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1.
Front Immunol ; 12: 624685, 2021.
Article in English | MEDLINE | ID: mdl-33679769

ABSTRACT

Antigen-specific therapy for multiple sclerosis may lead to a more effective therapy by induction of tolerance to a wide range of myelin-derived antigens without hampering the normal surveillance and effector function of the immune system. Numerous attempts to restore tolerance toward myelin-derived antigens have been made over the past decades, both in animal models of multiple sclerosis and in clinical trials for multiple sclerosis patients. In this review, we will give an overview of the current approaches for antigen-specific therapy that are in clinical development for multiple sclerosis as well provide an insight into the challenges for future antigen-specific treatment strategies for multiple sclerosis.


Subject(s)
Adoptive Transfer , Desensitization, Immunologic , Multiple Sclerosis/therapy , Myelin Proteins/administration & dosage , Peptide Fragments/administration & dosage , Vaccination , Vaccines/therapeutic use , Adoptive Transfer/adverse effects , Adoptive Transfer/history , Adoptive Transfer/trends , Animals , Autoimmunity , Desensitization, Immunologic/adverse effects , Desensitization, Immunologic/history , Desensitization, Immunologic/trends , Diffusion of Innovation , Forecasting , History, 20th Century , History, 21st Century , Humans , Immune Tolerance , Multiple Sclerosis/history , Multiple Sclerosis/immunology , Multiple Sclerosis/metabolism , Myelin Proteins/adverse effects , Myelin Proteins/immunology , Myelin Proteins/metabolism , Peptide Fragments/adverse effects , Peptide Fragments/immunology , Peptide Fragments/metabolism , Vaccination/adverse effects , Vaccination/history , Vaccination/trends , Vaccines/adverse effects
2.
Neurosci Lett ; 725: 134872, 2020 04 23.
Article in English | MEDLINE | ID: mdl-32112820

ABSTRACT

BACKGROUND: Studies have demonstrated that the failure of oligodendrocyte precursor cells (OPCs) differentiation as a major cause of remyelination failure in demyelinating disease. The reasons for this failure are not completely understood. We hypothesized that the present of myelin debris in CNS play an important role in poor OPCs differentiation in the mouse model of demyelinating disease. METHODS: Mice were fed by the food mixed with normal or 0.2 % cuprizone (CPZ) for 6 weeks. Then the learning and memory impairment were tested by Morris water maze test. The spontaneous alternation behavior and depression-like symptoms were assessed by tail suspension test and open filed test. The number of OPCs and oligodendrocytes were counted by immunofluorescence. After exposed to CPZ for 6 weeks, the mice were then receiving stereotactic injection of NEP1-40 into the CA3 of hippocampus. The behavioral, learning and memory changes were assessed by tail suspension test and open field test. The differentiation of OPCs were detected by immunofluorescence and western blot. RESULTS: The mice in CPZ group are more likely to show signs of depression and they showed impairment of long-term learning and memory function. The differentiation of OPCs were impaired in CPZ group. We found that mice treated with NEP1-40 showed less depression-like symptom in TST and higher locomotor activity in the OFT than the mice treated with PBS. CONCLUSIONS: Our study suggest that NEP1-40 can promote OPC differentiation and survival. Further study should focus on the effect of NEP1-40 on the differentiation and survival of OPCs in vitro.


Subject(s)
Cell Differentiation/drug effects , Cuprizone/toxicity , Demyelinating Diseases/drug therapy , Hippocampus/drug effects , Myelin Proteins/administration & dosage , Oligodendrocyte Precursor Cells/drug effects , Peptide Fragments/administration & dosage , Animals , Cell Differentiation/physiology , Chelating Agents/toxicity , Demyelinating Diseases/chemically induced , Demyelinating Diseases/metabolism , Hippocampus/cytology , Hippocampus/metabolism , Male , Mice , Mice, Inbred C57BL , Oligodendrocyte Precursor Cells/metabolism , Phenotype , Stereotaxic Techniques
3.
Mol Neurobiol ; 54(10): 8321-8331, 2017 12.
Article in English | MEDLINE | ID: mdl-27921243

ABSTRACT

This study was intended to compare the therapeutic efficacies of NEP1-40 and SiNgR199 on treating spinal cord injury (SCI). Nogo-A, growth associated protein 43 (GAP-43), microtubule associated protein 2 (MAP-2), and amyloid ßA4 precursor protein (APP) expressions were determined using western blot and quantitative PCR. Neurite outgrowth detected the growth of neurites, and BDA anterograde tracing was used to label the regenerated axonal. Rats' behavior was assessed with Basso, Beattie, and Bresnahan locomotor rating scale (BBB). Somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) were recorded to evaluate the recovery of the sensory and motor systems. Successful establishment of SCI model was verified by immunocytochemical analysis. The increased expression of APP, as well as the decreased expression of GAP-43 and MAP-2, was observed in the SCI model group, but the trends were reversed after the treatments of NEP1-40, siNgR199, and NEP1-40 + siNgR199. Compared with the SCI group, the average neurite length and the BDA-positive fibers were increased in the NEP1-40, siNgR199, and NEP1-40 + siNgR199 groups. The rats in the siNgR199 group and the NEP1-40 + siNgR199 group both showed significantly higher BBB scores than SCI model group and NEP1-40 group. Suggested by electrophysiological evaluation, both the latency and the amplitude of SEPs as well as MEPs had recovered in the NEP1-40, siNgR199, and NEP1-40 + siNgR199 groups after SCI. Both NEP1-40 and siNgR had repairing effects on SCI, suggesting their role in facilitating axonal regeneration after SCI.


Subject(s)
Axons/physiology , Myelin Proteins/administration & dosage , Nerve Regeneration/physiology , Nogo Receptor 1/administration & dosage , Peptide Fragments/administration & dosage , RNA Interference , Spinal Cord Injuries/drug therapy , Animals , Axons/drug effects , Disease Models, Animal , Male , Nerve Regeneration/drug effects , RNA Interference/physiology , Random Allocation , Rats , Rats, Sprague-Dawley , Spinal Cord Injuries/pathology
4.
J Drug Target ; 24(1): 13-23, 2016.
Article in English | MEDLINE | ID: mdl-26061295

ABSTRACT

Therapeutics targeting the Nogo-A signal pathway hold promise to promote recovery following brain injury. Based on the temporal characteristics of Nogo-A expression in the process of cerebral ischemia and reperfusion, we tested a novel asynchronous treatment, in which TAT-M9 was used in the early stage to decrease neuronal loss, and TAT-NEP1-40 was used in the delayed stage to promote neurite outgrowth after bilateral common carotid artery occlusion (BCCAO) in mice. Both TAT-M9 and TAT-NEP1-40 were efficiently delivered into the brains of mice by intraperitoneal injection. TAT-M9 treatment promoted neuron survival and inhibited neuronal apoptosis. Asynchronous therapy with TAT-M9 and TAT-NEP1-40 increased the expression of Tau, GAP43 and MAP-2 proteins, and enhanced short-term and long-term cognitive functions. In conclusion, the asynchronous treatment had a long-term neuroprotective effect, which reduced neurologic injury and apoptosis, promoted neurite outgrowth and enhanced functional recovery after ischemia. It suggests that this asynchronous treatment could be a promising therapy for cerebral ischemia in humans.


Subject(s)
Brain Ischemia/physiopathology , Myelin Proteins/drug effects , Neuroprotective Agents/pharmacology , Peptide Fragments/pharmacology , tat Gene Products, Human Immunodeficiency Virus/pharmacology , Animals , Apoptosis/drug effects , Behavior Rating Scale , Cell Survival/drug effects , Disease Models, Animal , Drug Administration Schedule , GAP-43 Protein/metabolism , Male , Mice , Mice, Inbred C57BL , Microtubule-Associated Proteins/metabolism , Myelin Proteins/administration & dosage , Myelin Proteins/pharmacology , Neurites/drug effects , Nogo Proteins , Peptide Fragments/administration & dosage , Random Allocation , Reperfusion Injury/physiopathology , tat Gene Products, Human Immunodeficiency Virus/administration & dosage
5.
Biomed Mater ; 10(4): 045016, 2015 Aug 04.
Article in English | MEDLINE | ID: mdl-26238410

ABSTRACT

The adult mammalian central nervous system has limited ability to regenerate after injury. This is due, in part, to the presence of myelin-associated axon growth inhibitory proteins such as Nogo-A that bind and activate the Nogo receptor, leading to profound inhibition of actin-based motility within the growing axon tip. This paper presents an in vitro study of the use of a Nogo receptor-blocking peptide to antagonize the inhibitory effect of Nogo-A on axon growth. Alginate nanospheres were fabricated using an emulsion technique and loaded with Nogo receptor-blocking peptide, or with other model proteins. Protein release profiles were studied, and retention of the bioactivity of released proteins was verified. Primary dorsal root ganglion neurons were cultured and their ability to grow neurites was challenged with Nogo-A chimeric protein in the absence or presence of Nogo receptor antagonist peptide-loaded alginate nanospheres. Our results demonstrate that peptide released from alginate nanospheres could overcome the growth inhibitory effect of Nogo-A, suggesting that a similar peptide delivery strategy using alginate nanospheres might be used to improve axon regeneration within the injured central nervous system.


Subject(s)
Alginates/chemistry , Axons/physiology , Myelin Proteins/administration & dosage , Nanocapsules/chemistry , Nerve Regeneration/physiology , Peptides/administration & dosage , Animals , Axons/diagnostic imaging , Axons/drug effects , Cell Enlargement/drug effects , Cells, Cultured , Diffusion , Drug Interactions , Ganglia, Spinal/drug effects , Ganglia, Spinal/physiology , Ganglia, Spinal/ultrastructure , Glucuronic Acid/chemistry , Hexuronic Acids/chemistry , Male , Nanocapsules/ultrastructure , Nanospheres/chemistry , Nanospheres/ultrastructure , Nerve Regeneration/drug effects , Nogo Proteins , Peptides/chemistry , Rats , Rats, Sprague-Dawley , Ultrasonography
6.
J Control Release ; 213: 103-111, 2015 Sep 10.
Article in English | MEDLINE | ID: mdl-26122130

ABSTRACT

Myelin-associated inhibitors (MAIs) and chondroitin sulfate proteoglycans (CSPGs) are major contributors to axon growth inhibition following spinal cord injury and limit functional recovery. The NEP1-40 peptide competitively binds the Nogo receptor and partially blocks inhibition from MAIs, while chondroitinase ABC (ChABC) enzymatically digests CSPGs, which are upregulated at the site of injury. In vitro studies showed that the combination of ChABC and NEP1-40 increased neurite extension compared to either treatment alone when dissociated embryonic dorsal root ganglia were seeded onto inhibitory substrates containing both MAIs and CSPGs. Furthermore, the ability to provide sustained delivery of biologically active ChABC and NEP1-40 from biomaterial scaffolds was achieved by loading ChABC into lipid microtubes and NEP1-40 into poly (lactic-co-glycolic acid) (PLGA) microspheres, obviating the need for invasive intrathecal pumps or catheters. Fibrin scaffolds embedded with the drug delivery systems (PLGA microspheres and lipid microtubes) were capable of releasing active ChABC for up to one week and active NEP1-40 for over two weeks in vitro. In addition, the loaded drug delivery systems in fibrin scaffolds decreased CSPG deposition and development of a glial scar, while also increasing axon growth after spinal cord injury in vivo. Therefore, the sustained, local delivery of ChABC and NEP1-40 within the injured spinal cord may block both myelin and CSPG-associated inhibition and allow for improved axon growth.


Subject(s)
Chondroitin ABC Lyase/administration & dosage , Delayed-Action Preparations/chemistry , Drug Delivery Systems/methods , Myelin Proteins/administration & dosage , Peptide Fragments/administration & dosage , Spinal Cord Injuries/drug therapy , Tissue Scaffolds/chemistry , Animals , Chickens , Chondroitin ABC Lyase/therapeutic use , Female , Fibrin/chemistry , Lactic Acid/chemistry , Myelin Proteins/therapeutic use , Neurogenesis/drug effects , Peptide Fragments/therapeutic use , Polyglycolic Acid/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer , Rats, Long-Evans , Spinal Cord Injuries/metabolism , Spinal Cord Injuries/pathology
7.
J Neurotrauma ; 31(24): 1955-66, 2014 Dec 15.
Article in English | MEDLINE | ID: mdl-24964223

ABSTRACT

Axonal growth and neurological recovery after traumatic spinal cord injury (SCI) is limited by the presence of inhibitory proteins in myelin, several of which act via the NgR1 protein in neurons. A truncated soluble ligand-binding fragment of NgR1 serves as a decoy and promotes recovery in acute and chronic rodent SCI models. To develop the translational potential of these observations, we created a human sequence-derived NgR1(310)-Fc protein. This protein is active in vitro. When the human NgR1 decoy is administered by continuous intracerebroventricular infusion to rats with a spinal contusion injury at doses of 0.09-0.53 mg/kg/d, neurological recovery is improved. Effective doses double the percentage of rats able to bear weight on their hindlimbs. Next, we considered the half-life and distribution of NgR1(310)-Fc after bolus delivery to the lumbar intrathecal space. The protein is found throughout the neuraxis and has a tissue half-life of approximately 2 days in the rat, and 5 days in the nonhuman primate. At an intermittent, once every 4 day, lumbar bolus dosing schedule of 0.14 mg/kg/d, NgR1(310)-Fc promoted locomotor rat recovery from spinal cord contusion at least as effectively as continuous infusion in open field and grid walking tasks. Moreover, the intermittent lumbar NgR1(310)-Fc treatment increased the growth of raphespinal axons into the lumbar spinal cord after injury. Thus, human NgR1(310)-Fc provides effective treatment for recovery from traumatic SCI in this preclinical model with a simplified administration regimen that facilitates clinical testing.


Subject(s)
Myelin Proteins/administration & dosage , Neuroprotective Agents/administration & dosage , Receptors, Cell Surface/administration & dosage , Receptors, Fc/administration & dosage , Recovery of Function/drug effects , Spinal Cord Injuries/drug therapy , Animals , Disease Models, Animal , Female , GPI-Linked Proteins/administration & dosage , Humans , Injections, Spinal , Nogo Receptor 1 , Rats , Rats, Sprague-Dawley , Recombinant Proteins/administration & dosage
8.
Neurobiol Dis ; 58: 270-80, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23811498

ABSTRACT

Nogo receptor 1 (NgR1) mediates the inhibitory effects of several myelin-associated inhibitors (MAIs) on axonal regeneration in the central nervous system. A truncated soluble NgR1 (sNgR) has been reported to act as a decoy receptor to block the actions of MAIs. In this study, we fused the sNgR to nerve growth factor (NGF) and used NGF as a carrier to deliver sNgR to the intercellular space to neutralize MAIs. NGF in NGF-sNgR remained biologically active and induced sprouting of calcitonin gene related peptide containing axons when expressed in the spinal cord using a lentiviral vector (LV). Secreted NGF-sNgR promoted neurite outgrowth of dissociated dorsal root ganglion neurons on myelin protein substrate. In a rat dorsal column transection model, regenerating sensory axons were found to grow into the lesion cavity in animals injected with LV/NGF-sNgR, while in animals injected with LV/GFP or LV/NGF-GFP few sensory axons entered the lesion cavity. The results indicate that NGF-sNgR fusion protein can reduce the inhibition of MAIs and facilitate sensory axon regeneration. The fusion constructs may be modified to target other molecules to promote axonal regeneration and the concept may also be adapted to develop gene therapy strategies to treat other disorders.


Subject(s)
Axons/drug effects , Lentivirus/physiology , Myelin Proteins/administration & dosage , Nerve Growth Factor/metabolism , Nerve Regeneration/drug effects , Spinal Cord Injuries/therapy , Animals , Axons/physiology , Calcitonin Gene-Related Peptide/metabolism , Cell Differentiation/drug effects , Disease Models, Animal , Gene Expression Regulation/drug effects , Lentivirus/genetics , Male , Myelin Basic Protein/metabolism , Myelin Proteins/biosynthesis , Nerve Growth Factor/biosynthesis , Nerve Regeneration/physiology , Neurites/drug effects , Nogo Proteins , PC12 Cells , Rats , Rats, Wistar , Recombinant Fusion Proteins/administration & dosage , Serotonin/metabolism , Spinal Cord Injuries/complications
9.
Genet Mol Res ; 10(4): 2987-95, 2011 Nov 29.
Article in English | MEDLINE | ID: mdl-22180032

ABSTRACT

The hypoxic-ischemic encephalopathy caused by peripartum asphyxia is a serious disease in newborn infants, and effective therapies need to be developed to reduce injury-related disorders. We evaluated the effects of NEP1-40 and fasudil on Nogo-A expression in neonatal hypoxic-ischemic brain damage (HIBD) rats. Seven-day-old Wistar rats were randomly divided into control, HIBD, NEP1-40, and fasudil groups. NEP1-40 and fasudil groups were injected intraperitoneally with these compounds. Rat brains at 6, 24, 72 h, and 7 days after HIBD were collected to determine histopathological damage and the expression levels of Nogo-A. Histopathological damage was reduced in NEP1-40 and fasudil groups compared with the untreated HIBD group. The expression of Nogo-A in the HIBD group was significantly higher than that in control, NEP1-40 and fasudil groups at the same times. Compared with the fasudil group, the expression levels of Nogo-A were significantly reduced in the NEP1-40 group. We conclude that NPE1-40 and fasudil have potential for neuroprotective effects in the neonatal rat HIBD model, mediated by inhibiting Nogo-A/ Rho pathways.


Subject(s)
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives , Brain/drug effects , Hypoxia-Ischemia, Brain/prevention & control , Myelin Proteins/biosynthesis , Myelin Proteins/therapeutic use , Neuroprotective Agents/therapeutic use , Peptide Fragments/therapeutic use , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/administration & dosage , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/therapeutic use , Animals , Animals, Newborn , Brain/metabolism , Brain/pathology , Carotid Arteries/drug effects , Carotid Arteries/metabolism , Carotid Arteries/pathology , Female , Gene Expression/drug effects , Hypoxia-Ischemia, Brain/genetics , Hypoxia-Ischemia, Brain/metabolism , Hypoxia-Ischemia, Brain/pathology , Immunohistochemistry , In Situ Hybridization , Injections, Intraperitoneal , Ligation/methods , Male , Myelin Proteins/administration & dosage , Myelin Proteins/genetics , Neurons/cytology , Neurons/drug effects , Neurons/metabolism , Neuroprotective Agents/administration & dosage , Nogo Proteins , Peptide Fragments/administration & dosage , Rats , Rats, Wistar
10.
J Autoimmun ; 37(4): 300-10, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21962567

ABSTRACT

Lymphnode swelling during immune responses is a transient, finely regulated tissue rearrangement, accomplished with the participation of the extracellular matrix. Here we show that murine and human reactive lymph nodes express SPARC in the germinal centres. Defective follicular dendritic cell networking in SPARC-deficient mice is accompanied by a severe delay in the arrangement of germinal centres and development of humoral autoimmunity, events that are linked to Th17 development. SPARC is required for the optimal and rapid differentiation of Th17 cells, accordingly we show delayed development of experimental autoimmune encephalomyelitis whose pathogenesis involves Th17. Not only host radioresistant cells, namely follicular dendritic cells, but also CD4(+) cells are the relevant sources of SPARC, in vivo. Th17 differentiation and germinal centre formation mutually depend on SPARC for a proper functional crosstalk. Indeed, Th17 cells can enter the germinal centres in SPARC-competent, but not SPARC-deficient, mice. In summary, SPARC optimizes the changes occurring in lymphoid extracellular matrix harboring complex interactions between follicular dendritic cells, B cells and Th17 cells.


Subject(s)
B-Lymphocytes/metabolism , Dendritic Cells, Follicular/metabolism , Encephalomyelitis, Autoimmune, Experimental/immunology , Extracellular Matrix/metabolism , Multiple Sclerosis/immunology , Osteonectin/metabolism , Th17 Cells/metabolism , Animals , Animals, Genetically Modified , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Cell Communication/genetics , Cell Differentiation/genetics , Dendritic Cells, Follicular/immunology , Dendritic Cells, Follicular/pathology , Disease Models, Animal , Disease Progression , Encephalomyelitis, Autoimmune, Experimental/chemically induced , Encephalomyelitis, Autoimmune, Experimental/genetics , Humans , Immunity, Humoral/genetics , Immunization , Mice , Mice, Inbred C57BL , Mice, Knockout , Myelin Proteins/administration & dosage , Myelin-Oligodendrocyte Glycoprotein , Osteonectin/genetics , Osteonectin/immunology , Th17 Cells/immunology , Th17 Cells/pathology
11.
Neurol India ; 59(4): 579-85, 2011.
Article in English | MEDLINE | ID: mdl-21891937

ABSTRACT

BACKGROUND AND AIMS: Studies have shown that administration of NEP1-40, a Nogo-66 receptor antagonist peptide, improves locomotor recovery in rats. We hypothesize that combining NEP1-40 with another promising therapy, neural stem cell transplantation, might further improve the degree of locomotor recovery. In the present study, we examined whether NEP1-40 combined with bone marrow stromal cells-derived neurospheres (BMSC-NSs) transplantation would produce synergistic effects on recovery. MATERIAL AND METHODS: Adult Sprague-Dawley rats were subjected to spinal cord injury (SCI) at the T10 vertebral level. Immediately after injury, rats were administrated NEP1-40 intrathecally for 4 weeks. BrdU-labeled BMSC-NSs (2×105 ) were transplanted into the injured site 7 days after SCI. Locomotor recovery was assessed for 10 weeks with BBB scoring. Animals were perfused transcardially 10 weeks after contusion, and histological examinations were performed. RESULTS: The combined therapy group showed statistically better locomotor recovery than the control group at 7 weeks of contusion. Neither of the two single-agent treatments improved locomotor function. The average area of the cystic cavity was significantly smaller in the combined therapy group than in the control group. Fluorescence microscopic analysis showed that NEP1-40 dramatically inhibited the formation of glial scar and promoted the axons penetration into the scar barrier. CONCLUSION: This study revealed that BMSC-NSs and NEP 1-40 exhibit synergistic effects on recovery in rat SCI. This may represent a potential new strategy for the treatment of SCI.


Subject(s)
Bone Marrow Transplantation/methods , Cicatrix/prevention & control , Myelin Proteins/administration & dosage , Peptide Fragments/administration & dosage , Recovery of Function/physiology , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/surgery , Analysis of Variance , Animals , Bone Marrow Cells/drug effects , Bone Marrow Cells/physiology , Bromodeoxyuridine/metabolism , Cell Differentiation/physiology , Cell Survival/drug effects , Cells, Cultured , Disease Models, Animal , Injections, Spinal , Locomotion/drug effects , Locomotion/physiology , Nerve Tissue Proteins/metabolism , Neuroglia/pathology , Rats , Rats, Sprague-Dawley , Spinal Cord Injuries/complications , Spinal Cord Injuries/pathology
12.
J Autoimmun ; 37(3): 228-41, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21752599

ABSTRACT

The respective roles of inflammatory and neurodegenerative processes in the pathology of multiple sclerosis (MS) and in its animal model experimental autoimmune encephalomyelitis (EAE) are controversial. Novel treatment strategies aim to operate within the CNS to induce neuroprotection and repair processes in addition to their anti-inflammatory properties. In this study we analyzed and compared the in situ pathological manifestations of EAE utilizing two different models, namely the relapsing-remitting PLP-induced and the chronic MOG-induced diseases. To characterize pathological changes, both transmission electron microscopy (TEM) and immunohistochemistry were employed. The effect of the approved MS drug glatiramer acetate (GA, Copaxone) on myelin damage/repair and on motor neuron loss/preservation was studied in both EAE models. Ultrastructural spinal cord analysis revealed multiple white matter damage foci, with different patterns in the two EAE models. Thus, the relapsing-remitting model was characterized mainly by widespread myelin damage and by remyelinating fibers, whereas in the chronic model axonal degeneration was more prevalent. Loss of lower motor neurons was manifested only in mice with chronic MOG-induced disease. In the GA-treated mice, smaller lesions, increased axonal density and higher prevalence of normal appearing axons were observed, as well as decreased demyelination and degeneration. Furthermore, quantitative analysis of the relative remyelination versus demyelination, provides for the first time evidence of significant augmentation of remyelination after GA treatment. The loss of motor neurons in GA-treated mice was also reduced in comparison to that of EAE untreated mice. These effects were obtained even when GA treatment was applied in a therapeutic schedule, namely after the appearance of clinical symptoms. Hence, the remyelination and neuronal preservation induced by GA are in support of the neuroprotective consequences of this treatment.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/pathology , Inflammation/pathology , Multiple Sclerosis, Relapsing-Remitting/pathology , Nerve Degeneration/prevention & control , Neuroprotective Agents/administration & dosage , Peptides/administration & dosage , Spinal Cord/pathology , Animals , Axons/drug effects , Axons/ultrastructure , Chronic Disease , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/chemically induced , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/immunology , Female , Glatiramer Acetate , Humans , Immunohistochemistry , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/immunology , Mice , Mice, Inbred C57BL , Microscopy, Electron, Transmission , Motor Neurons/drug effects , Motor Neurons/ultrastructure , Multiple Sclerosis, Relapsing-Remitting/chemically induced , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Multiple Sclerosis, Relapsing-Remitting/immunology , Myelin Proteins/administration & dosage , Myelin Proteins/adverse effects , Myelin Proteolipid Protein/administration & dosage , Myelin Proteolipid Protein/adverse effects , Myelin Sheath/drug effects , Myelin Sheath/ultrastructure , Myelin-Associated Glycoprotein/ultrastructure , Myelin-Oligodendrocyte Glycoprotein , Neuroprotective Agents/therapeutic use , Peptides/therapeutic use , Spinal Cord/drug effects , Spinal Cord/ultrastructure
13.
J Drug Target ; 19(2): 86-95, 2011 Feb.
Article in English | MEDLINE | ID: mdl-20367026

ABSTRACT

Currently available therapeutics has been less effective in promoting functional recovery from stroke or other injuries in the central nervous system (CNS). Axonal damage is a characteristic pathology seen in CNS injuries. Previously, it was reported that Nogo-A extracellular peptide residues 1-40 (NEP1-40), a competitive antagonist of Nogo-66 receptor (NgR1), has the ability to promote axonal regrowth and functional recovery after CNS injury. However, delivery of the therapeutic proteins into the brain parenchyma is limited due to its inability to cross the blood-brain barrier (BBB). We first generated a biologically active NEP1-40 fusion protein containing the protein transduction domain (PTD) of the transactivator of transcription (TAT), TAT-NEP1-40, which crosses the BBB in vivo after systemic delivery. The TAT-NEP1-40 can protect PC12 cells against oxygen and glucose deprivation (OGD) and promote neurite outgrowth when added exogenously to culture medium. The TAT-NEP1-40 protein transduced into the brain continued to sustain biological activities and protected the brain against ischemia/reperfusion injury through inhibition of neuronal apoptosis. Collectively, our data suggest that TAT-NEP1-40 may be a novel therapeutic candidate for axonal regeneration and functional recovery from CNS injuries such as cerebral hypoxia-ischemia, cerebral hemorrhage, brain trauma, and also for spinal cord injury.


Subject(s)
Gene Products, tat/administration & dosage , Myelin Proteins/administration & dosage , Peptide Fragments/administration & dosage , Stroke/drug therapy , Animals , Axons/drug effects , Axons/pathology , Drug Delivery Systems , GPI-Linked Proteins/drug effects , GPI-Linked Proteins/metabolism , Humans , Myelin Proteins/drug effects , Myelin Proteins/metabolism , Myelin Proteins/pharmacokinetics , Nerve Regeneration/drug effects , Nogo Receptor 1 , PC12 Cells , Peptide Fragments/pharmacokinetics , Rats , Receptors, Cell Surface/drug effects , Receptors, Cell Surface/metabolism , Recovery of Function , Stroke/pathology , Stroke Rehabilitation
15.
Ann Neurol ; 68(5): 593-601, 2010 Nov.
Article in English | MEDLINE | ID: mdl-21031576

ABSTRACT

OBJECTIVE: Antigen-specific therapy targeting selective inhibition of autoreactive responses holds promise for controlling multiple sclerosis (MS) without disturbing homeostasis of the whole immune system. Key autoantigens in MS include myelin proteins, such as myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG). In this study, we examined the effect of transdermal therapy with myelin peptides on immune responses in the skin, lymph nodes, and peripheral blood immune cells of MS patients. METHODS: In a 1-year placebo-controlled study, 30 patients with relapsing-remitting MS were treated transdermally with a mixture of 3 myelin peptides: MBP85-99, PLP139-151, and MOG35-55, or placebo. The phenotype of immune cells in the skin was assessed using immunohistochemistry. Cell populations in lymph nodes were analyzed using flow cytometry. In peripheral blood immune cells, cytokine production was measured by enzyme-linked immunosorbent assay, and myelin-specific proliferation was examined by carboxyfluorescein succinimidyl ester-based assay. RESULTS: We found that myelin peptides applied transdermally to MS patients activated dendritic Langerhans cells in the skin at the site of immunization and induced a unique population of granular dendritic cells in local lymph nodes. In the periphery, transdermal immunization with myelin peptides resulted in the generation of type 1, interleukin-10-producing regulatory T cells, suppression of specific autoreactive proliferative responses, and suppression of interferon-γ and transforming growth factor-ß production. INTERPRETATION: We demonstrate for the first time the immunoregulatory potential of transdermal immunization with myelin peptides in MS patients.


Subject(s)
Autoimmunity/drug effects , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Myelin Proteins/administration & dosage , Peptide Fragments/administration & dosage , Administration, Cutaneous , Adolescent , Adult , Cell Proliferation/drug effects , Cytokines/blood , Drug Combinations , Female , Glycoproteins/administration & dosage , Humans , Lymph Nodes/cytology , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/immunology , Myelin Basic Protein/administration & dosage , Myelin Proteolipid Protein/administration & dosage , Myelin-Oligodendrocyte Glycoprotein , Skin/immunology
16.
Stroke ; 41(3): 544-9, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20075346

ABSTRACT

BACKGROUND AND PURPOSE: Although myelin-associated neurite outgrowth disinhibitors have shown promise in restoring motor function after stroke, their interactive effects with motor training have rarely been investigated. The present study examined whether a combinatorial treatment (NEP 1-40+motor rehabilitation) is more effective than either treatment alone in promoting motor recovery after focal ischemic injury. METHODS: Adult rats were assigned to one of 3 treatment groups (infarct/NEP 1-40+motor training, infarct/NEP 1-40 only, infarct/motor training only) and 2 control groups (infarct/no treatment, intact/no treatment). A focal ischemic infarct was induced by microinjecting endothelin-1 into the motor cortex. Therapeutic treatments were initiated 1 week postinfarct and included intraventricular infusion of the pharmacological agent NEP 1-40 and motor training (skilled reach task). Behavioral assessments on skilled reach, foot fault, and cylinder tests were conducted before the infarct and for 5 weeks postinfarct. RESULTS: Rats demonstrated significant forelimb impairment on skilled reach and foot fault tests after the infarct. Although all infarct groups improved over time, motor training alone and NEP 1-40 alone facilitated recovery on the skilled reach task at the end of treatment Weeks 2 and 4, respectively. However, only NEP 1-40 paired with motor training facilitated recovery after 1 week of treatment in addition to treatment at Weeks 2 and 4. Finally, only the NEP 1-40+motor training group maintained a performance level equivalent to that of the intact group over the entire period of posttreatment assessment. CONCLUSIONS: This study suggests that behavioral training interacts with the effects of the axonal growth promoter, NEP 1-40, and may accelerate behavioral recovery after focal cortical ischemia.


Subject(s)
Cerebral Infarction/drug therapy , Cerebral Infarction/rehabilitation , Exercise Therapy/methods , Motor Cortex , Myelin Proteins/administration & dosage , Peptide Fragments/administration & dosage , Recovery of Function/physiology , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Cerebral Infarction/physiopathology , Combined Modality Therapy/methods , Male , Motor Cortex/physiology , Motor Skills/physiology , Psychomotor Performance/drug effects , Psychomotor Performance/physiology , Rats , Rats, Long-Evans
17.
Exp Neurol ; 209(2): 446-68, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18234196

ABSTRACT

This study was undertaken as part of the NIH "Facilities of Research-Spinal Cord Injury" project to support independent replication of published studies. Here, we repeated a study reporting that treatment with the NgR antagonist peptide NEP1-40 results in enhanced growth of corticospinal and serotonergic axons and enhanced locomotor recovery after thoracic spinal cord injury. Mice received dorsal hemisection injuries at T8 and then received either NEP1-40, Vehicle, or a Control Peptide beginning 4-5 h (early treatment) or 7 days (delayed treatment) post-injury. CST axons were traced by injecting BDA into the sensorimotor cortex. Serotonergic axons were assessed by immunocytochemistry. Hindlimb motor function was assessed using the BBB and BMS scales, kinematic and footprint analyses, and a grid climbing task. There were no significant differences between groups in the density of CST axon arbors in the gray matter rostral to the injury or in the density of serotonergic axons caudal to the injury. Tract tracing revealed that a small number of CST axons extended past the lesion in the ventral column in some mice in all treatment groups. The proportion of mice with such axons was higher in the NEP1-40 groups that received early treatment. In one experiment, mice treated with either NEP1-40 or a Control Peptide (reverse sequence) had higher BBB and BMS scores than Vehicle-treated controls at the early post-injury testing intervals, but scores converged at later intervals. There were no statistically significant differences between groups on other functional outcome measures. In a second experiment comparing NEP-treated and Vehicle controls, there were no statistically significant differences on any of the functional outcome measures. Together, our results suggest that treatment with NEP1-40 created a situation that was slightly more conducive to axon regeneration or sprouting. Enhanced functional recovery was not seen consistently with the different functional assessments, however.


Subject(s)
Axons/drug effects , Motor Activity/drug effects , Myelin Proteins/administration & dosage , Myelin Proteins/antagonists & inhibitors , Peptide Fragments/administration & dosage , Receptors, Cell Surface/antagonists & inhibitors , Recovery of Function/drug effects , Regeneration/drug effects , Spinal Cord Injuries , Analysis of Variance , Animals , Axons/physiology , Behavior, Animal , Biomechanical Phenomena , Biotin/analogs & derivatives , Biotin/metabolism , Dextrans/metabolism , Disease Models, Animal , Female , GPI-Linked Proteins , Mice , Mice, Inbred C57BL , Nogo Receptor 1 , Psychomotor Performance/drug effects , Regeneration/physiology , Serotonin/metabolism , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/pathology , Spinal Cord Injuries/physiopathology , Time Factors
18.
Neuroscience ; 149(4): 931-42, 2007 Nov 23.
Article in English | MEDLINE | ID: mdl-17949921

ABSTRACT

The neural cell adhesion molecule (NCAM) plays a pivotal role in neural development, regeneration, synaptic plasticity, and memory processes. P2 is a 12-amino-acid peptide derived from the second immunoglobulin-like (Ig) module of NCAM mediating cis-homophilic interactions between NCAM molecules present on the same cell. P2 is a potent NCAM agonist, capable of promoting neuronal differentiation and survival in vitro. The aim of this study was to assess the effect of P2 on learning and memory. Rats treated with P2 intracerebroventricularly (1 h prior to test) performed significantly better than controls in the reinforced T-maze, a test of spatial working memory. Further, rats treated with P2 exhibited decreased anxiety-like behavior while learning the T-maze task. In the social recognition test, both intracerebroventricular (1 h prior to test) and systemic (1 and 24 h prior to test) P2 treatment enhanced short-term social memory and counteracted (administration 24 h prior test) scopolamine-induced social memory impairment. In contrast, P2 (1 h prior to test) did not significantly improve long-term (24 h) retention of social memory, nor did it have any significant effects on long-term memory evaluated by the Morris water maze (administration between 2 days before training and 5.5 h posttraining). In the open field test, P2 (1 h prior to test) decreased general locomotion and rearing, but did not influence any other anxiety-related behaviors, indicating only a minimal influence on baseline anxiety levels. Taken together, these data indicate that in vivo P2 enhances short-term memory and protects against the amnestic effects of scopolamine, while modulating emotional behavior in a learning or novelty-related task.


Subject(s)
Maze Learning/drug effects , Memory, Short-Term/drug effects , Myelin Proteins/administration & dosage , Amnesia/chemically induced , Analysis of Variance , Animals , Behavior, Animal/drug effects , Drug Administration Routes , Exploratory Behavior/drug effects , Male , Rats , Rats, Wistar , Reinforcement, Psychology , Scopolamine , Statistics, Nonparametric , Time Factors
19.
Neurosci Lett ; 424(3): 145-8, 2007 Sep 13.
Article in English | MEDLINE | ID: mdl-17720311

ABSTRACT

Neuropathic pain after periphery nerve injury is frequently accompanied by the regeneration of the injured nerve fibers. We tested in this study whether local administration of Nogo-66, a well-studied axon growth inhibiting peptide in the central nerve system, could reduce the pain related behavior after sciatic nerve transection in rat. Nogo-66 peptide was purified as a GST fusion protein. Its inhibitory function was testified by neurite outgrowth assay of primary cultured neurons, and then it was given directly at the lesion site by a minipump for 2 weeks. Mechanical nociceptive withdrawal responses and heat hyperalgesia responses were assessed during a 4-week period, and autotomy was evaluated during a 6-week period. The results showed that the mechanical allodynia and heat hyperalgesia scores of the rats treated with GST-Nogo-66 were significantly higher than the controls between 7 and 14 days after sciatic nerve transection. The autotomy scores in the GST-Nogo-66 group were significantly lower than the controls from 28 days after surgery. Taken together, the results of our present study suggest that Nogo-66 may be utilized to decrease the neuropathic pain after periphery nerve injury.


Subject(s)
Analgesics/administration & dosage , Myelin Proteins/administration & dosage , Sciatica/drug therapy , Animals , Disease Models, Animal , Male , Neuroma/drug therapy , Neuroma/pathology , Nogo Proteins , Pain Measurement/methods , Rats , Rats, Sprague-Dawley , Reaction Time/drug effects , Time Factors
20.
J Neurosci ; 26(51): 13279-86, 2006 Dec 20.
Article in English | MEDLINE | ID: mdl-17182778

ABSTRACT

The production and aggregation of cerebral amyloid-beta (Abeta) peptide are thought to play a causal role in Alzheimer's disease (AD). Previously, we found that the Nogo-66 receptor (NgR) interacts physically with both Abeta and the amyloid precursor protein (APP). The inverse correlation of Abeta levels with NgR levels within the brain may reflect regulation of Abeta production and/or Abeta clearance. Here, we assess the potential therapeutic benefit of peripheral NgR-mediated Abeta clearance in APPswe/PSEN-1deltaE9 transgenic mice. Through site-directed mutagenesis, we demonstrate that the central 15-28 aa of Abeta associate with specific surface-accessible patches on the leucine-rich repeat concave side of the solenoid structure of NgR. In transgenic mice, subcutaneous NgR(310)ecto-Fc treatment reduces brain Abeta plaque load while increasing the relative levels of serum Abeta. These changes in Abeta are correlated with improved spatial memory in the radial arm water maze. The benefits of peripheral NgR administration are evident when therapy is initiated after disease onset. Thus, the peripheral association of NgR(310)ecto-Fc with central Abeta residues provides an effective therapeutic approach for AD.


Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Brain/metabolism , Memory/physiology , Myelin Proteins/physiology , Receptors, Cell Surface/physiology , Spatial Behavior/physiology , Alzheimer Disease/therapy , Amyloid beta-Peptides/antagonists & inhibitors , Animals , Brain/physiology , COS Cells , Chlorocebus aethiops , GPI-Linked Proteins , Humans , Injections, Subcutaneous , Mice , Mice, Transgenic , Myelin Proteins/administration & dosage , Myelin Proteins/metabolism , Nogo Receptor 1 , Protein Binding/physiology , Rats , Receptors, Cell Surface/administration & dosage , Receptors, Cell Surface/metabolism
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