeostasis, aging, and cell death. This article is written to provide an overview about the information suggesting significant roles of NAD+ and NADH in neuronal death in certain neurological diseases. Our latest studies have suggested that intranasal administration with NAD+ can profoundly decrease ischemic brain damage. These observations suggest that NAD+ administration may be a novel therapeutic strategy for some neurological diseases.
TL;DR: Low CSF leptin levels are associated with poorer performance in learning and memory among HIV-infected men adjusting for usual predictors of HIV-associated neurocognitive impairment.
Abstract: The main objective of this study was to investigate the association between human CSF leptin levels and neuropsychological (NP) performance in the setting of HIV infection. We hypothesized that human CSF leptin levels positively correlate with NP performance. Leptin is an adipocyte-derived hormone that influences brain development and function, particularly learning and memory, in the mouse model. The extent to which leptin contributes to neurocognitive functioning in humans is less clear. A cross-sectional evaluation of CSF leptin and NP performance was performed. Leptin levels in CSF and serum samples from 59 HIV-positive men were measured by ELISA. Comprehensive, standardized NP testing was used to determine impairment status in global and specific domains. Lower CSF leptin levels and reduced leptin uptake into the central nervous system (CNS) correlated with impaired learning and memory performance in both univariate and multivariate analyses. In multivariate analyses, lower CSF leptin levels and reduced CNS leptin uptake were associated with worse NP performance in learning and memory, adjusting for CD4 nadir, antiretroviral treatment exposure, and HIV RNA levels in CSF. Low CSF leptin levels are associated with poorer performance in learning and memory among HIV-infected men adjusting for usual predictors of HIV-associated neurocognitive impairment. This association is consistent with prior in vitro and animal data suggesting leptin has a trophic or facilitatory role in the hippocampus, above and beyond its role in hypothalamic regulation.
TL;DR: There are a number of barriers in the assessment of neurological and neurocognitive effects in resource limited settings and some of these will be addressed.
Abstract: The global burden of the HIV epidemic is staggering, but in the short term, it is largely unfelt in the developed world. Almost one million people have been infected with HIV in North America, and the results of effective antiretroviral therapy have dramatically improved survival and quality of life. However, there are 25 million infected in sub-Saharan Africa alone, and antiretroviral treatment is scarce. Ninety-five percent of new infections occur in the developing world where resources are limited. Very little is known about NeuroAIDS in the developing world where few studies have been conducted on the neurologic and neurocognitive effects of antiretroviral treatment. HIV Clade differences and other factors could have dramatic effects on treatment effectiveness. There are a number of barriers in the assessment of neurological and neurocognitive effects in resource limited settings and some of these will be addressed.
TL;DR: Enteric neural activity appears to modulate interactions between the intestinal mucosa and pathogenic bacteria in a biomedical model for the human intestine.
Abstract: The extensively innervated intestinal mucosa encompasses a vast surface exposed to an array of potentially infectious microorganisms. We investigated the role of enteric nerves in modulating intracellular internalization of a multidrug-resistant Salmonella typhimurium DT104 field isolate in mucosa–submucosa sheets from the porcine ileum, a biomedical model for the human intestine. The effects of transmural electrical stimulation and drugs on intracellular internalization of Salmonella over 90 min was determined by a gentamicin-resistance assay relative to untreated tissues from the same animal serving as controls. The actin inhibitor cytochalasin D reduced internalization of Salmonella, and the mucus-disrupting agent dithiothreitol decreased its mucosal adherence. Transmural electrical stimulation increased, and neuronal conduction blockers saxitoxin and lidocaine decreased Salmonella internalization in stimulated and unstimulated tissues. Furthermore, the alpha-adrenergic/imidazoline receptor ligand phentolamine and the 5-HT3 receptor antagonist tropisetron decreased internalization in stimulated tissues. Based on these findings, enteric neural activity appears to modulate interactions between the intestinal mucosa and pathogenic bacteria.
TL;DR: This IN Tat model of neuroinflammation may be useful to study HIV-1-induced neurodegeneration, and five genes of interest in the Tat-treated mice that were significantly elevated in the microarrays were validated by RT-PCR.
Abstract: Intranasal (IN) delivery of HIV-1 Tat in aging mice was investigated as a possible model for HIV-1 infection in the brain. After IN administration, the distribution of [125I]-labeled Tat in the brains of Swiss Webster mice was evaluated by autoradiography and gamma counting. [125I]-labeled Tat was detected at the highest concentrations in the olfactory bulb, cervical nodes, and trigeminal nerve tract. In another experiment, APPSw transgenic mice were used to model chronic Tat exposure. The mice were treated intranasally with 6 μg Tat (n = 4) or vehicle (n = 4) three times per week for 4 weeks. Total RNA was isolated from the frontal cortex, and differential gene expression analysis was performed using gene microarrays. Gene ontology profiles indicated innate immunity, inflammatory and apoptotic responses. Five genes of interest in the Tat-treated mice that were significantly elevated in the microarrays were validated by RT-PCR. One gene, the Toll-like receptor 9 (Tlr9), has previously been shown to activate signaling cascades leading to innate immunity and enhanced HIV-1 gene expression. A second gene, Fas, plays a key role in neuroinflammation. Two cysteine-rich cytokines associated with chemotaxis were elevated: MCP-1 (Ccl2), which is chemotactic for monocytes, and Ccl17 (TARC), which is chemotactic for lymphocytes. Finally, the gene sestrin was significantly elevated and has been associated with oxidative stress, in particular amyloid beta-induced oxidative stress. This IN Tat model of neuroinflammation may be useful to study HIV-1-induced neurodegeneration.