Douglas L Feinstein

Jesse Brown VA Medical Center, Chicago, Illinois, United States

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Publications (151)605.51 Total impact

  • Paul E. Polak, Shao Xia Lin, Dale Pelligrino, Douglas L. Feinstein
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    ABSTRACT: Reduced levels of noradrenaline (NA) in CNS of multiple sclerosis patients could be due to metabolism by catechol-O-methyltransferase (COMT). In mice immunized with myelin oligodendrocyte glycoprotein peptide, the BBB permeable COMT inhibitor dinitrocatechol (DNC) reduced clinical signs; while entacapone, a non-BBB permeable inhibitor, had no effect. Spinal cord NA levels were slightly increased by DNC, and there was an inverse correlation between NA levels and average clinical signs. Spinal cord COMT mRNA levels were not increased during EAE, but were found increased in frontal cortex of MS patients. These results suggest that COMT inhibitors could provide benefit to MS patients.
    Journal of Neuroimmunology. 09/2014;
  • David Braun, Jose L.M. Madrigal, Douglas L. Feinstein
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    ABSTRACT: It has been known for many years that the endogenous neurotransmitter noradrenaline (NA) exerts antiinflammatory and neuroprotective effects both in vitro and in vivo. In many cases the site of action of NA are betaadrenergic receptors (βARs), causing an increase in intracellular levels of cAMP which initiates a broad cascade of events including suppression of inflammatory transcription factor activities, alterations in nuclear localization of proteins, and induction of patterns of gene expression mediated through activity of the CREB transcription factor. These changes lead not only to reduced inflammatory events, but also contribute to neuroprotective actions of NA by increasing expression of neurotrophic substances including BDNF, GDNF, and NGF. These properties have prompted studies to determine if treatments with drugs to raise CNS NA levels could provide benefit in various neurological conditions and diseases having an inflammatory component. Moreover, increasing evidence shows that disruptions in endogenous NA levels occurs in several diseases and conditions including Alzheimer’s disease (AD), Parkinson’s disease (PD), Down’s syndrome, posttraumatic stress disorder (PTSD), and multiple sclerosis (MS), suggesting that damage to NA producing neurons is a common factor that contributes to the initiation or progression of neuropathology. Methods to increase NA levels, or to reduce damage to noradrenergic neurons, therefore represent potential preventative as well as therapeutic approaches to disease.
    Current Neuropharmacology 07/2014; 12(4). · 2.03 Impact Factor
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    ABSTRACT: The most commonly used immunogen to induce experimental autoimmune encephalomyelitis (EAE) is MOG35-55 , a 21-residue peptide derived from myelin oligodendrocyte glycoprotein. In most studies, mice exhibit a chronic disease; however, in some studies mice show a transient disease. One variable that is not often controlled for is the peptide fraction of the purified MOG material, which can vary from less than 50% to over 90%, with the remainder of mass primarily comprised of the counter-ion used for peptide purification. We compared the development of clinical signs in female C57Bl6 mice immunized with two commercially available MOG35-55 peptides of similar purity but different peptide fraction (MOG-A being 45%; MOG-B being 72%). A single immunization with MOG-A induced a chronic disease course with some recovery at later stages, while immunization with MOG-B induced a similar course of disease but with significantly lower average clinical scores despite the higher peptide content of MOG-B. The addition of a booster immunization significantly increased clinical severity with both preparations, and significantly reduced the average day of onset using MOG-A. To determine if the counter-ion could influence disease, we compared MOG-B-containing trifluoroacetate (TFA) with MOG-B-containing acetate. Although disease incidence and severity were similar, the average day of disease onset occurred approximately 5 days earlier with the use of MOG-B-containing TFA. These results demonstrate that differences in peptide fraction influence the course of EAE disease, which may be due in part to the levels of counter-ions present in the purified material. These findings underscore the fact that a knowledge of peptide fraction is as critical as knowledge of peptide purity when using peptides from different sources. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 01/2014; · 3.97 Impact Factor
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    ABSTRACT: To determine whether intraosseous infusion of a lipid emulsion reverses cardiac pharmacotoxicity in anaesthetized rats. Prospective, randomized animal study. Academic research laboratory. Adult, male Sprague-Dawley rats. We assigned 25 male Sprague-Dawley rats into four groups: intraosseous lipid emulsion, intraosseous saline, IV lipid emulsion, and sham/null. Rats were anesthetized with 1.5% isoflurane and 95% oxygen. The left internal carotid artery and both internal jugular veins were cannulated and a flow probe was placed on the right carotid artery. Subsequently, in animals assigned to the intraosseous groups, the greater trochanter of the left proximal femur was exposed and the intraosseous space was cannulated. After surgical recovery, bupivacaine (10 mg/kg) was injected IV over 20 seconds followed 10 seconds later by treatment with one of the following: intraosseous lipid-emulsion (10 mL/kg over 180 s), intraosseous saline (10 mL/kg over 180 s), IV lipid-emulsion (10 mL/kg over 90 s), or no treatment (sham/null). Electrocardiogram, aortic blood pressure, and carotid blood flow were recorded continuously. Rats treated with intraosseous lipid emulsion experienced a significantly faster recovery of hemodynamic variables (return of 50% flow; median [CI]: 160 s [105-263 s]) than did rats treated with saline (471 s [283-611 s]; p < 0.05) or animals with no treatment (415 s [340-539 s], p < 0.05), but at a similar rate to animals treated with IV lipid emulsion (176 s [152-217 s], p = not significant). All groups experienced persistent negative chronotropic effects. A compensatory increase in systemic arterial pressure was observed in rats treated with lipid emulsion. These proof-of-principle data indicate that intraosseous infusion of lipid emulsion rapidly reverses bupivacaine-induced cardiac toxicity in rats. Further studies are warranted to optimize this novel route of lipid emulsion injection in emergency situations when intravascular access is not secured.
    Critical care medicine 10/2013; · 6.37 Impact Factor
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    ABSTRACT: We previously showed that dimethyl fumarate (DMF) reduces inflammatory activation in astrocytes, involving activation of transcription factor Nrf2. However, the pathways causing Nrf2 activation were not examined. We now show that DMF modifies expression of histone deacetylases (HDACs) in primary rat astrocytes. After 4h incubation, levels of HDAC1, 2, and 4 mRNAs were increased by DMF; however, after 24h, levels returned to or were below control values. At that time, HDAC protein levels and overall activity were also reduced by DMF. Stimulation of astrocytes with pro-inflammatory cytokines significantly increased HDAC mRNA levels after 24h, although protein levels were not increased at that time point. In the presence of cytokines, DMF reduced HDAC mRNAs, proteins, and activity. Proteomic analysis of DMF-treated astrocytes identified 8 proteins in which lysine acetylation was increased by DMF, including histones H2a.1 and H3.3. A role for HDACs in mediating DMF actions is suggested by findings that the selective HDAC inhibitor SAHA increased nuclear Nrf2:DNA binding activity, reduced inflammatory activation of astrocytes which was reversed by a selective inhibitor of the Nrf2 target gene heme-oxygenase 1. These data show that DMF regulates astrocyte HDAC expression, which could contribute to Nrf2 activation, suppression of inflammatory responses and cause long-lasting changes in gene expression.
    Journal of neuroimmunology 08/2013; · 2.84 Impact Factor
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    ABSTRACT: The vervet is an old world monkey increasingly being used as a model for human diseases. In addition to plaques and tangles, an additional hallmark of Alzheimer's disease is damage to neurons that synthesize noradrenaline (NA). We characterized amyloid burden in the posterior temporal lobe of young and aged vervets, and compared that with changes in NA levels and astrocyte activation. Total amyloid beta (Aβ)40 and Aβ42 levels were increased in the aged group, as were numbers of amyloid plaques detected using antibody 6E10. Low levels of Aβ42 were detected in 1 of 5 younger animals, although diffusely stained plaques were observed in 4 of these. Increased glial fibrillary acidic protein staining and messenger RNA levels were significantly correlated with increased age, as were cortical NA levels. Levels of Aβ42 and Aβ40, and the number of 6E10-positive plaques, were correlated with NA levels. Interestingly messenger RNA levels of glial derived neurotrophic factor, important for noradrenergic neuronal survival, were reduced with age. These findings suggest that amyloid pathology in aged vervets is associated with astrocyte activation and higher NA levels.
    Neurobiology of aging 04/2013; · 5.94 Impact Factor
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    ABSTRACT: This study has established the presence of IgM against S-nitrosylated proteins in cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients using S-nitrosocysteine epitope (anti-SNOcys) as previously shown in serum. Anti-SNOcys IgM increased significantly in CSF during relapsing-remitting MS compared to milder neurological conditions. Evidence from albumin, IgG and IgM suggest that the production of anti-SNOcys IgM is intrathecal rather than the result of ingress from serum. Two correlations during relapse: between CSF level of anti-SNOcys IgM and time elapsed since relapse onset; and between CSF and serum anti-SNOcys IgM levels, suggest that this antibody may have potential as a biomarker.
    Journal of neuroimmunology 01/2013; · 2.84 Impact Factor
  • Ali J Ghods, Roberta Glick, David Braun, Douglas Feinstein
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    ABSTRACT: Dimethylfumarate (DMF), a drug used in the treatment of psoriasis and multiple sclerosis, has been shown to limit the growth of melanoma cells. The ability of DMF to inhibit the Rel protein has been used to explain the antioncogenic properties of this drug. Studies analyzing the effect of DMF in gliomas are limited. Therefore, we investigated the potential antitumor effects of DMF by assessing its effects on proliferation, cell death, and differentiation in gliomas in several glioma models. Mouse glioma Gl261, human glioblastoma A172 and human glioblastoma cells from patients were exposed to DMF at therapeutic concentrations (100 μM) and supratherapeutic concentrations (300 μM) and studies to assess proliferation, cellular lysis, and differentiation undertaken. The 5-bromo-2'-deoxyuridine (BRDU) proliferation assay and lactate dehydrogenase LDH cell lysis assay were used. Immunocytochemistry was used to assess differentiation: CD133 (stem cell marker), Nestin (progenitor marker), Sox2 (progenitor marker), β-tubulin III (neuronal marker), glial fibrillary acidic protein (astrocytic marker), and myelin basic protein (oligodendrocytic marker). We also assessed cellular expression of nuclear factor kappa B (NF-κB) via immunocytochemistry. Proliferation significantly decreased and tumor cell lysis significantly increased in all tumor cell lines after exposure to DMF. The human glioblastoma cells expressed the Neuronal Stem Cell marker CD133, Progenitor Cell markers, Neuronal and Astrocytic Cell Markers in vitro. When exposed to DMF, a drastic decline in CD133 expression was observed in addition to a decrease in the expression of NF-κB. DMF appears to have a promising role in the treatment of malignant brain neoplasms. DMF reduced proliferation rate, generated cell lysis, decreased the expression of NF-κB, and restricted the growth of CD133 cells in gliomas. This suggests that DMF may be considered for further antitumor studies, and provide a new treatment modality for brain tumors.
    Surgical Neurology International 01/2013; 4:160. · 1.18 Impact Factor
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    ABSTRACT: BACKGROUND: Inhalational anesthetics have been shown to influence T cell functions both in vitro and in vivo, in many cases inducing T cell death, suggesting that exposure to these drugs could modify the course of an autoimmune disease. We tested the hypothesis that in mice immunized to develop experimental autoimmune encephalomyelitis (EAE), a well established model of multiple sclerosis (MS), treatment with the commonly used inhalational anesthetic sevoflurane would attenuate disease symptoms. METHODS: C57Bl6 female mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide residues 35 to 55 to induce a chronic demyelinating disease. At day 10 after immunization, the mice were subjected to 2 h of 2.5% sevoflurane in 100% oxygen, or 100% oxygen, alone. Following treatment, clinical scores were monitored up to 4 weeks, after which brain histology was performed to measure the effects on astrocyte activation and lymphocyte infiltration. Effects of sevoflurane on T cell activation were studied using splenic T cells isolated from MOG peptide-immunized mice, restimulated ex vivo with MOG peptide or with antibodies to CD3 and CD28, and in the presence of different concentrations of sevoflurane. T cell responses were assessed 1 day later by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for proliferation, lactate dehydrogenase (LDH) release for cell death, and inflammatory activation by production of interleukin (IL)-17 and interferon (IFN)gamma. RESULTS: Clinical scores in the oxygen-treated group increased until day 28 at which time they showed moderate to severe disease (average clinical score of 2.9). In contrast, disease progression in the sevoflurane-treated group increased to 2.1 at day 25, after which it remained unchanged until the end of the study. Immunohistochemical analysis revealed reduced numbers of infiltrating leukocytes and CD4+ cells in the CNS of the sevoflurane-treated mice, as well as reduced glial cell activation. In splenic T cells, low doses of sevoflurane reduced IFNgamma production, cell proliferation, and increased LDH release. CONCLUSIONS: These results are the first to show attenuation of EAE disease by an inhaled anesthetic and are consistent with previous reports that inhaled anesthetics, including sevoflurane, can suppress T cell activation that, in the context of autoimmune diseases such as MS, could lead to reduced clinical progression.
    Journal of Neuroinflammation 12/2012; 9(1):272. · 4.35 Impact Factor
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    ABSTRACT: Ansamycins are very effective HSP90 inhibitors that showed significant beneficial effects in the treatment of EAE. However, their toxicity and poor stability in solution limit their clinical use. In the present study we have characterized the anti-inflammatory properties of a novel HSP90 inhibitor, PU-H71, and tested its effects in EAE. Our findings show that PU-H71 reduced lipopolysaccharide astrocyte activation but failed to reduce the inflammatory cytokine activation. In contrast to ansamycins, PU-H71 weakly affects EAE clinical course. In conclusion, although PU-H71 displayed some anti-inflammatory properties, it appeared in vivo less effective than the more toxic HSP90 inhibitors.
    Journal of neuroimmunology 11/2012; · 2.84 Impact Factor
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    ABSTRACT: The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase with a central role in the regulation of cell growth and proliferation, and several intracellular processes, such as mRNA transcription and translation, autophagy and cytoskeletal organization. The relevance of this pathway in the regulation of the immune system is well characterized. mTOR is essential for the proper activation and proliferation of effector T cells, restricts the development of regulatory T cells, and downregulates innate immune responses. Recently, a direct role of mTOR in the modulation of glial functions has also been recognized. Data from our group and others support the notion that mTOR is involved in microglial proinflammatory activation. The kinase regulates several intracellular processes in astrocytes, among which the rate of mRNA degradation of the inducible form of NO synthase. Therefore, the inhibition of mTOR kinase activity in glial cells results in anti-inflammatory actions, suggesting possible beneficial effects of mTOR inhibitors (like rapamycin) in the treatment of inflammatory-based pathologies of the central nervous system. In contrast, mTOR plays an important role in the regulation of oligodendrocyte development and myelination process as well as several neuronal functions, which may limit this therapeutic approach. Nevertheless, as reviewed here, there is robust evidence that rapamycin ameliorates the clinical course of both the relapsing-remitting and the chronic experimental autoimmune encephalomyelitis (EAE), and significantly reduces the hyperalgesia observed before clinical development of EAE. These findings may have important clinical implications for the therapy of multiple sclerosis. © 2012 Wiley Periodicals, Inc.
    Glia 10/2012; · 5.07 Impact Factor
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    ABSTRACT: BACKGROUND:: Previous studies indicate epinephrine adversely affects arterial oxygenation when administered in a rat model of local anesthetic overdose. The authors tested whether epinephrine alone exerts similar effects in the intact animal. METHODS:: Anesthetized rats received a single intravenous injection of epinephrine (25, 50, or 100 mcg/kg); matched cohorts were pretreated with phentolamine (100 mcg/kg); n = 5 for each of the six treatment groups. Arterial pressure and blood gases were measured at baseline, 1 and 10 min after epinephrine administration. Pulmonary capillary pressures during epinephrine infusion with normal and increased flows were measured in an isolated lung preparation. RESULTS:: Epinephrine injection in the intact animal caused hypoxemia, hypercapnia, and acidosis at all doses. Arterial oxygen tension was reduced within 1 min of injection. Hyperlactatemia occurred by 10 min after 50 and 100 mcg/kg. Rate pressure product was decreased by 10 min after 100 mcg/kg epinephrine. Pretreatment with phentolamine attenuated these effects except at 100 mcg/kg epinephrine. In the isolated lung preparation, epinephrine in combination with increased pulmonary flow increased pulmonary capillary pressure and lung water. CONCLUSIONS:: Bolus injection of epinephrine in the intact, anesthetized rat impairs pulmonary oxygen exchange within 1 min of treatment. Effects were blunted by α-adrenergic receptor blockade. Edema occurred in the isolated lung above a threshold pulmonary capillary pressure when epinephrine treatment was coupled with an increase in pulmonary flow. These results potentially argue against using traditional doses of epinephrine for resuscitation, particularly in the anesthetized patient.
    Anesthesiology 08/2012; 117(4):745-754. · 5.16 Impact Factor
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    ABSTRACT: Current treatments used in Multiple Sclerosis (MS) are partly effective in the early stages of the disease but display very limited benefits in patients affected by progressive MS. One possible explanation is that these therapies are unable to target the inflammatory component most active during the progressive phase of the disease, and compartmentalized behind the blood-brain barrier. Our findings show that Rapamycin ameliorates clinical and histological signs of chronic EAE when administered during ongoing disease. Moreover, Rapamycin significantly reduced the hyperalgesia observed before clinical development of EAE which, in turn, is completely abolished by the administration of the drug.
    Journal of neuroimmunology 02/2012; 243(1-2):43-51. · 2.84 Impact Factor
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    ABSTRACT: Experimental autoimmune encephalomyelitis (EAE) is an animal model of autoimmune disease that presents with pathological and clinical features similar to those of multiple sclerosis (MS) including inflammation and neurodegeneration. This study investigated whether blueberries, which possess immunomodulatory, anti-inflammatory, and neuroprotective properties, could provide protection in EAE. Dietary supplementation with 1% whole, freeze-dried blueberries reduced disease incidence by >50% in a chronic EAE model (p < 0.01). When blueberry-fed mice with EAE were compared with control-fed mice with EAE, blueberry-fed mice had significantly lower motor disability scores (p = 0.03) as well as significantly greater myelin preservation in the lumbar spinal cord (p = 0.04). In a relapsing-remitting EAE model, blueberry-supplemented mice showed improved cumulative and final motor scores compared to control diet-fed mice (p = 0.01 and 0.03, respectively). These data demonstrate that blueberry supplementation is beneficial in multiple EAE models, suggesting that blueberries, which are easily administered orally and well-tolerated, may provide benefit to MS patients.
    Journal of Agricultural and Food Chemistry 02/2012; · 3.11 Impact Factor
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    ABSTRACT: The endogenous neurotransmitter noradrenaline (NA) plays several roles in maintaining brain homeostasis, including exerting anti-inflammatory and neuroprotective effects. The primary source of NA in the CNS are tyrosine hydroxylase (TH)-positive neurons located in the Locus coeruleus (LC) which send projections throughout the brain and spinal cord. We recently demonstrated that dysregulation of the LC:Noradrenergic system occurs in experimental autoimmune encephalomyelitis as well as in MS patients, associated with damage occurring to LC neurons. Vindeburnol, a structural analog of the cerebral vasodilator vincamine, was previously reported to increase TH expression and activity in LC neurons. Female C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein (MOG)(35-55) peptide, and treated with vindeburnol at the first appearance of clinical signs. Clinical signs continued to increase for about 1 week, at which point mice in the vehicle group continued to worsen while vindeburnol-treated mice showed improvement. Pro-inflammatory cytokine production from splenic T cells was not reduced by vindeburnol suggesting primarily central actions of treatment. In the cerebellum, vindeburnol decreased astrocyte activation and reduced the number of demyelinated regions. Vindeburnol reduced astrocyte activation in the LC, reduced TH+ neuronal hypertrophy, increased expression of several genes involved in LC survival and maturation, and increased NA levels in the spinal cord. These results suggest that treatments with drugs such as vindeburnol which target LC survival or function could be of benefit in MS patients.
    Journal of Neurochemistry 01/2012; 121(2):206-16. · 3.97 Impact Factor
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    ABSTRACT: Damage to noradrenergic neurons in the locus coeruleus (LC) is a hallmark of Alzheimer's disease (AD) and may contribute to disease progression. In 5xFAD transgenic mice, which accumulate amyloid burden at early ages, the LC undergoes stress as evidenced by increased astrocyte activation, neuronal hypertrophy, reduced levels of LC-enriched messenger RNAs (mRNAs), and increased inflammatory gene expression. Central nervous system (CNS) noradrenaline (NA) levels in 5-month-old male 5xFAD mice were increased using the NA precursor L-threo-3,4-dihydroxyphenylserine (L-DOPS). After 1 month, L-DOPS treatment improved learning in the Morris water maze test compared with vehicle-treated mice. L-DOPS increased CNS NA levels, and average latency times in the water maze test were inversely correlated to NA levels. L-DOPS reduced astrocyte activation and Thioflavin-S staining; increased mRNA levels of neprilysin and insulin degrading enzyme, and of several neurotrophins; and increased brain-derived neurotrophic factor protein levels. These data demonstrate the presence of LC stress in a robust mouse model of AD, and suggest that raising CNS NA levels could provide benefit in AD.
    Neurobiology of aging 06/2011; 33(8):1651-63. · 5.94 Impact Factor
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    ABSTRACT: The authors tested whether cocaine depresses mitochondrial acylcarnitine exchange and if a drug that enhances glucose metabolism could protect against cocaine-induced cardiac dysfunction. Oxygen consumption with and without cocaine was compared in rat cardiac mitochondria using octanoylcarnitine (lipid) or pyruvate (nonlipid) substrates. Isolated hearts from rats with or without a pioglitazone-supplemented diet were exposed to cocaine. The 0.5 mM cocaine inhibited respiration supported by octanoylcarnitine (82 ± 10.4 and 45.7 ± 4.24 ngatomO min⁻¹ · mg⁻¹ · protein ± SEM, for control and cocaine treatment, respectively; P < 0.02) but not pyruvate-supported respiration (281 ± 12.5 and 267 ± 12.7 ngatomO min⁻¹ · mg⁻¹ · protein ± SEM; P = 0.45). Cocaine altered contractility, lusitropy, coronary resistance, and lactate production in isolated heart. These effects were each blunted in pioglitazone-treated hearts. The pioglitazone diet attenuated the drop in the rate-pressure product (P = 0.002), cocaine-induced diastolic dysfunction (P = 0.04), and myocardial vascular resistance (P = 0.05) compared with that of controls. Lactate production was higher in pretreated hearts (P = 0.008) and in ventricular myocytes cultured with pioglitazone (P = 0.0001). Cocaine inhibited octanoylcarnitine-supported mitochondrial respiration. A pioglitazone diet significantly attenuated the effects of cocaine on isolated heart. The authors postulate that inhibition of acylcarnitine exchange could contribute to cocaine-induced cardiac dysfunction and that metabolic modulation warrants additional study.
    Anesthesiology 06/2011; 114(6):1389-95. · 5.16 Impact Factor
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    ABSTRACT: Cyclic GMP (cGMP)-mediated pathways regulate inflammatory responses in immune and CNS cells. Recently, cGMP phosphodiesterase inhibitors such as sildenafil, commonly used to treat sexual dysfunction in humans including multiple sclerosis (MS) patients, have been reported to be neuroprotective in animal models of stroke, Alzheimer's disease, and focal brain lesion. In this work, we have examined if sildenafil ameliorates myelin oligodendrocyte glycoprotein peptide (MOG₃₅₋₅₅)-induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We show for the first time that treatment with sildenafil after disease onset markedly reduces the clinical signs of EAE by preventing axonal loss and promoting remyelination. Furthermore, sildenafil decreases CD3+ leukocyte infiltration and microglial/macrophage activation in the spinal cord, while increasing forkhead box transcription factor 3-expressing T regulatory cells (Foxp3 Tregs). However, sildenafil treatment did not significantly affect MOG₃₅₋₅₅-stimulated proliferation or release of Th1/Th2 cytokines in splenocytes but decreased ICAM-1 in spinal cord infiltrated cells. The presence of reactive astrocytes forming scar-like structures around infiltrates was enhanced by sildenafil suggesting a possible mechanism for restriction of leukocyte spread into healthy parenchyma. These results highlight novel actions of sildenafil that may contribute to its beneficial effects in EAE and suggest that treatment with this widely used and well-tolerated drug may be a useful therapeutic intervention to ameliorate MS neuropathology.
    Acta Neuropathologica 04/2011; 121(4):499-508. · 9.73 Impact Factor
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    ABSTRACT: DMF (dimethyl fumarate) exerts anti-inflammatory and pro-metabolic effects in a variety of cell types, and a formulation (BG-12) is being evaluated for monotherapy in multiple sclerosis patients. DMF modifies glutathione (GSH) levels that can induce expression of the anti-inflammatory protein HO-1 (haem oxygenase-1). In primary astrocytes and C6 glioma cells, BG-12 dose-dependently suppressed nitrite production induced by either LI [LPS (lipopolysaccharide) at 1 μg/ml plus IFNγ (interferon γ) at 20 units/ml] or a mixture of pro-inflammatory cytokines, with greater efficacy in C6 cells. BG-12 reduced NOS2 (nitric oxide synthase 2) mRNA levels and activation of a NOS2 promoter, reduced nuclear levels of NF-κB (nuclear factor κB) p65 subunit and attenuated loss of IκBα (inhibitory κBα) in both cell types, although with greater effects in astrocytes. In astrocytes, LI decreased mRNA levels for GSHr (GSH reductase) and GCL (c-glutamylcysteine synthetase), and slightly suppressed GSHs (GSH synthetase) mRNAs. Co-treatment with BG-12 prevented those decreased and increased levels above control values. In contrast, LI reduced GSHp (GSH peroxidase) and GCL in C6 cells, and BG-12 had no effect on those levels. BG-12 increased nuclear levels of Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2), an inducer of GSH-related enzymes, in astrocytes but not C6 cells. In astrocytes, GSH was decreased by BG-12 at 2 h and increased at 24 h. Prior depletion of GSH using buthionine-sulfoximine increased the ability of BG-12 to reduce nitrites. In astrocytes, BG-12 increased HO-1 mRNA levels and effects on nitrite levels were blocked by an HO-1 inhibitor. These results demonstrate that BG-12 suppresses inflammatory activation in astrocytes and C6 glioma cells, but with distinct mechanisms, different dependence on GSH and different effects on transcription factor activation.
    ASN Neuro 03/2011; 3(2). · 3.64 Impact Factor
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    Paul E Polak, Sergey Kalinin, Douglas L Feinstein
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    ABSTRACT: The endogenous neurotransmitter noradrenaline exerts anti-inflammatory and neuroprotective effects in vitro and in vivo. Several studies report that noradrenaline levels are altered in the central nervous system of patients with multiple sclerosis and rodents with experimental autoimmune encephalomyelitis, which could contribute to pathology. Since the major source of noradrenaline are neurons in the locus coeruleus, we hypothesized that alterations in noradrenaline levels are a consequence of stress or damage to locus coeruleus neurons. In C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein peptide 35-55 to develop chronic disease, cortical and spinal cord levels of noradrenaline were significantly reduced versus control mice. Immunohistochemical staining revealed increased astrocyte activation in the ventral portion of the locus coeruleus in immunized mice. The immunized mice showed neuronal damage in the locus coeruleus detected by a reduction of average cell size of tyrosine hydroxylase stained neurons. Analysis of the locus coeruleus of multiple sclerosis and control brains showed a significant increase in astrocyte activation, a reduction in noradrenaline levels, and neuronal stress indicated by hypertrophy of tyrosine hydroxylase stained cell bodies. However, the magnitude of these changes was not correlated with extent of demyelination or of cellular infiltrates. Together these findings demonstrate the presence of inflammation and neuronal stress in multiple sclerosis as well as in experimental autoimmune encephalomyelitis. Since reduced noradrenaline levels could be permissive for increased inflammation and neuronal damage, these results suggest that methods to raise noradrenaline levels or increase locus coeruleus function may be of benefit in treating multiple sclerosis.
    Brain 02/2011; 134(Pt 3):665-77. · 10.23 Impact Factor

Publication Stats

6k Citations
605.51 Total Impact Points

Institutions

  • 2005–2014
    • Jesse Brown VA Medical Center
      Chicago, Illinois, United States
  • 1998–2014
    • University of Illinois at Chicago
      • • Department of Anesthesiology (Chicago)
      • • Department of Physiology and Biophysics (Chicago)
      Chicago, Illinois, United States
  • 2009
    • Pennsylvania State University
      University Park, Maryland, United States
    • Complutense University of Madrid
      • Departamento de Farmacología
      Madrid, Madrid, Spain
  • 2008
    • Rush University Medical Center
      • Department of Neurosurgery
      Chicago, IL, United States
  • 2006
    • Case Western Reserve University
      • Department of Neurosciences
      Cleveland, OH, United States
  • 1992–2006
    • Cornell University
      • Department of Neurology and Neuroscience
      Ithaca, NY, United States
  • 2004
    • Autonomous University of Barcelona
      Cerdanyola del Vallès, Catalonia, Spain
    • Kern Medical Center
      Bakersfield, California, United States
  • 2000–2004
    • University of Bonn
      • Department of Neurobiology
      Bonn, North Rhine-Westphalia, Germany
  • 1991–1992
    • The Scripps Research Institute
      • Department of Cell and Molecular Biology
      La Jolla, California, United States
  • 1989
    • University of Pennsylvania
      Philadelphia, Pennsylvania, United States