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1.
Sci Rep ; 8(1): 9392, 2018 06 20.
Article in English | MEDLINE | ID: mdl-29925848

ABSTRACT

In multiple sclerosis (MS), demyelinated CNS lesions fail to sufficiently remyelinate, despite the presence of oligodendrocyte precursor cells (OPCs) capable of differentiating into mature oligodendrocytes. MS lesions contain damaged myelin debris that can inhibit OPC maturation and hinder repair. rHIgM22 is an experimental human recombinant IgM antibody that promotes remyelination in animal models and is being examined in patients with MS. rHIgM22 binds to CNS myelin and partially rescues OPC process outgrowth on myelin. Since rHIgM22 does not affect OPC process outgrowth in vitro on permissive substrate, we examined the possibility that it acts by enhancing phagocytic clearance of myelin debris by microglia. In this study, we tested if rHIgM22 binding could tag myelin for microglial phagocytosis. A mouse microglial cell line and primary rat microglia were treated with myelin and rHIgM22 and assayed for myelin phagocytosis. We found that: 1) rHIgM22 stimulates myelin phagocytosis in a dose-dependent manner; 2) rHIgM22-mediated myelin phagocytosis requires actin polymerization; and 3) rHIgM22-stimulation of myelin phagocytosis requires activity of rHIgM22 Fc domain and activation of Complement Receptor 3. Since myelin inhibits OPC differentiation, stimulation of phagocytic clearance of damaged myelin may be an important means by which rHIgM22 promotes remyelination.


Subject(s)
Antibodies/immunology , Antibodies/metabolism , Immunoglobulin M/immunology , Microglia/cytology , Microglia/metabolism , Myelin Sheath/metabolism , Animals , Cell Differentiation/physiology , Cell Line , Cells, Cultured , Humans , Mice , Phagocytes/cytology , Phagocytes/metabolism , Phagocytosis/physiology , Rats
2.
Eur J Pharmacol ; 796: 76-89, 2017 Feb 05.
Article in English | MEDLINE | ID: mdl-27993643

ABSTRACT

Neuregulins are important growth factors involved in cardiac development and response to stress. Certain isoforms and fragments of neuregulin have been found to be cardioprotective. The effects of a full-length neuregulin-1ß isoform, glial growth factor 2 (GGF2; USAN/INN; also called cimaglermin) were investigated in vitro. Various dosing regimens were then evaluated for their effects on left ventricular (LV) function in rats with surgically-induced myocardial infarction. In vitro, GGF2 bound with high affinity to erythroblastic leukemia viral oncogene (ErbB) 4 receptors, potently promoted Akt phosphorylation, as well as reduced cell death following doxorubicin exposure in HL1 cells. Daily GGF2 treatment beginning 7-14 days after left anterior descending coronary artery ligation produced improvements in LV ejection fraction and other measures of LV function and morphology. The improvements in LV function (e.g. 10% point increase in absolute LV ejection fraction) with GGF2 were dose-dependent. LV performance was substantially improved when GGF2 treatment was delivered infrequently, despite a serum half-life of less than 2h and could be maintained for more than 10 months with treatment once weekly or once every 2 weeks. These studies confirm previous findings that GGF2 may improve contractile performance in the failing rat heart and that infrequent exposure to GGF2 may improve LV function and impact remodeling in the failing myocardium. GGF2 is now being developed for the treatment of heart failure in humans.


Subject(s)
Heart Ventricles/drug effects , Myocardial Infarction/physiopathology , Neuregulin-1/pharmacology , Ventricular Dysfunction/drug therapy , Amino Acid Sequence , Animals , CHO Cells , Cricetinae , Cricetulus , Cytoprotection/drug effects , Doxorubicin/adverse effects , Drug Administration Schedule , Heart Failure/complications , Humans , Mice , Myocardial Infarction/complications , Neuregulin-1/administration & dosage , Neuregulin-1/chemistry , Neuregulin-1/metabolism , Rats , Receptor, ErbB-4/metabolism
3.
J Neurotrauma ; 34(3): 685-694, 2017 02.
Article in English | MEDLINE | ID: mdl-27503053

ABSTRACT

Magnesium (Mg2+) homeostasis is impaired following spinal cord injury (SCI) and the loss of extracellular Mg2+ contributes to secondary injury by various mechanisms, including glutamate neurotoxicity. The neuroprotective effects of high dose Mg2+ supplementation have been reported in many animal models. Recent studies found that lower Mg2+ doses also improved neurologic outcomes when Mg2+ was formulated with polyethylene glycol (PEG), suggesting that a PEG/ Mg2+ formulation might increase Mg2+ delivery to the injured spinal cord, compared with that of MgSO4 alone. Here, we assessed spinal extracellular Mg2+ and glutamate levels following SCI in rats using microdialysis. Basal levels of extracellular Mg2+ (∼0.5 mM) were significantly reduced to 0.15 mM in the core and 0.12 mM in the rostral peri-lesion area after SCI. A single intravenous infusion of saline or of MgSO4 at 192 µmoL/kg did not significantly change extracellular Mg2+ concentrations. However, a single infusion of AC105 (a MgCl2 in PEG) at an equimolar Mg2+ dose significantly increased the Mg2+ concentration to 0.3 mM (core area) and 0.25 mM (rostral peri-lesion area). Moreover, multiple AC105 treatments completely restored the depleted extracellular Mg2+ concentrations after SCI to levels in the uninjured spinal cord. Repeated MgSO4 infusions slightly increased the Mg2+ concentrations while saline infusion had no effect. In addition, AC105 treatment significantly reduced extracellular glutamate levels in the lesion center after SCI. These results indicate that intravenous infusion of PEG-formulated Mg2+ normalized the Mg2+ homeostasis following SCI and reduced potentially neurotoxic glutamate levels, consistent with a neuroprotective mechanism of blocking excitotoxicity.


Subject(s)
Drug Delivery Systems/methods , Extracellular Fluid/metabolism , Glutamic Acid/metabolism , Magnesium Sulfate/administration & dosage , Polyethylene Glycols/administration & dosage , Spinal Cord Injuries/metabolism , Animals , Excitatory Amino Acid Agonists , Extracellular Fluid/drug effects , Female , Infusions, Intravenous , Magnesium Sulfate/metabolism , Microdialysis/methods , Polyethylene Glycols/metabolism , Rats , Rats, Long-Evans , Spinal Cord Injuries/drug therapy , Thoracic Vertebrae
4.
J Neurotrauma ; 33(24): 2202-2216, 2016 12 15.
Article in English | MEDLINE | ID: mdl-27125815

ABSTRACT

A porcine model of spinal cord injury (SCI) was used to evaluate the neuroprotective effects of magnesium chloride (MgCl2) within a polyethylene glycol (PEG) formulation, called "AC105" (Acorda Therapeutics Inc., Ardsley, NY). Specifically, we tested the hypothesis that AC105 would lead to greater tissue sparing at the injury site and improved behavioral outcome when delivered in a clinically realistic time window post-injury. Four hours after contusion/compression injury, Yucatan minipigs were randomized to receive a 30-min intravenous infusion of AC105, magnesium sulfate (MgSO4), or saline. Animals received 4 additional infusions of the same dose at 6-h intervals. Behavioral recovery was tested for 12 weeks using two-dimensional (2D) kinematics during weight-supported treadmill walking and the Porcine Injury Behavior Scale (PTIBS), a 10-point locomotion scale. Spinal cords were evaluated ex vivo by diffusion-weighted magnetic resonance imaging (MRI) and subjected to histological analysis. Treatment with AC105 or MgSO4 did not result in improvements in locomotor recovery on the PTIBS or in 2D kinematics on weight-supported treadmill walking. Diffusion weighted imaging (DWI) showed severe loss of tissue integrity at the impact site, with decreased fractional anisotropy and increased mean diffusivity; this was not improved with AC105 or MgSO4 treatment. Histological analysis revealed no significant increase in gray or white matter sparing with AC105 or MgSO4 treatment. Finally, AC105 did not result in higher Mg2+ levels in CSF than with the use of standard MgSO4. In summary, when testing AC105 in a porcine model of SCI, we were unable to reproduce the promising therapeutic benefits observed previously in less-severe rodent models of SCI.


Subject(s)
Disease Models, Animal , Magnesium Chloride/administration & dosage , Polyethylene Glycols/administration & dosage , Spinal Cord Injuries/diagnostic imaging , Spinal Cord Injuries/prevention & control , Acute Disease , Animals , Drug Compounding , Drug Evaluation, Preclinical/methods , Female , Locomotion/drug effects , Locomotion/physiology , Magnesium Chloride/chemistry , Polyethylene Glycols/chemistry , Random Allocation , Recovery of Function/drug effects , Recovery of Function/physiology , Spinal Cord Injuries/physiopathology , Swine , Swine, Miniature , Thoracic Vertebrae
5.
J Pharmacol Exp Ther ; 350(2): 455-68, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24917542

ABSTRACT

Both preclinical evidence and clinical evidence suggest that α7 nicotinic acetylcholine receptor activation (α7nAChR) improves cognitive function, the decline of which is associated with conditions such as Alzheimer's disease and schizophrenia. Moreover, allosteric modulation of α7nAChR is an emerging therapeutic strategy in an attempt to avoid the rapid desensitization properties associated with the α7nAChR after orthosteric activation. We used a calcium assay to screen for positive allosteric modulators (PAMs) of α7nAChR and report on the pharmacologic characterization of the novel compound RO5126946 (5-chloro-N-[(1S,3R)-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide), which allosterically modulates α7nAChR activity. RO5126946 increased acetylcholine-evoked peak current and delayed current decay but did not affect the recovery of α7nAChRs from desensitization. In addition, RO5126946's effects were absent when nicotine-evoked currents were completely blocked by coapplication of the α7nAChR-selective antagonist methyl-lycaconitine. RO5126946 enhanced α7nAChR synaptic transmission and positively modulated GABAergic responses. The absence of RO5126946 effects at human α4ß2nAChR and 5-hydroxytryptamine 3 receptors, among others, indicated selectivity for α7nAChRs. In vivo, RO5126946 is orally bioavailable and brain-penetrant and improves associative learning in a scopolamine-induced deficit model of fear conditioning in rats. In addition, procognitive effects of RO5126946 were investigated in the presence of nicotine to address potential pharmacologic interactions on behavior. RO5126946 potentiated nicotine's effects on fear memory when both compounds were administered at subthreshold doses and did not interfere with procognitive effects observed when both compounds were administered at effective doses. Overall, RO5126946 is a novel α7nAChR PAM with cognitive-enhancing properties.


Subject(s)
Benzamides/pharmacology , Sulfonamides/pharmacology , alpha7 Nicotinic Acetylcholine Receptor/drug effects , Allosteric Regulation , Animals , Cells, Cultured , Cognition/drug effects , Hippocampus/drug effects , Humans , Learning/drug effects , Male , Memory/drug effects , Nicotine/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/physiology , Receptors, Glutamate/physiology
6.
ChemMedChem ; 4(5): 706-18, 2009 May.
Article in English | MEDLINE | ID: mdl-19330784

ABSTRACT

Controlled variation in intracellular calcium concentration is a key component of the immune response signaling pathway in lymphocytes. Store-operated calcium entry (SOCE) in these cells provides a prolonged increase in cytoplasmic Ca(2+) concentrations and ultimately leads to the production of pro-inflammatory cytokines. Molecules that inhibit SOCE could therefore be useful immunomodulating agents for the treatment of rheumatoid arthritis, psoriasis, inflammatory bowel disease, and other conditions. Although the presence of the SOCE signaling pathway in lymphocytes and other cells involved in the immune response has been known for many years, key proteins involved in SOCE were identified only recently. The identification of these proteins may further enable the identification of agents that inhibit SOCE without affecting other cellular processes. This contribution documents representative examples of the small-molecule inhibitors of SOCE that have been reported to date. Where possible, methods that were used to characterize the mechanism of action of the inhibitors are also described.


Subject(s)
Calcium Channel Blockers/chemistry , Calcium/metabolism , Animals , Calcineurin/metabolism , Calcineurin Inhibitors , Calcium Channel Blockers/pharmacology , Calcium Channels/physiology , Calcium Signaling , Humans , Immunologic Factors/chemistry , Immunologic Factors/pharmacology , Mice , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/metabolism , Rats
7.
Eur Neuropsychopharmacol ; 19(7): 466-75, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19223157

ABSTRACT

Neurotensin (NT) is a neuropeptide implicated in the pathophysiology of schizophrenia and in mediating the efficacy of antipsychotic drugs. NT is also involved in the regulation of body temperature and pain sensitivity. Using neurotensin receptor 1 (NTR1) knockout (KO) and wild-type (WT) mice, these studies evaluated the involvement of NTR1 in the behavioral responses produced by peripheral administration of NT agonists (NT-2 and NT69L). Animals were characterized in paradigms designed to assess hypothermia, antinociception, and antipsychotic-like effects. Under basal conditions, there were no phenotypic differences between NTR1 KO and WT mice. In WT mice, both NTR1 agonists decreased core body temperature (active doses in mg/kg, i.p., for NT-2 and NT69L, respectively: 1 and 3), increased tail withdrawal latencies (1 and 3), produced decreased spontaneous climbing (0.1, 0.3, 1 and 1, 3, 10) and reversed apomorphine-induced climbing (0.3, 1 and 1, 3). In contrast, none of the effects of either agonist were present in KO mice. These results suggest that NTR1: (1) does not play a major role in the control of basal thermoregulation, nociception or psychomotor stimulation in mice (barring possible developmental plasticity), (2) does mediate these behavioral responses to NT agonists, and (3) may play a role in the potential antipsychotic effects of these agonists.


Subject(s)
Behavior, Animal/drug effects , Body Temperature/drug effects , Neurotensin/analogs & derivatives , Neurotensin/agonists , Oligopeptides/pharmacology , Peptide Fragments/pharmacology , Receptors, Neurotensin/metabolism , Analysis of Variance , Animals , Apomorphine/pharmacology , Binding, Competitive/drug effects , Dopamine Agonists/pharmacology , Dose-Response Relationship, Drug , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/drug effects , Neurotensin/pharmacology , Pain/drug therapy , Protein Binding/drug effects , RNA, Messenger/metabolism , Radioligand Assay , Reaction Time/drug effects , Receptors, Neurotensin/deficiency , Receptors, Neurotensin/genetics , Reflex, Startle/drug effects
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