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1.
Brain Nerve ; 71(11): 1169-1181, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31722303

RESUMO

Amyotrophic lateral sclerosis (ALS) is the most rapidly progressive motor neuron disease (MND) in adults, characterized by the selective death of motor neurons in the motor cortex, brainstem, and spinal cord. Riluzole and edaravone are the only approved drugs available in Japan to date. Approximately 10% of ALS cases are familial in rature, defined as the existence of disease-causing mutation. SOD1 is the most frequent causative gene for ALS among Japanese individuals, while C9orf72 mutation is more prevalent in Western countries. Genotype-phenotype correlation described in the literature of familial ALS enables to establish models of the disease. This review article describes the clinical characteristics of familial ALS based on each disease-causing mutation. The pathomechanism of ALS including proteostasis, RNA metabolism, and axonal pathology are discussed in detail. We also reviewed the status of development of therapeutic strategies for familial ALS based on analysis of animal models and induced pluripotent stem cells.


Assuntos
Esclerose Amiotrófica Lateral/genética , Adulto , Esclerose Amiotrófica Lateral/terapia , Animais , Axônios/patologia , Proteína C9orf72/genética , Modelos Animais de Doenças , Humanos , Células-Tronco Pluripotentes Induzidas , Japão , Neurônios Motores/patologia , Mutação , Superóxido Dismutase-1/genética
2.
Nature ; 571(7766): 565-569, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31316206

RESUMO

Parkinson's disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles1,2. An early-onset form of Parkinson's disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes3. PINK1 and Parkin (encoded by PRKN) are involved in the clearance of damaged mitochondria in cultured cells4, but recent evidence obtained using knockout and knockin mouse models have led to contradictory results regarding the contributions of PINK1 and Parkin to mitophagy in vivo5-8. It has previously been shown that PINK1 and Parkin have a key role in adaptive immunity by repressing presentation of mitochondrial antigens9, which suggests that autoimmune mechanisms participate in the aetiology of Parkinson's disease. Here we show that intestinal infection with Gram-negative bacteria in Pink1-/- mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8+ T cells in the periphery and in the brain. Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with L-DOPA. These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson's disease, which highlights the relevance of the gut-brain axis in the disease10.


Assuntos
Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/fisiopatologia , Intestinos/microbiologia , Doença de Parkinson/genética , Doença de Parkinson/microbiologia , Proteínas Quinases/deficiência , Proteínas Quinases/genética , Animais , Apresentação do Antígeno/imunologia , Autoantígenos/imunologia , Axônios/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Citrobacter rodentium/imunologia , Citrobacter rodentium/patogenicidade , Modelos Animais de Doenças , Neurônios Dopaminérgicos/imunologia , Neurônios Dopaminérgicos/patologia , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/patologia , Feminino , Intestinos/imunologia , Intestinos/patologia , Levodopa/uso terapêutico , Masculino , Camundongos , Mitocôndrias/imunologia , Mitocôndrias/patologia , Neostriado/imunologia , Neostriado/microbiologia , Neostriado/patologia , Neostriado/fisiopatologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Proteínas Quinases/imunologia , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia
3.
Forensic Sci Int ; 301: e49-e54, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31230858

RESUMO

Gunshot wounds (GSW) are one of the most common causes of penetrating spinal injury, however few data are available regarding GSW causing an indirect fatal nervous tissue injury, such as that induced by the concussive force secondary to the bullet penetration. This report describes a rare case of a death following a GSW spine injury at the level of C2 vertebral body, without direct contact with the spinal cord, as seen with computed tomography scan performed soon after the death. At autopsy, vertebral canal and dura mater, as well as spinal cord and medulla oblongata, appeared devoid of pathologies and/or lesions, major viscera were unaltered. The cause of death was attributed to a cardiorespiratory arrest subsequent to the GSW injury of the C2 vertebral bone. Histopathological analysis of spinal cord and medulla oblongata was performed by means of conventional stainings, and glial fibrillary acidic protein (GFAP) and Neurofilaments 200kD (NF) immunohistochemistry. Histological alterations stood out against a tissue with no other evident sign of neuropathology, and could be observed from the caudalmost part of the medulla oblongata to the level of the inferior olivary nucleus. Main structural changes were found in the white matter, involving often the adjacent gray matter, where they appeared as multiple scattered areas of degeneration, lacking the usual staining affinity, and showing a disrupted fibrillary pattern as evidenced by myelin staining, and GFAP- and NF-immunolabelling. The shock wave secondary to the impact on the C2 vertebral bone is likely to have been the cause of a widespread neuronal-axonal histopathological damage at the spinal-medullary junction and caudal medulla oblongata that is compatible with a severe fatal respiratory dysfunction and dysregulation of the autonomic pathways subserving the control of blood pressure and cardiac activity.


Assuntos
Vértebras Cervicais/lesões , Vértebras Cervicais/patologia , Morte Súbita/etiologia , Bulbo/patologia , Ferimentos por Arma de Fogo/patologia , Axônios/patologia , Vértebras Cervicais/diagnóstico por imagem , Patologia Legal , Parada Cardíaca/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Respiratória/etiologia , Tomografia Computadorizada por Raios X , Substância Branca/patologia , Ferimentos por Arma de Fogo/diagnóstico por imagem
4.
Life Sci ; 232: 116501, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31163175

RESUMO

AIMS: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). The disease mechanisms driving progressive MS remain unresolved. Without this information, current therapeutic strategies are unsatisfactory in preventing disease progression. Our previous work revealed that DL-3-n-butylphthalide (NBP) treatment reduced demyelination in an ethidium bromide mouse model of demyelination. Here, we examine the effect of NBP in the cuprizone model of demyelination by evaluating the pathologic, functional, and behavioral consequences of treatment with NBP. MATERIALS AND METHODS: Forty mice were divided randomly into 4 groups: a normal diet group, a cuprizone diet group, and two NBP groups (10 and 20 mg/kg). CNS infiltration by microglia, axon health and myelination were assessed using immunohistochemistry and electron microscopy, and the levels of cytoplasmic complexes were assessed by Western blotting. KEY FINDINGS: The results showed the neuroprotective effects of the NBP included suppressing the microglia activation through inhibition of nuclear factor-κB (NF-κB) expression, thus decreasing activation of the NF-κB signaling pathway. In particular, myelin density was increased due to an increased mean number of mature oligodendrocytes (OLs) in the high-dose NBP (20 mg/kg) subgroup through reduced oligodendrocyte apoptosis. Meanwhile, increased expression of myelin sheath proteins, including proteolipid protein (PLP) and myelin basic protein (MBP), was observed in the same subgroup. SIGNIFICANCE: These data suggest that NBP may not only have anti-inflammatory properties but also promote the survival of OLs in a mouse cuprizone model of demyelination. NBP may have a potential role in the treatment of MS.


Assuntos
Benzofuranos/farmacologia , Doenças Desmielinizantes/tratamento farmacológico , Esclerose Múltipla/metabolismo , Animais , Astrócitos/metabolismo , Axônios/patologia , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/fisiologia , Cuprizona/farmacologia , Doenças Desmielinizantes/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/fisiopatologia , Bainha de Mielina/metabolismo , NF-kappa B/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Oligodendroglia/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
5.
Neuron ; 103(3): 412-422.e4, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31221560

RESUMO

Selective synaptic and axonal degeneration are critical aspects of both brain development and neurodegenerative disease. Inhibition of caspase signaling in neurons is a potential therapeutic strategy for neurodegenerative disease, but no neuron-specific modulators of caspase signaling have been described. Using a mass spectrometry approach, we discovered that RUFY3, a neuronally enriched protein, is essential for caspase-mediated degeneration of TRKA+ sensory axons in vitro and in vivo. Deletion of Rufy3 protects axons from degeneration, even in the presence of activated CASP3 that is competent to cleave endogenous substrates. Dephosphorylation of RUFY3 at residue S34 appears required for axon degeneration, providing a potential mechanism for neurons to locally control caspase-driven degeneration. Neuronally enriched RUFY3 thus provides an entry point for understanding non-apoptotic functions of CASP3 and a potential target to modulate caspase signaling specifically in neurons for neurodegenerative disease.


Assuntos
Axônios/patologia , Degeneração Neural/patologia , Proteínas do Tecido Nervoso/fisiologia , Animais , Axônios/enzimologia , Caspase 3/fisiologia , Células Cultivadas , Ativação Enzimática , Gânglios Espinais/citologia , Gânglios Espinais/embriologia , Camundongos , Camundongos Knockout , Degeneração Neural/enzimologia , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/deficiência , Fosforilação , Processamento de Proteína Pós-Traducional , Receptor trkA/fisiologia , Células Receptoras Sensoriais/fisiologia , Relação Estrutura-Atividade
6.
J Clin Neurosci ; 66: 235-238, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31153749

RESUMO

AIM: Muscle abnormalities after spinal cord ischemia caused by subarachnoid hemorrhage (SAH) have not been explored for degenerative variations in the soma of second motor neurons of the spinal cord gray matter. This study aimed to investigate histopathological alterations in the gray matter and the role of peripheral nerves in SAH. MATERIAL AND METHODS: Twenty-two rabbits were allocated in the control (Group I, n = 5), SHAM (Group II, n = 5), and research (Group III, n = 12) groups. Muscle weakness of the upper extremities innervated by radial nerves was evaluated at the initial day, and outcomes were recorded as control data. Re-measurements were done after injecting 0.5 ml of SF for SHAM and autolog artery blood inside craniocervical subarachnoid space for the study group. After 3 weeks, radial nerve roots, their ganglia, and segments of the spinal cord around C5-6 root entry zones were extracted bilaterally. Degenerated second motor neuron somas and the degenerated radial nerve motor axons at the intervertebral foramen were assessed. RESULTS: The average degenerated soma intensity/mm3 at the C5-6 levels in the spinal cord was 2 ±â€¯1/mm3, 13 ±â€¯4/mm3, and 56 ±â€¯10/mm3 for Groups I, II, and Group III. The average degenerated axon intensity of radial nerves was 3 ±â€¯1/mm2, 34 ±â€¯9/mm2, and 234 ±â€¯78/mm2 for Groups I, II, and III. CONCLUSION: Gray matter ischemia in the spinal cord may lead to axonal deterioration on equal levels at the peripheral nerves with advanced SAH. Detected or undetected spinal SAH should be considered an important factor on the etiology of second motor neuron diseases.


Assuntos
Axônios/patologia , Medula Cervical/patologia , Degeneração Neural/patologia , Nervo Radial/patologia , Isquemia do Cordão Espinal/patologia , Hemorragia Subaracnóidea/patologia , Animais , Modelos Animais de Doenças , Neurônios Motores/patologia , Debilidade Muscular/etiologia , Debilidade Muscular/patologia , Degeneração Neural/etiologia , Coelhos , Isquemia do Cordão Espinal/etiologia , Hemorragia Subaracnóidea/complicações
7.
Nat Neurosci ; 22(8): 1269-1275, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31235933

RESUMO

Inhibitory extracellular matrices form around mature neurons as perineuronal nets containing chondroitin sulfate proteoglycans that limit axonal sprouting after CNS injury. The enzyme chondroitinase (Chase) degrades inhibitory chondroitin sulfate proteoglycans and improves axonal sprouting and functional recovery after spinal cord injury in rodents. We evaluated the effects of Chase in rhesus monkeys that had undergone C7 spinal cord hemisection. Four weeks after hemisection, we administered multiple intraparenchymal Chase injections below the lesion, targeting spinal cord circuits that control hand function. Hand function improved significantly in Chase-treated monkeys relative to vehicle-injected controls. Moreover, Chase significantly increased corticospinal axon growth and the number of synapses formed by corticospinal terminals in gray matter caudal to the lesion. No detrimental effects were detected. This approach appears to merit clinical translation in spinal cord injury.


Assuntos
Condroitinases e Condroitim Liases/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Axônios/patologia , Condroitinases e Condroitim Liases/administração & dosagem , Condroitinases e Condroitim Liases/efeitos adversos , Substância Cinzenta/patologia , Mãos/inervação , Mãos/fisiopatologia , Injeções Intralesionais , Macaca mulatta , Masculino , Microglia/patologia , Neurônios Motores/patologia , Desempenho Psicomotor , Tratos Piramidais/patologia , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/fisiopatologia , Suínos , Sinapses/patologia , Resultado do Tratamento
8.
Psychopharmacology (Berl) ; 236(9): 2761-2771, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31165206

RESUMO

RATIONALE: As the hub of memory and space, hippocampus is very sensitive to a wide variety of injuries and is one of the earliest brain structures to develop neurodegenerative changes in AD. Previous research has showed a protective effect of potassium 2-(l-hydroxypentyl)-benzoate (PHPB) on cognitive deficits in animal models of AD. However, it is unclear whether this protective effect is associated with hippocampal alterations. OBJECTIVES: The present study was conducted to evaluate the protective effect of PHPB on hippocampal neurodegenerative changes in middle-aged APP/PS1 mice. METHODS: Ten-month-old male APP/PS1 transgenic mice and age-matched wild-type mice were randomly divided into three groups. PHPB-treated APP/PS1 group received 30 mg/kg PHPB by oral gavage once daily for 12 weeks. Wild-type group and APP/PS1 group received the same volume of water alone. Twelve weeks later, mice (13-month-old) were tested for in vivo 1H-MRS examination and then sacrificed for subsequent biochemical and pathological examinations using transmission electron microscopy, Golgi staining, immunohistochemistry, and western blotting. RESULTS: We found that PHPB treatment significantly improved the micromorphology of hippocampal neurons and subcellular organelles, ameliorated synapse loss and presynaptic axonal dystrophy, increased hippocampal dendritic spine density and dendritic complexity, enhanced the expression of hippocampal synapse-associated proteins, and improved hippocampal metabolism in middle-aged APP/PS1 mice. CONCLUSIONS: Our study showed for the first time the protective effect of PHPB on hippocampal neurons, synapses, and dystrophic axons in APP/PS1 mice, which to some extent revealed the possible mechanism for its ability to improve cognition in animal models of AD.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Axônios/metabolismo , Hipocampo/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Presenilina-1/metabolismo , Sinapses/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Benzoatos/administração & dosagem , Cognição/efeitos dos fármacos , Cognição/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Pentanóis/administração & dosagem , Potássio/administração & dosagem , Presenilina-1/genética , Distribuição Aleatória , Sinapses/genética , Sinapses/patologia , Resultado do Tratamento
9.
Cell Mol Life Sci ; 76(21): 4355-4368, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31041455

RESUMO

Axons in the central nervous system (CNS) typically fail to regenerate after injury. This failure is multi-factorial and caused in part by disruption of the axonal cytoskeleton. The cytoskeleton, in particular microtubules (MT), plays a critical role in axonal transport and axon growth during development. In this regard, members of the kinesin superfamily of proteins (KIFs) regulate the extension of primary axons toward their targets and control the growth of collateral branches. KIF2A negatively regulates axon growth through MT depolymerization. Using three different injury models to induce SCI in adult rats, we examined the temporal and cellular expression of KIF2A in the injured spinal cord. We observed a progressive increase of KIF2A expression with maximal levels at 10 days to 8 weeks post-injury as determined by Western blot analysis. KIF2A immunoreactivity was present in axons, spinal neurons and mature oligodendrocytes adjacent to the injury site. Results from the present study suggest that KIF2A at the injured axonal tips may contribute to neurite outgrowth inhibition after injury, and that its increased expression in inhibitory spinal neurons adjacent to the injury site might contribute to an intrinsic wiring-control mechanism associated with neuropathic pain. Further studies will determine whether KIF2A may be a potential target for the development of regeneration-promoting or pain-preventing therapies.


Assuntos
Cinesina/análise , Cinesina/metabolismo , Traumatismos da Medula Espinal/metabolismo , Animais , Axônios/metabolismo , Axônios/patologia , Modelos Animais de Doenças , Cinesina/genética , Masculino , Regeneração Nervosa/genética , Neurônios/metabolismo , Neurônios/patologia , Ratos , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/patologia
10.
Neurochem Res ; 44(7): 1726-1735, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31087207

RESUMO

Tacrolimus, a calcineurin (CaN) inhibitor, has been used for treatment of refractory allergic ocular disease, although its role in optic nerve degeneration remains to be elucidated. In this study, we investigated whether tacrolimus modulates tumor necrosis factor (TNF)-mediated axonal degeneration and whether it alters nuclear factor of activated T cells (NFATc), a downstream effector of CaN signaling. Immunoblot analysis showed no significant difference in CaNAα protein levels in optic nerve on day 3, 7, or 14 after TNF injection compared with PBS injection. However, a significant increase in NFATc1 protein level was observed in optic nerve 7 days after TNF injection. This increase was negated by simultaneous administration of tacrolimus. Administration of tacrolimus alone did not change the NFATc1 protein level in comparison to that observed after PBS injection. A significant increase in TNF protein level was observed in optic nerve 14 days after TNF injection and this increase was prevented by tacrolimus. Immunohistochemical analysis showed the immunoreactivity of NFATc1 to be increased in optic nerve after TNF injection. This increased immunoreactivity was colocalized with glial fibrillary acidic protein and was suppressed by tacrolimus. Treatment of tacrolimus significantly ameliorated the TNF-mediated axonal loss. These results suggest that tacrolimus is neuroprotective against axon loss in TNF-induced optic neuropathy and that the effect arises from suppression of the CaN/NFATc1 pathway.


Assuntos
Axônios/efeitos dos fármacos , Degeneração Neural/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Doenças do Nervo Óptico/prevenção & controle , Tacrolimo/uso terapêutico , Fatores de Transcrição/antagonistas & inibidores , Animais , Axônios/patologia , Inibidores de Calcineurina/uso terapêutico , Masculino , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Nervo Óptico/patologia , Doenças do Nervo Óptico/induzido quimicamente , Doenças do Nervo Óptico/patologia , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
11.
Prion ; 13(1): 83-93, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30966865

RESUMO

The major neurological feature of prion diseases is a neuronal loss accomplished through either apoptosis or autophagy. In this review, I compared axonal alterations in prion diseases to those described 40 years earlier as a result of nerve ligation. I also demonstrated that autophagic vacuoles and autophagosomes are a major part of dystrophic neurites. Furthermore, I summarized the current status of the autophagy in prion diseases and hypothesize, that spongiform change may originate from the autophagic vacuoles. This conclusion should be supported by other methods, in particular laser confocal microscopy. We observed neuronal autophagic vacuoles in different stages of formation, and our interpretation of the 'maturity' of their formation may or may not equate to actual developmental stages. Initially, a part of the neuronal cytoplasm was sequestrated within double or multiple membranes (phagophores) and often exhibited increased electron-density. The intracytoplasmic membranes formed labyrinth-like structures that suggest a multiplication of those membranes. The autophagic vacuoles then expand and eventually, a vast area of the cytoplasm was transformed into a merging mass of autophagic vacuoles. Margaret R. Matthews published a long treatise in the Philosophical Transactions of the Royal Society of London in which she had described in great detail the ultrastructure of postganglionic branches of the superior cervical ganglion in the rat following ligation of them. The earliest changes observed by Matthews between 6 h to 2 days in the proximal stump were distensions of proximal axons. Analogously, in our models, an increased number of 'regular' (round) and 'irregular' MVB and some autophagic vacuoles were observed collectively, both processes were similar.


Assuntos
Axônios/patologia , Encéfalo/patologia , Neurônios/patologia , Doenças Priônicas/patologia , Gânglio Cervical Superior/patologia , Animais , Apoptose , Autofagia , Modelos Animais de Doenças , Humanos
12.
Restor Neurol Neurosci ; 37(2): 181-196, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31006701

RESUMO

BACKGROUND: The "post-paralytic syndrome" after facial nerve reconstruction has been attributed to (i) malfunctioning axonal guidance at the fascicular (branches) level, (ii) collateral branching of the transected axons at the lesion site, and (iii) intensive intramuscular terminal sprouting of regenerating axons which causes poly-innervation of the neuromuscular junctions (NMJ). OBJECTIVE: The first two reasons were approached by an innovative technique which should provide the re-growing axons optimal conditions to elongate and selectively re-innervate their original muscle groups. METHODS: The transected facial nerve trunk was inserted into a 3-way-conduit (from isogeneic rat abdominal aorta) which should "guide" the re-growing facial axons to the three main branches of the facial nerve (zygomatic, buccal and marginal mandibular). The effect of this method was tested also on hypoglossal axons after hypoglossal-facial anastomosis (HFA). Coaptational (classic) FFA (facial-facial anastomosis) and HFA served as controls. RESULTS: When compared to their coaptation (classic) alternatives, both types of 3-way-conduit operations (FFA and HFA) promoted a trend for reduction in the collateral axonal branching (the proportion of double- or triple-labelled perikarya after retrograde tracing was slightly reduced). In contrast, poly-innervation of NMJ in the levator labii superioris muscle was increased and vibrissal (whisking) function was worsened. CONCLUSIONS: The use of 3-way-conduit provides no advantages to classic coaptation. Should the latter be impossible (too large interstump defects requiring too long interpositional nerve grafts), this type of reconstruction may be applied. (230 words).


Assuntos
Aorta Abdominal/transplante , Axônios , Nervo Facial/cirurgia , Regeneração Nervosa , Procedimentos Neurocirúrgicos , Procedimentos Cirúrgicos Reconstrutivos , Anastomose Cirúrgica , Animais , Axônios/patologia , Axônios/fisiologia , Músculos Faciais/inervação , Músculos Faciais/patologia , Nervo Facial/patologia , Nervo Facial/fisiopatologia , Traumatismos do Nervo Facial/cirurgia , Feminino , Nervo Hipoglosso/patologia , Nervo Hipoglosso/fisiopatologia , Nervo Hipoglosso/cirurgia , Atividade Motora , Regeneração Nervosa/fisiologia , Junção Neuromuscular/patologia , Junção Neuromuscular/fisiopatologia , Ratos Wistar , Recuperação de Função Fisiológica , Vibrissas/inervação
13.
Nat Commun ; 10(1): 1777, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992453

RESUMO

Nerve conduction (NC) studies generate measures of peripheral nerve function that can reveal underlying pathology due to axonal loss, demyelination or both. We perform a genome-wide association study of sural NC amplitude and velocity in 7045 Icelanders and find a low-frequency splice-donor variant in PRPH (c.996+1G>A; MAF = 1.32%) associating with decreased NC amplitude but not velocity. PRPH encodes peripherin, an intermediate filament (IF) protein involved in cytoskeletal development and maintenance of neurons. Through RNA and protein studies, we show that the variant leads to loss-of-function (LoF), as when over-expressed in a cell line devoid of other IFs, it does not allow formation of the normal filamentous structure of peripherin, yielding instead punctate protein inclusions. Recall of carriers for neurological assessment confirms that from an early age, homozygotes have significantly lower sural NC amplitude than non-carriers and are at risk of a mild, early-onset, sensory-negative, axonal polyneuropathy.


Assuntos
Condução Nervosa/genética , Periferinas/genética , Polineuropatias/genética , Sítios de Splice de RNA/genética , Nervo Sural/fisiopatologia , Adulto , Idade de Início , Idoso , Axônios/patologia , Estudos de Casos e Controles , Linhagem Celular , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Homozigoto , Humanos , Islândia/epidemiologia , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Polineuropatias/epidemiologia , Polineuropatias/fisiopatologia , Prevalência , Processamento de RNA/fisiologia
14.
Histochem Cell Biol ; 152(1): 35-45, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30976911

RESUMO

Prostate autonomic and sensory axons control glandular growth, fluid secretion, and smooth muscle contraction and are remodeled during cancer and inflammation. Morphogenetic signaling pathways reawakened during disease progression may drive this axon remodeling. These pathways are linked to proliferative activities in prostate cancer and benign prostate hyperplasia. However, little is known about which developmental signaling pathways guide axon investment into prostate. The first step in defining these pathways is pinpointing when axon subtypes first appear in prostate. We accomplished this by immunohistochemically mapping three axon subtypes (noradrenergic, cholinergic, and peptidergic) during fetal, neonatal, and adult stages of mouse prostate development. We devised a method for peri-prostatic axon density quantification and tested whether innervation is uniform across the proximo-distal axis of dorsal and ventral adult mouse prostate. Many axons directly interact with or innervate neuroendocrine cells in other organs, so we examined whether sensory or autonomic axons innervate neuroendocrine cells in prostate. We first detected noradrenergic, cholinergic, and peptidergic axons in prostate at embryonic day (E) 14.5. Noradrenergic and cholinergic axon densities are uniform across the proximal-distal axis of adult mouse prostate while peptidergic axons are denser in the periurethral and proximal regions. Peptidergic and cholinergic axons are closely associated with prostate neuroendocrine cells whereas noradrenergic axons are not. These results provide a foundation for understanding mouse prostatic axon development and organization and, provide strategies for quantifying axons during progression of prostate disease.


Assuntos
Axônios/metabolismo , Próstata/embriologia , Próstata/inervação , Animais , Axônios/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Próstata/citologia , Próstata/patologia
15.
Int J Mol Sci ; 20(7)2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30978957

RESUMO

The complexity of central nervous system (CNS) degenerative/inflammatory diseases and the lack of substantially effective treatments point to the need for a broader therapeutic approach to target multiple components involved in the disease pathogenesis. We suggest a novel approach directed for the elimination of pathogenic agents from the CNS and, in parallel, its enrichment with an array of neuroprotective substances, using a "cerebrospinal fluid (CSF) exchange" procedure, in which endogenous (pathogenic) CSF is removed and replaced by artificial CSF (aCSF) enriched with secretions of human mesenchymal stem cells (MSCs). MSCs produce a variety of neuroprotective agents and have shown beneficial effects when cells are transplanted in animals and patients with CNS diseases. Our data show that MSCs grown in aCSF secrete neurotrophic factors, anti-inflammatory cytokines, and anti-oxidant agents; moreover, MSC-secretions-enriched-aCSF exerts neuroprotective and immunomodulatory effects in neuronal cell lines and spleen lymphocytes. Treatment of experimental-autoimmune-encephalomyelitis (EAE) mice with this enriched-aCSF using an intracerebroventricular (ICV) CSF exchange procedure ("CSF exchange therapy") caused a significant delay in the onset of EAE and amelioration of the clinical symptoms, paralleled by a reduction in axonal damage and demyelination. These findings point to the therapeutic potential of the CSF exchange therapy using MSC-secretions-enriched-aCSF in inflammatory/degenerative diseases of the CNS.


Assuntos
Líquido Cefalorraquidiano/química , Encefalomielite Autoimune Experimental/líquido cefalorraquidiano , Encefalomielite Autoimune Experimental/terapia , Hidratação , Células-Tronco Mesenquimais/química , Animais , Axônios/patologia , Linhagem Celular , Células Cultivadas , Doenças Desmielinizantes/líquido cefalorraquidiano , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/terapia , Encefalomielite Autoimune Experimental/patologia , Feminino , Hidratação/métodos , Humanos , Camundongos Endogâmicos C57BL
16.
J Mol Histol ; 50(3): 263-271, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31016544

RESUMO

Oxidative stress with mitochondrial defects has a central role in the development and deterioration of Multiple sclerosis (MS). According to new findings of the effects of metformin on mitochondrial function, has attracted a lot of attention. Furthermore, it is suggested that metformin exerts its beneficial influence through AMP-activated protein kinase (AMPK) pathway. In the current study, we investigated the possible protective effects of metformin on oxidative stress and mitochondrial function by activating the AMPK pathway in the cuprizone-induced demyelination. Mice were fed with cuprizone for 6 weeks. Animals simultaneously received metformin. After sacrificing animals, myelinations, and gliosis, changes in transcription factor and biochemical analysis were assessed. Transmission electron microscopy and luxol fast blue staining revealed that the myelinated axons within corpus callosum of cuprizone-induced demyelination animals increased after administration of metformin. Metformin also upregulated the expression of mitochondrial biogenesis genes. Furthermore, the biochemical analysis demonstrated that metformin ameliorated the oxidative stress induced by cuprizone. Immunohistochemistry analysis showed that astrogliosis and microgliosis were decreased after metformin administration while it enhanced the number of oligodendrocytes. Our data implicated that metformin exerts its therapeutic effects on MS by AMPK signaling improved mitochondrial homeostasis and protected oligodendrocytes.


Assuntos
Metformina/administração & dosagem , Mitocôndrias/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Proteínas Quinases/genética , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Hemostasia/efeitos dos fármacos , Hemostasia/genética , Humanos , Camundongos , Mitocôndrias/genética , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/patologia , Oligodendroglia/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
17.
Neurochem Res ; 44(7): 1533-1548, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30941547

RESUMO

Iron oxide (Fe2O3) nanoparticles (NPs) attract the attention of clinicians for its unique magnetic and paramagnetic properties, which are exclusively used in neurodiagnostics and therapeutics among the other biomedical applications. Despite numerous research findings has already proved neurotoxicity of Fe2O3-NPs, factors affecting neurobehaviour has not been elucidated. In this study, mice were exposed to Fe2O3-NPs (25 and 50 mg/kg body weight) by oral intubation daily for 30 days. It was observed that Fe2O3-NPs remarkably impair motor coordination and memory. In the treated brain regions, mitochondrial damage, depleted energy level and decreased ATPase (Mg2+, Ca2+ and Na+/K+) activities were observed. Disturbed ion homeostasis and axonal demyelination in the treated brain regions contributes to poor motor coordination. Increased intracellular calcium ([Ca2+]i) and decreased expression of growth associated protein 43 (GAP43) impairs vesicular exocytosis could result in insufficient signal between neurons. In addition, levels of dopamine (DA), norepinephrine (NE) and epinephrine (EP) were found to be altered in the subjected brain regions in correspondence to the expression of monoamine oxidases (MAO). Along with all these factors, over expression of glial fibrillary acidic protein (GFAP) confirms the neuronal damage, suggesting the evidences for behavioural changes.


Assuntos
Comportamento Animal/efeitos dos fármacos , Compostos Férricos/toxicidade , Nanopartículas Metálicas/toxicidade , Monoaminoxidase/metabolismo , Trifosfato de Adenosina/metabolismo , Administração Oral , Animais , Axônios/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Doenças Desmielinizantes/etiologia , Exocitose/efeitos dos fármacos , Compostos Férricos/administração & dosagem , Compostos Férricos/química , Proteínas de Choque Térmico HSP27/metabolismo , Ferro/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/química , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Atividade Motora/efeitos dos fármacos
18.
BMC Neurol ; 19(1): 62, 2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-30979362

RESUMO

BACKGROUND: Trigeminal neuralgia (TN) is characterized by facial pain that may be sudden, intense, and recurrent. Neurosurgical interventions, such as radiofrequency rhizotomy, can relieve TN pain, but their mechanisms and effects are unknown. The aim of the present study was to investigate the microstructural tissue changes of the trigeminal nerve (TGN) in patients with TN after they underwent radiofrequency rhizotomy. METHODS: Thirty-seven patients with TN were recruited, and diffusion tensor imaging was obtained before and two weeks after radiofrequency rhizotomy. By manually selecting the cisternal segment of the TGN, we measured the volume of the TGN, fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD), and radial diffusivity (RD). The TGN volume and mean value of the DTI metrics of the post-rhizotomy lesion side were compared with those of the normal side and those of the pre-rhizotomy lesion side, and they were correlated to the post-rhizotomy visual analogue scale (VAS) pain scores after a one-year follow-up. RESULTS: The alterations before and after rhizotomy showed a significantly increased TGN volume and FA, and a decreased ADC, AD, and RD. The post-rhizotomy lesion side showed a significantly decreased TGN volume, FA, and AD compared with the normal side; however, no significant difference in the ADC and RD were found between the groups. The TGN volume was significantly higher in the non-responders than in the responders (P = 0.016). CONCLUSION: Our results may reflect that the effects of radiofrequency rhizotomy in TN patients include axonal damage with perineural edema and that prolonged swelling associated with recurrence might be predicted by MRI images. Further studies are necessary to understand how DTI metrics can quantitatively represent the pathophysiology of TN and to examine the application of DTI in the treatment of TN.


Assuntos
Nervo Trigêmeo/diagnóstico por imagem , Nervo Trigêmeo/patologia , Neuralgia do Trigêmeo/diagnóstico por imagem , Neuralgia do Trigêmeo/patologia , Neuralgia do Trigêmeo/cirurgia , Adulto , Axônios/patologia , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rizotomia , Resultado do Tratamento , Nervo Trigêmeo/cirurgia
19.
Int J Mol Sci ; 20(4)2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30823515

RESUMO

BACKGROUND: Spinal cord (SC) lesions in Theiler's murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) resemble important features of brain lesions in progressive multiple sclerosis (MS) including inflammation, demyelination, and axonal damage. The aim of the present study was a comparison of SC lesions in MS and TMEV-IDD focusing on spatial and temporal distribution of demyelination, inflammation, SC atrophy (SCA), and axonal degeneration/loss in major descending motor pathways. METHODS: TMEV and mock-infected mice were investigated clinically once a week. SC tissue was collected at 42, 98, 147, and 196 days post infection, and investigated using hematoxylin and eosin (HE) staining, immunohistochemistry targeting myelin basic protein (demyelination), Mac3 (microglia/macrophages), phosphorylated neurofilaments (axonal damage) and transmission electron microscopy. RESULTS: Demyelination prevailed in SC white matter in TMEV-IDD, contrasting a predominant gray matter involvement in MS. TMEV-infected mice revealed a significant loss of axons similar to MS. Ultrastructural analysis in TMEV-IDD revealed denuded axons, degenerative myelin changes, axonal degeneration, as well as remyelination. SCA is a consistent finding in the SC of MS patients and was also detected at a late time point in TMEV-IDD. CONCLUSION: This comparative study further indicates the suitability of TMEV-IDD as animal model also for the investigation of progressive SC lesions in MS.


Assuntos
Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/virologia , Modelos Animais de Doenças , Esclerose Múltipla/patologia , Doenças da Medula Espinal/patologia , Medula Espinal/patologia , Theilovirus , Animais , Axônios/patologia , Feminino , Imuno-Histoquímica/métodos , Camundongos
20.
Int J Mol Sci ; 20(6)2019 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-30909624

RESUMO

Peripheral nerve injury is a common posttraumatic complication. The precise surgical repair of nerve lesion does not always guarantee satisfactory motor and sensory function recovery. Therefore, enhancement of the regeneration process is a subject of many research strategies. It is believed that polyethylene glycol (PEG) mediates axolemmal fusion, thus enabling the direct restoration of axon continuity. It also inhibits Wallerian degeneration and recovers nerve conduction. This systemic review, performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, describes and summarizes published studies on PEG treatment efficiency in various nerve injury types and repair techniques. Sixteen original experimental studies in animal models and one in humans were analyzed. PEG treatment superiority was reported in almost all experiments (based on favorable electrophysiological, histological, or behavioral results). To date, only one study attempted to transfer the procedure into the clinical phase. However, some technical aspects, e.g., the maximal delay between trauma and successful treatment, await determination. PEG therapy is a promising prospect that may improve the surgical treatment of peripheral nerve injuries in the clinical practice.


Assuntos
Regeneração Nervosa/efeitos dos fármacos , Polietilenoglicóis/farmacologia , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Traumatismos dos Nervos Periféricos/etiologia , Polietilenoglicóis/uso terapêutico , Recuperação de Função Fisiológica/efeitos dos fármacos , Resultado do Tratamento
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