Loss of NF-κB p50 function synergistically augments microglial priming in the middle-aged brain.

Background: While NF-κB p50 function is impaired in central nervous system disease, aging in non-CNS tissues, and response to reactive oxygen species, the role of NF-κB p50 in aging-associated microglial pro-inflammatory priming is poorly understood.

Methods: Male NF-κB p50 and NF-κB p50 mice at three different ages (1.5-3.

Atypical microglial response to biodiesel exhaust in healthy and hypertensive rats.

Accumulating evidence suggests a deleterious role for urban air pollution in central nervous system (CNS) diseases and neurodevelopmental disorders. Microglia, the resident innate immune cells and sentinels in the brain, are a common source of neuroinflammation and are implicated in air pollution-induced CNS effects. While renewable energy, such as soy-based biofuel, is of increasing public interest, there is little information on how soy biofuel may affect the brain, especially in people with preexisting disease conditions.

Synthesis, Nicotinic Acetylcholine Receptor Binding, and in Vitro and in Vivo Pharmacological Properties of 2'-Fluoro-(substituted thiophenyl)deschloroepibatidine Analogues.

The synthesis, nAChR in vitro and in vivo pharmacological properties of 2'-fluoro-3'-(substituted thiophenyl)deschloroepibatidine analogues (5a-f, 6a-d, and 7a-c) are presented herein. All had subnanomolar affinity at α4β2*-nAChRs. Contrary to lead structure epibatidine, a potent nAChR agonist, all were potent α4β2- and α3β4-AChR antagonists in an in vitro functional assay.

Synthesis, Nicotinic Acetylcholine Binding, and in Vitro and in Vivo Pharmacological Properties of 2'-Fluoro-(carbamoylpyridinyl)deschloroepibatidine Analogues.

In this study, we report the synthesis, nAChR in vitro and in vivo pharmacological properties of 2'-fluoro-(carbamoylpyridinyl)deschloroepibatidine analogues (5, 6a,b, and 7a,b), which are analogues of our lead structure epibatidine. All of the analogues had subnanomolar binding affinity for α4β2*-nAChRs, and all were potent antagonists of α4β2-nAChRs in an in vitro functional assay. Analogues 6a,b were also highly selective for α4β2- relative to α3β4- and α7-nAChRs.

Akt Regulates Axon Wrapping and Myelin Sheath Thickness in the PNS.

Unlabelled: The signaling pathways that regulate myelination in the PNS remain poorly understood. Phosphatidylinositol-4,5-bisphosphate 3-kinase 1A, activated in Schwann cells by neuregulin and the extracellular matrix, has an essential role in the early events of myelination. Akt/PKB, a key effector of phosphatidylinositol-4,5-bisphosphate 3-kinase 1A, was previously implicated in CNS, but not PNS myelination.

Microglial priming through the lung-brain axis: the role of air pollution-induced circulating factors.

Air pollution is implicated in neurodegenerative disease risk and progression and in microglial activation, but the mechanisms are unknown. In this study, microglia remained activated 24 h after ozone (O3) exposure in rats, suggesting a persistent signal from lung to brain. Ex vivo analysis of serum from O3-treated rats revealed an augmented microglial proinflammatory response and β-amyloid 42 (Aβ42) neurotoxicity independent of traditional circulating cytokines, where macrophage-1 antigen-mediated microglia proinflammatory priming.

Synthesis, nicotinic acetylcholine receptor binding, in vitro and in vivo pharmacology properties of 3'-(substituted pyridinyl)-deschloroepibatidine analogs.

Over the last several years we have synthesized and studied the in vitro and in vivo nAChR pharmacological properties of epibatidine (4) analogs. In this study we report the synthesis, nAChR in vitro and in vivo pharmacological properties of 3'-(substituted pyridinyl)-deschloroepibatidine analogs (5a-e and 6a-e). All of the analogs had high binding affinity for α4β2(∗)-nAChRs.

In vitro and in vivo neuronal nicotinic receptor properties of (+)- and (-)-pyrido[3,4]homotropane [(+)- and (-)-PHT]: (+)-PHT is a potent and selective full agonist at α6β2 containing neuronal nicotinic acetylcholine receptors.

Pyrido[3,4]homotropane (PHT) is a conformationally rigid, high affinity analogue of nicotine. (+)-PHT was previously shown to be 266 times more potent than (-)-PHT for inhibition of [(3)H]epibatidine binding to nAChRs but had no antinociceptive activity in mouse tail-flick or hot-plate tests and was not a nicotinic antagonist even when administered intrathecally. While (-)-PHT had no agonist activity, it was a potent, nicotinic antagonist in the test.

Redox regulation of NF-κB p50 and M1 polarization in microglia.

Redox-signaling is implicated in deleterious microglial activation underlying CNS disease, but how ROS program aberrant microglial function is unknown. Here, the oxidation of NF-κB p50 to a free radical intermediate is identified as a marker of dysfunctional M1 (pro-inflammatory) polarization in microglia. Microglia exposed to steady fluxes of H2 O2 showed altered NF-κB p50 protein-protein interactions, decreased NF-κB p50 DNA binding, and augmented late-stage TNFα expression, indicating that H2 O2 impairs NF-κB p50 function and prolongs amplified M1 activation.

The role of MAC1 in diesel exhaust particle-induced microglial activation and loss of dopaminergic neuron function.

Increasing reports support that air pollution causes neuroinflammation and is linked to central nervous system (CNS) disease/damage. Diesel exhaust particles (DEP) are a major component of urban air pollution, which has been linked to microglial activation and Parkinson's disease-like pathology. To begin to address how DEP may exert CNS effects, microglia and neuron-glia cultures were treated with either nanometer-sized DEP (< 0.

Pesticides, microglial NOX2, and Parkinson's disease.

Accumulating evidence indicates that pesticide exposure is associated with an increased risk for developing Parkinson's disease (PD). Several pesticides known to damage dopaminergic (DA) neurons, such as paraquat, rotenone, lindane, and dieldrin also demonstrate the ability to activate microglia, the resident innate immune cell in the brain. While each of these environmental toxicants may impact microglia through unique mechanisms, they all appear to converge on a common final pathway of microglial activation: NADPH oxidase 2 (NOX2) activation.

The outdoor air pollution and brain health workshop.

Accumulating evidence suggests that outdoor air pollution may have a significant impact on central nervous system (CNS) health and disease. To address this issue, the National Institute of Environmental Health Sciences/National Institute of Health convened a panel of research scientists that was assigned the task of identifying research gaps and priority goals essential for advancing this growing field and addressing an emerging human health concern. Here, we review recent findings that have established the effects of inhaled air pollutants in the brain, explore the potential mechanisms driving these phenomena, and discuss the recommended research priorities/approaches that were identified by the panel.

Bupropion and its main metabolite reverse nicotine chronic tolerance in the mouse.

Introduction: Although the antidepressant bupropion is prescribed to aid in smoking cessation, little is known concerning its mechanisms of action in this regard. One factor that might influence quit success is nicotine tolerance, which could promote high levels of nicotine intake in order to maintain nicotine's subjective effects (thereby making attempts to reduce smoking more difficult).

Methods: To explore whether bupropion and its active hydroxymetabolite modulate nicotine tolerance, mice were injected for 14 days with saline or nicotine.

Targeting microglia-mediated neurotoxicity: the potential of NOX2 inhibitors.

Microglia are key sentinels of central nervous system health, and their dysfunction has been widely implicated in the progressive nature of neurodegenerative diseases. While microglia can produce a host of factors that are toxic to neighboring neurons, NOX2 has been implicated as a common and essential mechanism of microglia-mediated neurotoxicity. Accumulating evidence indicates that activation of the NOX2 enzyme complex in microglia is neurotoxic, both through the production of extracellular reactive oxygen species that damage neighboring neurons as well as the initiation of redox signaling in microglia that amplifies the pro-inflammatory response.

Air pollution & the brain: Subchronic diesel exhaust exposure causes neuroinflammation and elevates early markers of neurodegenerative disease.

Background: Increasing evidence links diverse forms of air pollution to neuroinflammation and neuropathology in both human and animal models, but the effects of long-term exposures are poorly understood.

Objective: We explored the central nervous system consequences of subchronic exposure to diesel exhaust (DE) and addressed the minimum levels necessary to elicit neuroinflammation and markers of early neuropathology.

Methods: Male Fischer 344 rats were exposed to DE (992, 311, 100, 35 and 0 μg PM/m³) by inhalation over 6 months.

Chronic apocynin treatment attenuates beta amyloid plaque size and microglial number in hAPP(751)(SL) mice.

Background: NADPH oxidase is implicated in neurotoxic microglial activation and the progressive nature of Alzheimer's Disease (AD). Here, we test the ability of two NADPH oxidase inhibitors, apocynin and dextromethorphan (DM), to reduce learning deficits and neuropathology in transgenic mice overexpressing human amyloid precursor protein with the Swedish and London mutations (hAPP(751)(SL)).

Methods: Four month old hAPP(751)(SL) mice were treated daily with saline, 15 mg/kg DM, 7.

Diesel exhaust activates and primes microglia: air pollution, neuroinflammation, and regulation of dopaminergic neurotoxicity.

Background: Air pollution is linked to central nervous system disease, but the mechanisms responsible are poorly understood.

Objectives: Here, we sought to address the brain-region-specific effects of diesel exhaust (DE) and key cellular mechanisms underlying DE-induced microglia activation, neuroinflammation, and dopaminergic (DA) neurotoxicity.

Methods: Rats were exposed to DE (2.

Microglial activation and chronic neurodegeneration.

Microglia, the resident innate immune cells in the brain, have long been implicated in the pathology of neurodegenerative diseases. Accumulating evidence points to activated microglia as a chronic source of multiple neurotoxic factors, including tumor necrosis factor-α, nitric oxide, interleukin-1β, and reactive oxygen species (ROS), driving progressive neuron damage. Microglia can become chronically activated by either a single stimulus (e.

Reactive microgliosis: extracellular micro-calpain and microglia-mediated dopaminergic neurotoxicity.

Microglia, the innate immune cells in the brain, can become chronically activated in response to dopaminergic neuron death, fuelling a self-renewing cycle of microglial activation followed by further neuron damage (reactive microgliosis), which is implicated in the progressive nature of Parkinson's disease. Here, we use an in vitro approach to separate neuron injury factors from the cellular actors of reactive microgliosis and discover molecular signals responsible for chronic and toxic microglial activation. Upon injury with the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium, N27 cells (dopaminergic neuron cell line) released soluble neuron injury factors that activated microglia and were selectively toxic to dopaminergic neurons in mixed mesencephalic neuron-glia cultures through nicotinamide adenine dinucleotide phosphate oxidase.

Air pollution: mechanisms of neuroinflammation and CNS disease.

Air pollution has been implicated as a chronic source of neuroinflammation and reactive oxygen species (ROS) that produce neuropathology and central nervous system (CNS) disease. Stroke incidence and Alzheimer's and Parkinson's disease pathology are linked to air pollution. Recent reports reveal that air pollution components reach the brain; systemic effects that impact lung and cardiovascular disease also impinge upon CNS health.

Inhibition of vimentin or beta1 integrin reverts morphology of prostate tumor cells grown in laminin-rich extracellular matrix gels and reduces tumor growth in vivo.

Prostate epithelial cells grown embedded in laminin-rich extracellular matrix (lrECM) undergo morphologic changes that closely resemble their architecture in vivo. In this study, growth characteristics of three human prostate epithelial sublines derived from the same cellular lineage, but displaying different tumorigenic and metastatic properties in vivo, were assessed in three-dimensional lrECM gels. M12, a highly tumorigenic and metastatic subline, was derived from the immortalized, prostate epithelial P69 cell line by selection in athymic, nude mice and found to contain a deletion of 19p-q13.

NADPH oxidase as a therapeutic target in Alzheimer's disease.

At present, available treatments for Alzheimer's disease (AD) are largely unable to halt disease progression. Microglia, the resident macrophages in the brain, are strongly implicated in the pathology and progressively degenerative nature of AD. Specifically, microglia are activated in response to both beta amyloid (Abeta) and neuronal damage, and can become a chronic source of neurotoxic cytokines and reactive oxygen species (ROS).

Nicotine physical dependence in the mouse: involvement of the alpha7 nicotinic receptor subtype.

Although chronic nicotine produces dependence in mice, the role of specific nicotinic receptors has not been examined in knockout animals. The present study utilized alpha7 nicotinic receptor knockout mice to explore the role of this receptor subunit in nicotine dependence. Mice were chronically exposed to nicotine (0 or 200 microg/ml) in their drinking water and assayed for somatic withdrawal signs, hyperalgesia (tail-flick and hot-plate) and spontaneous activity following nicotine cessation.

Nicotine physical dependence and tolerance in the mouse following chronic oral administration.

Rationale: Although nicotine dependence and tolerance develop in rats, few studies have examined these processes in the mouse. Establishing such mouse models would eventually allow for an examination of the role of specific nicotinic receptor subtypes in mediating these processes (i.e.

Morphogenic role for acetylcholinesterase in axonal outgrowth during neural development.

Acetylcholinesterase (AChE) is the enzyme that hydrolyzes the neurotransmitter acetylcholine at cholinergic synapses and neuromuscular junctions. However, results from our laboratory and others indicate that AChE has an extrasynaptic, noncholinergic role during neural development. This article is a review of our findings demonstrating the morphogenic role of AChE, using a neuronal cell culture model.