RESUMO
Vaccines have been considered in treating many CNS degenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), epilepsy, multiple sclerosis (MS), spinal cord injury (SCI), and stroke. DNA vaccines have emerged as novel therapeutic agents because of the simplicity of their generation and application. Myelin components such as NOGO, MAG and OMGP are known to trigger demyelinating autoimmunity and to prevent axonal regeneration. For these reasons DNA vaccines encoding NOGO, MAG and OMGP, and fragments thereof, make them suitable vehicles for treatment of SCIs and MS. We need to obtain a deeper understanding of the immunologic mechanisms underlying the neuroprotective immunity to optimize the design of DNA vaccines for their use in clinical setting. In this review, we discuss recent findings suggesting that DNA vaccines hold a promising future for the treatment of axonal degeneration and demyelination.
Assuntos
Axônios/imunologia , Axônios/fisiologia , Doenças do Sistema Nervoso Central/imunologia , Doenças do Sistema Nervoso Central/terapia , Regeneração Nervosa/imunologia , Vacinas de DNA/imunologia , Axônios/patologia , Humanos , Fármacos NeuroprotetoresRESUMO
It has long been recognized that the central nervous system (CNS) exhibits only limited capacity for axonal regeneration following injury. It has been proposed that myelin-associated inhibitory molecules are responsible for the nonpermissive nature of the CNS environment to axonal regeneration. Experimental strategies to enhance regeneration by neutralizing these inhibitory molecules are rapidly advancing toward clinical application. It is therefore important that the physiological distribution and functions of these supposed inhibitory molecules should be understood. In this review, we examine the distribution of these inhibitors of neurite outgrowth in relation to the longitudinal polarization of the myelinated axon into the node of Ranvier and associated domains and explore their potential domain specific physiological functions. Potential implications for the therapeutic strategy of neutralizing these inhibitory molecules to promote neural repair are discussed.
Assuntos
Axônios/efeitos dos fármacos , Bainha de Mielina/fisiologia , Fatores de Crescimento Neural/antagonistas & inibidores , Fatores de Crescimento Neural/metabolismo , Animais , Humanos , Nós Neurofibrosos/efeitos dos fármacos , Nós Neurofibrosos/metabolismoRESUMO
The molecular mechanisms underlying the involvement of oligodendrocytes in formation of the nodes of Ranvier (NORs) remain poorly understood. Here we show that oligodendrocyte-myelin glycoprotein (OMgp) aggregates specifically at NORs. Nodal location of OMgp does not occur along demyelinated axons of either Shiverer or proteolipid protein (PLP) transgenic mice. Over-expression of OMgp in OLN-93 cells facilitates process outgrowth. In transgenic mice in which expression of OMgp is down-regulated, myelin thickness declines, and lateral oligodendrocyte loops at the node-paranode junction are less compacted and even join together with the opposite loops, which leads to shortened nodal gaps. Notably, each of these structural abnormalities plus modest down-regulation of expression of Na(+) channel alpha subunit result in reduced conduction velocity in the spinal cords of the mutant mice. Thus, OMgp that is derived from glia has distinct roles in regulating nodal formation and function during CNS myelination.
RESUMO
Myelin-derived proteins, such as tenascin-R (TN-R), myelin associate glycoprotein (MAG), and Nogo-A, inhibit the CNS regeneration. By targeting specifically the inhibitory epitopes, we have investigated whether vaccination with a recombinant DNA molecule encoding multiple domains of myelin inhibitors may be useful in CNS repair. We show here that the recombinant DNA vaccine is able to activate the immune system but does not induce experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Importantly, it promotes axonal regeneration in a spinal cord injury model. Thus, the application of DNA vaccine, encoding multiple specific domains of major inhibitory proteins and/or their receptors, provides another promising approach to overcome the inhibitory barriers during CNS regeneration.
Assuntos
Axônios/fisiologia , Encefalomielite Autoimune Experimental/terapia , Regeneração Nervosa/imunologia , Neuritos/fisiologia , Traumatismos da Medula Espinal/terapia , Vacinas de DNA/uso terapêutico , Animais , Axônios/imunologia , Células COS , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Feminino , Humanos , Imunoterapia Ativa/métodos , Atividade Motora/efeitos dos fármacos , Proteínas da Mielina/genética , Proteínas da Mielina/imunologia , Glicoproteína Associada a Mielina/genética , Glicoproteína Associada a Mielina/imunologia , Neuritos/imunologia , Proteínas Nogo , Estrutura Terciária de Proteína/genética , Ratos , Ratos Endogâmicos Lew , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/imunologia , Tenascina/genética , Tenascina/imunologia , Vacinas de DNA/genéticaRESUMO
Autografts have been extensively studied to facilitate optic nerve (ON) regeneration in animal experiments, but the clinical application of this approach to aid autoregeneration has not yet been attempted. This study aims to explore the guided regeneration by an artificial polyglycolic acid-chitosan conduit coated with recombinant L1-Fc. Consistent with previous studies; in vitro assay showed that both chitosan, a natural biomaterial, and the neural cell adhesion molecule L1-Fc enhanced neurite outgrowth. Rat optic nerve transection was used as an in vivo model. The implanted PGA-chitosan conduit was progressively degraded and absorbed, accompanied by significant axonal regeneration as revealed by immunohistochemistry, anterograde and retrograde tracing. The polyglycolic acid-chitosan conduit coated with L1-Fc showed more effective to promote axonal regeneration and remyelination. Taken together, our observations demonstrated that the L1-Fc coated PGA-chitosan conduits provided a compatible and supportive canal to guild the injured nerve regeneration and remyelination.
Assuntos
Quitosana/uso terapêutico , Regeneração Nervosa/efeitos dos fármacos , Molécula L1 de Adesão de Célula Nervosa/uso terapêutico , Traumatismos do Nervo Óptico/tratamento farmacológico , Ácido Poliglicólico/uso terapêutico , Animais , Materiais Biocompatíveis/uso terapêutico , Linhagem Celular Tumoral , Feminino , Regeneração Nervosa/fisiologia , Nervo Óptico/citologia , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/fisiologia , Traumatismos do Nervo Óptico/patologia , Ratos , Ratos Wistar , Proteínas Recombinantes/uso terapêuticoRESUMO
Neurons and glia in the vertebrate central nervous system arise in temporally distinct, albeit overlapping, phases. Neurons are generated first followed by astrocytes and oligodendrocytes from common progenitor cells. Increasing evidence indicates that axon-derived signals spatiotemporally modulate oligodendrocyte maturation and myelin formation. Our previous observations demonstrate that F3/contactin is a functional ligand of Notch during oligodendrocyte maturation, revealing the existence of another group of Notch ligands. Here, we establish that NB-3, a member of the F3/contactin family, acts as a novel Notch ligand to participate in oligodendrocyte generation. NB-3 triggers nuclear translocation of the Notch intracellular domain and promotes oligodendrogliogenesis from progenitor cells and differentiation of oligodendrocyte precursor cells via Deltex1. In primary oligodendrocytes, NB-3 increases myelin-associated glycoprotein transcripts. Thus, the NB-3/Notch signaling pathway may prove to be a molecular handle to treat demyelinating diseases.
Assuntos
Proteínas de Transporte/fisiologia , Moléculas de Adesão Celular Neuronais/fisiologia , Neurônios/citologia , Oligodendroglia/citologia , Receptores de Superfície Celular/fisiologia , Células-Tronco/citologia , Fatores de Transcrição , Transporte Ativo do Núcleo Celular , Animais , Diferenciação Celular , Células Cultivadas , Contactinas , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Wistar , Receptor Notch1 , Transdução de SinaisRESUMO
We report Nogo-A as an oligodendroglial component congregating and interacting with the Caspr-F3 complex at paranodes. However, its receptor Nogo-66 receptor (NgR) does not segregate to specific axonal domains. CHO cells cotransfected with Caspr and F3, but not with F3 alone, bound specifically to substrates coated with Nogo-66 peptide and GST-Nogo-66. Binding persisted even after phosphatidylinositol- specific phospholipase C (PI-PLC) removal of GPI-linked F3 from the cell surface, suggesting a direct interaction between Nogo-66 and Caspr. Both Nogo-A and Caspr co-immunoprecipitated with Kv1.1 and Kv1.2, and the developmental expression pattern of both paralleled compared with Kv1.1, implicating a transient interaction between Nogo-A-Caspr and K(+) channels at early stages of myelination. In pathological models that display paranodal junctional defects (EAE rats, and Shiverer and CGT(-/-) mice), distances between the paired labeling of K(+) channels were shortened significantly and their localization shifted toward paranodes, while paranodal Nogo-A congregation was markedly reduced. Our results demonstrate that Nogo-A interacts in trans with axonal Caspr at CNS paranodes, an interaction that may have a role in modulating axon-glial junction architecture and possibly K(+)-channel localization during development.