1.
Oxidative stress and cerebral endothelial cells: Regulation of the blood-brain-barrier and antioxidant based interventions.
Abstract
While numerous lines of evidence point to increased levels of oxidative stress playing a causal role in a number ofneurodegenerative conditions, our current understanding of the specific role of oxidative stress in the genesis and/or propagation of neurodegenerative diseases remains poorly defined. Even more challenging to the "oxidative stress theory of neurodegeneration" is the fact that many antioxidant-based clinical trials and therapeutic interventions have been largely disappointing in their therapeutic benefit. Together, these factors have led researchers to begin to focus on understanding the contribution of highly localized structures, and defined anatomical features, within the brain as the sites responsible for oxidative stress-induced neurodegeneration. This review focuses on the potential for oxidative stress within the cerebrovascular architecture serving as a modulator of neurodegeneration in a variety of pathological settings. In particular, this review highlights important implications for vascular-derived oxidative stress in the initiating and promoting pathophysiology in the brain, identifying new roles for cerebrovascular oxidative stress in a variety of brain disorders. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.
Copyright © 2011. Published by Elsevier B.V.
64Cu-{N-[1,4,8,11-Tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine}.
Authors
Source
Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2011.
2011 Sep 15 [updated 2011 Dec 22].
Excerpt
Chemokine receptors are G-protein–coupled receptors that direct cell movement (when activated by a ligand) toward higher concentrations of chemokines. Chemokine receptor 4 (CXCR4) and its ligand, stromal cell–derived factor-1 (SDF-1 or CXCL12), are known to play a major role in the migration of progenitor cells during embryonic development of the central nervous, cardiovascular, and hematopoietic systems (1, 2). In addition, this CXCR4/SDF-1 receptor system has a function in the development, progression, and spread of various cancers (3), and the CXCR4 acts as a co-receptor for human immunodeficiency virus (HIV) on CD4+ T cells (4). It has also been suggested that CXCR4/SDF-1 interaction participates in the pathogenesis of neurodegenerative and inflammatory conditions (5). CXCR4 is expressed by many different types of cancers, and overexpression of CXCR4 in cancers indicates poor prognosis with aggressive and metastatic tumors and resistance to chemotherapy (6). CXCR4 is considered to play an important role in HIV infections and cancers (4). It is critical to perform imaging studies to measure CXCR4 levels under in vivo conditions for various pathological and physiological conditions (7). 99mTc-SDF-1 has been used with single-photon emission computed tomography (SPECT) to determine changes in CXCR4 expression in the heart after a myocardial infarction. 64Cu-1,1'-[1,4-Phenylenebis(methylene)]-bis[1,4,8,11-tetraazacyclotetradecane] (64Cu-AMD3100), a bicyclam inhibitor of CXCR4 activity, has been studied in mice bearing orthotopic breast tumors and in mice with lung metastases with positron emission tomography (PET) (8). {N-[1,4,8,11-Tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine} (AMD3465) is a monocyclam CXCR4 inhibitor with a ~15-fold higher affinity for CXCR4 than AMD3100. De Silva et al. (9) radiolabeled AMD3465 with 64Cu to form 64Cu-AMD3465 for PET imaging of CXCR4 expression in xenograft tumors in mice.
Sections
Tau reduction does not prevent motor deficits in two mouse models of Parkinson's disease.
Source
Gladstone Institute of Neurological Disease, San Francisco, California, United States of America.
Abstract
Many neurodegenerative diseases are increasing in prevalence and cannot be prevented or cured. If they shared common pathogenic mechanisms, treatments targeting such mechanisms might be of benefit in multiple conditions. The tau protein has been implicated in the pathogenesis of diverse neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Tau reduction prevents cognitive deficits, behavioral abnormalities and other pathological changes in multiple AD mouse models. Here we examined whether tau reduction also prevents motor deficits and pathological alterations in two mouse models of PD, generated by unilateral striatal injection of 6-hydroxydopamine (6-OHDA) or transgene-mediated neuronal expression of human wildtype α-synuclein. Both models were evaluated on Tau(+/+), Tau(+/-) and Tau(-/-) backgrounds in a variety of motor tests. Tau reduction did not prevent motor deficits caused by 6-OHDA and slightly worsened one of them. Tau reduction also did not prevent 6-OHDA-induced loss of dopaminergic terminals in the striatum. Similarly, tau reduction did not prevent motor deficits in α-synuclein transgenic mice. Our results suggest that tau has distinct roles in the pathogeneses of AD and PD and that tau reduction may not be of benefit in the latter condition.
Fibrillar Amyloid-β1-42 Modifies Actin Organization Affecting the Cofilin Phosphorylation State: A Role for Rac1/cdc42 Effector Proteins and the Slingshot Phosphatase.
Source
Laboratory of Cellular and Molecular Neurosciences, University of Chile and International Center for Biomedicine (ICC), Santiago, Chile.
Abstract
The neuronal cytoskeleton regulates numerous processes that occur in normal homeostasis. Under pathologicalconditions such as those of Alzheimer's disease (AD), major alterations in cytoskeleton organization have been observed and changes in both microtubules and actin filaments have been reported. Many neurodegenerativeconsequences of AD are linked to the production and accumulation of amyloid peptides (Aβ) and their oligomers, produced from the internal cleavage of the amyloid-β protein precursor. We previously reported that fibrillar Aβ1-42 (fAβ) treatment of hippocampal neurons induced an increase in Rac1 and Cdc42 activities linking fAβ effects with changes in actin dynamics. Here we show fAβ-induces increased activity of PAK1 and cyclin-dependent kinase 5, and that p21-activated kinase (PAK1) activation targets the LIMK1-cofilin signaling pathway. Increased cofilin dephosphorylation under conditions of enhanced LIM-Kinase 1 (LIMK1) activity suggests that fAβ co-stimulates bifurcating pathways impacting cofilin phosphorylation. Overexpression of slingshot (SSH) prevents the augment of F-actin induced by fAβ after 24 h, suggesting that fAβ-induced changes in actin assembly involve both LIMK1 and SSH. These results suggest that fAb may alter the PAK1/LIMK1/cofilin axis and therefore actin organization in AD.
Current Research on Opioid Receptor Function.
Source
The University of Texas Medical School at Houston, Houston, TX, USA. ying.xia@uth.tmc.edu.
Abstract
The use of opioid analgesics has a long history in clinical settings, although the comprehensive action of opioid receptors is still less understood. Nonetheless, recent studies have generated fresh insights into opioid receptor-mediated functions and their underlying mechanisms. Three major opioid receptors (μ-opioid receptor, MOR; δ-opioid receptor, DOR; and κ-opioid receptor, KOR) have been cloned in many species. Each opioid receptor is functionally sub-classified into several pharmacological subtypes, although, specific gene corresponding each of these receptor subtypes are still widely unidentified as only a single gene has been isolated for each opioid receptor. In addition to pain modulation and addiction, opioid receptors are widely involved in various physiological and pathophysiological activities, including the regulation of membrane ionic homeostasis, cell proliferation, emotional response, epileptic seizures, immune function, feeding, obesity, respiratory and cardiovascular control as well as the some neurodegenerativedisorders. In some species, they play an essential role in hibernation. One of the most exciting findings of the past decade is the opioid-receptor, especially DOR, mediated neuroprotection and cardioprotection. In the heart, PKC and KATP channels are involved in the opioid receptor-mediated cardioprotection. The up-regulation of DOR expression and release of endogenous opioids increase the neuronal tolerance to hypoxic/ischemic stress. The DOR signal triggers (depending on stress duration and severity) different mechanisms at multiple levels to preserve neuronal survival, including the stabilization of homeostasis and increased pro-survival signaling (e.g., PKC-ERK-Bcl 2) and anti-oxidative capacity. The DOR-mediated neuroprotection and cardioprotection have the potential to significantly alter the clinical pharmacology in terms of prevention and treatment of life-threatening conditions like stroke and myocardial infarction. The main purpose of this article is to review the recent work done on opioids and their receptor functions. It shall provide an informative reference for better understanding the opioid system and further elucidation of the opioid receptor function from a physiological and pharmacological point of view.
- PMID:
- 22204322
- [PubMed - as supplied by publisher]
Functional Roles of Synaptic and Extrasynaptic NMDA Receptors in Physiological and Pathological Neuronal Activities.
Source
School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, 200240 Shanghai, P. R. China. lstian@sjtu.edu.cn.
Abstract
The N-methyl-D-aspartate (NMDA) receptor is a major type of ionotropic glutamate receptor. Many studies have shown that NMDA receptors play a pivotal role in the central nervous system (CNS) under both physiological and pathologicalconditions. The functional diversity of NMDA receptors can be mainly attributed to their different subunit compositions that perform multiple functions in various situations. Furthermore, recent reports have indicated that synaptic and extrasynaptic NMDA receptors have distinct compositions and couple with different signaling pathways: while synaptic NMDA receptors tend to promote cell survival, extrasynaptic NMDA receptors promote cell death. Currently, intensive efforts are being made to study the pathological role of extrasynaptic NMDA receptors in order to find a more effective approach for the treatment of neurologic disorders. Here we reviewed some recent progress on the participation of synaptic and extrasynaptic NMDA receptors in neurologic diseases including epilepsy, ischemia, schizophrenia, depression and some neurodegenerative diseases.
- PMID:
- 22204320
- [PubMed - as supplied by publisher]
Neuromodulatory Propensity of Bacopa monnieri Leaf Extract Against 3-Nitropropionic Acid-Induced Oxidative Stress: In Vitro and In Vivo Evidences.
Source
Department of Biochemistry & Nutrition, CSIR-Central Food Technological Research Institute (CFTRI), Mysore, 570020, India.
Abstract
We previously reported the propensity of Bacopa monnieri (BM) leaf powder to modulate endogenous levels of oxidative stress markers in the brain of prepubertal mice. In this study, we tested the hypothesis that pretreatment with an alcoholic extract of BM (BME) could provide neuroprotection against 3-nitropropionic acid (3-NPA)-induced oxidative stress under in vitro and in vivo conditions. In chemical systems, BME exhibited multiple free radical scavenging ability. Further, BME pretreatment completely abolished 3-NPA-induced oxidative stress response in brain (striatum, St) mitochondria in vitro. Likewise, pretreatment of dopaminergic (N27 cell lines) cells with BME not only abrogated the generation of reactive oxygen species (ROS) levels, but also offered marked protection against 3-NPA-mediated cytotoxicity. These findings were further validated employing a 3-NPA mice model in vivo. We determined the degree of oxidative stress induction, redox status, enzymic antioxidants, protein oxidation, and cholinergic function in various brain regions of male mice provided with BME for 10 days (prophylaxis) followed by 3-NPA challenge (75 mg/kg bw/day, i.p.). BME prophylaxis completely prevented 3-NPA-induced oxidative dysfunctions in St and other brain regions. 3-NPA-induced robust elevation of oxidative markers (malondialdehyde levels, ROS generation, hydroperoxide levels and protein carbonyls) in cytosol of brain regions was predominantly abolished among mice given BME prophylaxis. Interestingly, BME prophylaxis also prevented the depletion of reduced glutathione, thiol levels, and perturbations in antioxidant enzymes caused by 3-NPA. Collectively these findings provide evidence on the significant prophylactic neuroprotective efficacy of BME in prepubertal mice brain. Based on these data, it is hypothesized that BME can serve as a useful adjuvant in protecting brain against oxidative-mediated neurodegenerative disorders involving oxidative stressconditions.
The importance of the multiple target action of green tea polyphenols for neuroprotection.
Source
Eve Topf Center for Neurodegenerative Diseases Research and Department of Molecular Pharmacology, Faculty of Medicine, Technion, Haifa, Israel.
Abstract
Mounting evidence suggests that lifestyle factors, especially nutrition are essential factor for healthy ageing. However, as a result of the increase in life expectance, neurodegenerative diseases like Alzheimer's and Parkinson's (AD and PD, respectively) are becoming an increasing burden, as aging is their main risk factor. Brain aging and neurodegenerativediseases of the elderly are characterized by oxidative damage, dysregulation of redox metals homeostasis and inflammation. Thus, it is not surprising that a large amount of drugs/agents in therapeutic use for these conditions are antioxidants/metal complexing, bioenergetic and anti-inflammatory agents. Natural plant polyphenols (flavonoids and non-flavonoids) are the most abundant antioxidants in the diet and as such, are ideal nutraceuticals for neutralizing stress-induced free radicals and inflammation. Human epidemiological and new animal data suggest that green and black flavonoids named catechins, may help protecting the aging brain and reduce the incidence of dementia, AD and PD. This review will present salient features of the beneficial multi-pharmacological actions of black and green tea polyphenols in aging and neurodegeneration, and speculate on their potential in drug combination to target distinct pathologies as a therapeutic disease modification approach.
- PMID:
- 22202078
- [PubMed - in process]
Intranasal treatment of neurodegenerative diseases and stroke.
Source
Department of Clinical Neurosciences and The Hotchkiss Brain Institute, The University of Calgary, Calgary, AB, Canada.
Abstract
Although the blood-brain barrier (BBB) restricts access to the central nervous system (CNS) for the use of systemically administered therapies, an alternative approach, the non-invasive method of intranasal delivery, can rapidly target delivery of molecules to the CNS. Intranasal delivery has the distinct advantages of circumventing the BBB while minimizing systemic exposure. This novel approach to treating neurological illnesses will be examined in detail in this review. We will review current understanding of the mechanisms underlying intranasal delivery to the CNS, along with discussion of pathways permitting entry from the nasal cavity into the CNS, particularly those involving the olfactory and trigeminal nerves. Significant preclinical research has been performed to develop and improve our current approaches to intranasal treatments. We will examine the evidence behind the use of intranasal delivery in chronic neurodegenerativeconditions such as Alzheimer's Disease and diabetes-mediated cerebral degeneration, as well as in acute conditionssuch as stroke.
- PMID:
- 22202044
- [PubMed - in process]
Ultrasound-Induced Blood-Brain Barrier Opening.
Source
Department of Biomedical Engineering, Columbia University, New York, NY. ek2191@columbia.edu.
Abstract
Over 4 million U.S. men and women suffer from Alzheimer's disease; 1 million from Parkinson's disease; 350,000 from multiple sclerosis (MS); and 20,000 from amyotrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. In addition, aging greatly increases the risk of neurodegenerative disease. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available. This is mainly due to the impermeability of the blood-brain barrier (BBB) that allows only 5% of the 7000 small-molecule drugs available to treat only a tiny fraction of these diseases. On the other hand, safe and localized opening of the BBB has been proven to present a significant challenge. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, is the only technique that can induce localized BBB opening noninvasively and regionally. FUS may thus have a huge impact in trans-BBB brain drug delivery. The primary objective in this paper is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS, which are responsible for inducing the BBB disruption. The mechanism of the BBB opening in vivo is monitored through the MRI and passive cavitation detection (PCD), and the safety of BBB disruption is assessed using H&E histology at distinct pressures, pulse lengths and microbubble diameters. It is hereby shown that the BBB can be disrupted safely and transiently under specific acoustic (pressures under 0.45 MPa) and microbubble (diameter under 8 µm) conditions.
- PMID:
- 22201586
- [PubMed - as supplied by publisher]
Memory after silent stroke: Hippocampus and infarcts both matter.
Source
Correspondence & reprint requests to Dr. Brickman: amb2139@columbia.edu.
Abstract
OBJECTIVE:
Memory decline commonly occurs among elderly individuals. This observation is often attributed to earlyneurodegenerative changes in the hippocampus and related brain regions. However, the contribution of vascular lesions, such as brain infarcts, to hippocampal integrity and age-associated memory decline remains unclear.
METHODS:
We studied 658 elderly participants without dementia from a prospective, community-based study on aging and dementia who received high-resolution structural MRI. Cortical and subcortical infarcts were identified, and hippocampal and relative brain volumes were calculated following standard protocols. Summary scores reflecting performance on tasks of memory, language, processing speed, and visuospatial function were derived from a comprehensive neuropsychological battery. We used multiple regression analyses to relate cortical and subcortical infarcts, hippocampal and relative brain volume, to measures of cognitive performance in domains of memory, language, processing speed, and visuospatial ability.
RESULTS:
Presence of brain infarcts was associated with a smaller hippocampus. Smaller hippocampus volume was associated with poorer memory specifically. Brain infarcts were associated with poorer memory and cognitive performance in all other domains, which was independent of hippocampus volume.
CONCLUSIONS:
Both hippocampal volume and brain infarcts independently contribute to memory performance in elderly individuals without dementia. Given that age-associated neurodegenerative conditions, such as Alzheimer disease, are defined primarily by impairment in memory, these findings have clinical implications for prevention and for identification of pathogenic factors associated with disease symptomatology.
An overview of human prion diseases.
Abstract
ABSTRACT: Prion diseases are transmissible, progressive and invariably fatal neurodegenerative conditions associated with misfolding and aggregation of a host-encoded cellular prion protein, PrPC. They have occurred in a wide range of mammalian species including human. Human prion diseases can arise sporadically, be hereditary or be acquired. Sporadic human prion diseases include Cruetzfeldt-Jacob disease (CJD), fatal insomnia and variably protease-sensitive prionopathy. Genetic or familial prion diseases are caused by autosomal dominantly inherited mutations in the gene encoding for PrPC and include familial or genetic CJD, fatal familial insomnia and Gerstmann-Straussler-Scheinker syndrome. Acquired human prion diseases account for only 5% of cases of human prion disease. They include kuru, iatrogenic CJD and a new variant form of CJD that was transmitted to humans from affected cattle via meat consumption especially brain. This review presents information on the epidemiology, etiology, clinical assessment, neuropathology and public health concerns of human prion diseases. The role of the PrP encoding gene (PRNP) in conferring susceptibility to human prion diseases is also discussed.
Aquaporin-4 promotes memory consolidation in Morris water maze.
Source
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, China.
Abstract
Aquaporin-4 (AQP4), the most abundant aquaporin in the brain, is polarized at the glial end-feet facing peri-synaptic areas. AQP4 has been hypothesized to modulate water and potassium fluxes associated with neuronal activity in pathophysiological states. However, the role of AQP4 in astroglial signaling under physiological conditions is unclear. Herein, AQP4 knockout mice and wild-type littermates were tested in the Morris water maze (MWM), which allows for investigating the role of AQP4 in long-term learning and memory. Compared with wild-type mice, AQP4 knockout mice appeared actually to find the platform more easy, but to forget more quickly, in the MWM, indicating that AQP4 knockout mice exhibited impaired memory consolidation in MWM. Moreover, the deficits of memory consolidations were associated with defects in theta-burst stimulation-induced long-term potentiation both in vivo and in vitro. Furthermore, AQP4 knockout mice were accompanied by a decrease in the incorporation of adult-generated granule cells into spatial memory networks. Taken together, our findings indicate that AQP4 plays a modulatory role in memory consolidation. Targeting glial AQP4 may be a new therapeutic strategy for neurodegenerative disorders and related memory impairment.
Health state values for use in the economic evaluation of treatments for Alzheimer's disease.
Source
Health Economics Group, Institute of Health Service Research, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK.
Abstract
Alzheimer's disease (AD) is a chronic, progressive, neurodegenerative disease that places a heavy burden on people with the condition, their families and carers, health care systems and society in general. Health-related quality of life (HR-QOL) in patients deteriorates as the cognitive, behavioural and functional symptoms of AD develop. The human and financial cost of AD is forecast to grow rapidly as populations age, and those responsible for planning and financing health care face the challenge of allocating increasingly scarce resources against current and future interventions targeted towards AD. These include calls for early detection and diagnosis, preventative strategies, new medications, residential care, supportive care, and meeting the needs of carers as well as patients. Health care funders in many health systems now require a demonstration of the value of new interventions through a comparison of benefits in terms of improvements in HR-QOL and costs relative to those of competing or existing practices. Changes in HR-QOL provide the basis for the calculation of the quality-adjusted life-year (QALY), a key outcome used in economic evaluations to compare treatments within and between different disease conditions. The objective of this systematic review was to provide a summary of the published health state values (utilities) for AD patients and their carers that are currently available to estimate QALYs for use in health economic evaluations of interventions in AD. The health care literature was searched for articles published in English between 2000 and 2011, using keywords and variants including 'quality-adjusted life years', 'health state indicators', 'health utilities' and the specific names of generic measures of HR-QOL and health state valuation techniques. Databases searched included MEDLINE, EMBASE, NHS EED, PsycINFO and ISI Web of Science. This review identified 12 studies that reported utility values associated with health states in AD. Values for AD health states categorized according to cognitive impairment (where 1 = perfect health and 0 = dead) ranged from mild AD (0.52-0.73) to moderate AD (0.30-0.53) to severe AD (0.12-0.49). Utility values were almost all based on two generic measures of HR-QOL: the EQ-5D and Health Utility Index mark 2/3 (HUI2/3). There were no health state values estimated from condition- or disease-specific measures of HR-QOL. The review also identified 18 published cost-utility analyses (CUAs) of treatments for AD. The CUAs incorporated results from only three of the identified health state valuation studies. Twelve CUAs relied on the same study for health state values. We conclude that the literature on health state values in AD is limited and overly reliant on a single symptom (cognition) to describe disease progression. Other approaches to characterizing disease progression in AD based on multiple outcomes or dependency may be better predictors of costs and utilities in economic evaluations. Patient and proxy ratings were poorly correlated, particularly in patients with more advanced AD. However, proxy ratings displayed the validity and reliability across the entire range of AD severity needed to detect long-term changes relevant to economic evaluation. Further longitudinal research of patient and carer HR-QOL based on multidimensional measures of outcome and utilities is needed.
Hyperpolarized [1-13C]dehydroascorbic acid.
Authors
Source
Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2011.
2011 Sep 15 [updated 2011 Dec 15].
Excerpt
Magnetic resonance spectroscopy (MRS) has been noninvasively used to detect small molecules in tissues in vivo (1-4). Proton (1H) and carbon-13 (13C) are the most frequently investigated MRS applications (5-7). One technique has been often used to enhance 13C nuclear spins with dynamic nuclear polarization (DNP), which dramatically increases sensitivities in MRS spectra of 13C-labeled substrates in solutions and tissues (2, 3, 8). DNP transfers high electron-spin polarization to nuclear spins via microwave irradiation. The 13C MRS signals from tissues are near background levels, whereas regions with hyperpolarized 13C-labeled substrates provide strong signals. Thus, hyperpolarized 13C-labeled substrates can provide >10,000-fold enhancement of the 13C MRS signals from the substrate and its subsequent metabolites. 13C-Labeled substrates must exhibit long spin-lattice relaxation time (T 1) values, be rapidly metabolized, and produce an observable change in the chemical shift (δ) value between the substrate and its metabolite(s). 13C-Labeled substrates, such as [1-13C]pyruvate, [2-13C]fructose, [13C]bicarbonate, α-keto[1-13C]isocaproate, and [1,4-13C2]fumarate have been studied using the DNP technique in tumors in preclinical studies to measure changes in metabolism in vivo through glycolysis, citric acid cycle, amino acid metabolism and fatty acid synthesis (1-3). Vitamin C (ascorbic acid, AA) is reversibly oxidized to DHA, which is a substrate of glucose transporters GLUT1 and GLUT3 (9). Epithelial cells of the intestine, liver, and kidney transport AA directly through sodium-dependent transporters, whereas most normal tissues acquire AA through transport of DHA (10). Intracellular DHA is then converted to AA through reaction with glutathione (GSH) or GSH-dependent enzymes and through NADPH-dependent thioredoxin reductases (11). On the other hand, tumor cells have been found to lack the capacity to transport AA and to exhibit upregulation of the GSH and thioredoxin antioxidant systems, reflecting high oxidative stress in tumor cells (10). High oxidative stress has also been implicated in neurodegenerative and cardiovascular conditions (12). Bohndiek et al. (13) generated a hyperpolarized small molecule, [1-13C]dehydroascorbic acid ([1-13C]DHA), as an imaging agent of 13C MRS for evaluation of intracellular reduction/oxidation (redox) status in tumors and other pathological conditions. [1-13C]DHA has been evaluated as an intracellular redox probe using tumor cells in vitro and in vivo. Keshari et al. (14) have performed MRS imaging of redox status in normal organs and prostate tumor in mice using hyperpolarized [1-13C]DHA.
Sections
Oxygen matters: tissue culture oxygen levels affect mitochondrial function and structure as well as responses to HIV viroproteins.
Source
1] Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA [2] Nebraska Center for Virology, University of Nebraska Lincoln, Lincoln, NE, USA.
Abstract
Mitochondrial dysfunction is implicated in a majority of neurodegenerative disorders and much study ofneurodegenerative disease is done on cultured neurons. In traditional tissue culture, the oxygen level that cells experience is dramatically higher (21%) than in vivo conditions (1-11%). These differences can alter experimental results, especially, pertaining to mitochondria and oxidative metabolism. Our results show that primary neurons cultured at physiological oxygen levels found in the brain showed higher polarization, lower rates of ROS production, larger mitochondrial networks, greater cytoplasmic fractions of mitochondria and larger mitochondrial perimeters than those cultured at higher oxygen levels. Although neurons cultured in either physiological oxygen or atmospheric oxygen exhibit significant increases in mitochondrial reactive oxygen species (ROS) production when treated with the human immunodeficiency virus (HIV) virotoxin trans-activator of transcription, mitochondria of neurons cultured at physiological oxygen underwent depolarization with dramatically increased cell death, whereas those cultured at atmospheric oxygen became hyperpolarized with no increase in cell death. Studies with a second HIV virotoxin, negative regulation factor (Nef), revealed that Nef treatment also increased mitochondrial ROS production for both the oxygen conditions, but resulted in mitochondrial depolarization and increased death only in neurons cultured in physiological oxygen. These results indicate a role for oxidative metabolism in a mechanism of neurotoxicity during HIV infection and demonstrate the importance of choosing the correct, physiological, culture oxygen in mitochondrial studies performed in neurons.
Cdk5: a multifaceted kinase in neurodegenerative diseases.
Source
Division of Life Science, Molecular Neuroscience Center and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
Abstract
Since the identification of cyclin-dependent kinase-5 (Cdk5) as a tau kinase and member of the Cdk family almost 20 years ago, deregulation of Cdk5 activity has been linked to an array of neurodegenerative diseases. As knowledge on the etiopathological mechanisms of these diseases evolved through the years, Cdk5 has also been implicated in additional cellular events that are affected under these pathological conditions. From the role of Cdk5 in the regulation of synaptic functions to its involvement in autophagy deregulation, significant insights have been obtained regarding the role of Cdk5 as a key regulator of neurodegeneration. Here, we summarize recent findings on the involvement of Cdk5 in the pathophysiological mechanisms underlying various neurodegenerative diseases.
Copyright © 2011 Elsevier Ltd. All rights reserved.
CSPα knockout causes neurodegeneration by impairing SNAP-25 function.
Source
1] Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA [2] Department of Neuroscience and Molecular Genetics, Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, TX, USA.
Abstract
At a synapse, the synaptic vesicle protein cysteine-string protein-α (CSPα) functions as a co-chaperone for the SNARE protein SNAP-25. Knockout (KO) of CSPα causes fulminant neurodegeneration that is rescued by α-synuclein overexpression. The CSPα KO decreases SNAP-25 levels and impairs SNARE-complex assembly; only the latter but not the former is reversed by α-synuclein. Thus, the question arises whether the CSPα KO phenotype is due to decreased SNAP-25 function that then causes neurodegeneration, or due to the dysfunction of multiple as-yet uncharacterized CSPα targets. Here, we demonstrate that decreasing SNAP-25 levels in CSPα KO mice by either KO or knockdown of SNAP-25 aggravated their phenotype. Conversely, increasing SNAP-25 levels by overexpression rescued their phenotype. Inactive SNAP-25 mutants were unable to rescue, showing that the rescue was specific. Under all conditions, the neurodegenerative phenotype precisely correlated with SNARE-complex assembly, indicating that impaired SNARE-complex assembly due to decreased SNAP-25 levels is the ultimate correlate of neurodegeneration. Our findings suggest that the neurodegeneration in CSPα KO mice is primarily produced by defective SNAP-25 function, which causes neurodegeneration by impairing SNARE-complex assembly.
Control of autophagy as a therapy for neurodegenerative disease.
Source
Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
Abstract
Autophagy is an intracellular degradation process that clears long-lived proteins and organelles from the cytoplasm. It involves the formation of double-membraned structures called autophagosomes that can engulf portions of cytoplasm containing oligomeric protein complexes and organelles, such as mitochondria. Autophagosomes fuse with lysosomes and their contents then are degraded. Failure of autophagy in neurons can result in the accumulation of aggregate-prone proteins and neurodegeneration. Pharmacological induction of autophagy can enhance the clearance of intracytoplasmic aggregate-prone proteins, such as mutant forms of huntingtin, and ameliorate pathology in cell and animal models ofneurodegenerative diseases. In this Review, the autophagic machinery and the signaling pathways that regulate the induction of autophagy are described. The ways in which dysfunctions at multiple stages in the autophagic pathways contribute to numerous neurological disorders are highlighted through the use of examples of Mendelian and complexconditions, including Alzheimer disease, Parkinson disease and forms of motor neuron disease. The different ways in which autophagic pathways might be manipulated for the therapeutic benefit of patients with neurodegenerative disorders are also considered.
Dynamic, adaptive changes in MAO-A binding after alterations in substrate availability: an in vivo [(11)C]-harmine positron emission tomography study.
Source
1] Vivian M Rakoff PET Imaging Centre, Toronto, Canada [2] Mood and Anxiety Disorders Division, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Canada [3] Day Clinic of Cognitive Neurology, University of Leipzig and Max-Planck-Institute for Cognition and Brain Sciences, Leipzig, Germany.
Abstract
Monoamine oxidase A (MAO-A) is an important target in the pathophysiology and therapeutics of major depressive disorder, aggression, and neurodegenerative conditions. We measured the effect of changes in MAO-A substrate on MAO-A binding in regions implicated in affective and neurodegenerative disease with [(11)C]-harmine positron emission tomography in healthy volunteers. Monoamine oxidase A V(T), an index of MAO-A density, was decreased (mean: 14%±9%) following tryptophan depletion in prefrontal cortex (P<0.031), and elevated (mean: 17%±11%) in striatum following carbidopa-levodopa administration (P<0.007). These findings suggest an adaptive role for MAO-A in maintaining monoamine neurotransmitter homeostasis by rapidly compensating fluctuating monoamine levels.Journal of Cerebral Blood Flow & Metabolism advance online publication, 21 December 2011; doi:10.1038/jcbfm.2011.184.
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