RESUMO
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by TDP-43 inclusions in the cortical and spinal motor neurons. It remains unknown whether and how pathogenic TDP-43 spreads across neural connections to progress degenerative processes in the cortico-spinal motor circuitry. Here we established novel mouse ALS models that initially induced mutant TDP-43 inclusions in specific neuronal or cell types in the motor circuits, and investigated whether TDP-43 and relevant pathological processes spread across neuronal or cellular connections. We first developed ALS models that primarily induced TDP-43 inclusions in the corticospinal neurons, spinal motor neurons, or forelimb skeletal muscle, by using adeno-associated virus (AAV) expressing mutant TDP-43. We found that TDP-43 induced in the corticospinal neurons was transported along the axons anterogradely and transferred to the oligodendrocytes along the corticospinal tract (CST), coinciding with mild axon degeneration. In contrast, TDP-43 introduced in the spinal motor neurons did not spread retrogradely to the cortical or spinal neurons; however, it induced an extreme loss of spinal motor neurons and subsequent degeneration of neighboring spinal neurons, suggesting a degenerative propagation in a retrograde manner in the spinal cord. The intraspinal degeneration further led to severe muscle atrophy. Finally, TDP-43 induced in the skeletal muscle did not propagate pathological events to spinal neurons retrogradely. Our data revealed that mutant TDP-43 spread across neuro-glial connections anterogradely in the corticospinal pathway, whereas it exhibited different retrograde degenerative properties in the spinal circuits. This suggests that pathogenic TDP-43 may induce distinct antero- and retrograde mechanisms of degeneration in the motor system in ALS.
Assuntos
Esclerose Lateral Amiotrófica , Degeneração Retrógrada , Animais , Camundongos , Esclerose Lateral Amiotrófica/patologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Neurônios Motores/metabolismo , Degeneração Retrógrada/metabolismo , Degeneração Retrógrada/patologia , Medula Espinal/patologiaRESUMO
BACKGROUND: Optical coherence tomography (OCT) gives the opportunity to examine retrograde degeneration of visual pathway damaged at various levels. OBJECTIVE: To estimate OCT data on retrograde degeneration of visual pathway damaged at various levels. MATERIAL AND METHODS: Ganglion cell layer (GCL) thickness was measured by OCT in 79 patients with visual pathway damaged at various levels and known duration of visual disturbances. Twenty-One patients were diagnosed with traumatic lesions of the optic nerves and/or chiasma. Fifty-eight patients had retro-genicular visual pathway damage. Thirty-three patients were examined for postoperative homonymous hemianopia after surgery for drug-resistant temporal lobe epilepsy. Twenty-five patients were diagnosed with occipital lobe damage following stroke (12 patients), surgery for arteriovenous malformation (11 patients) and traumatic brain injury (2 patients). All patients underwent assessment of visual acuity, automatic static perimetry, MRI/CT of the brain. Retinal ganglion cell complex was analyzed during OCT. RESULTS: GCL thinning following anterior visual pathway damage was detected in 20 out of 21 patients after ≥22 days. In case of post-genicular visual pathway damage, GCL thinning was found in 25 out of 58 patients (9 out of 33 ones after surgery for temporal lobe epilepsy and 16 out of 25 patients with occipital lobe lesion). After surgery for temporal lobe epilepsy, minimum period until GCL thinning detection after previous visual pathway damage was 3 months, in case of occipital lobe lesion - 5 months. CONCLUSION: Retrograde visual pathway degeneration is followed by GCL thinning and depends on the level of visual pathway lesion.
Assuntos
Degeneração Retrógrada , Vias Visuais , Humanos , Lobo Occipital/patologia , Células Ganglionares da Retina/patologia , Degeneração Retrógrada/patologia , Tomografia de Coerência Óptica , Vias Visuais/diagnóstico por imagem , Vias Visuais/patologiaRESUMO
BACKGROUND: Transection-induced axonal retrograde degeneration, in contrast to Wallerian degeneration, has not been widely recognized in clinical practice. AIMS OF THE STUDY: To assess a potential of corticospinal tractography for detecting axonal retrograde degeneration. METHODS: We assessed the corticospinal tractography of a 74-year-old woman with monoplegia of the lower limb due to a unilateral thoracic spinal cord tumor. RESULTS: The tractography revealed integrity reduction of the corticospinal tract in the cerebra contralateral to the spinal cord tumor. CONCLUSIONS: The present report supports that magnetic resonance tractography has the potential for detecting this under-recognized phenomenon.
Assuntos
Traumatismos da Medula Espinal , Neoplasias da Medula Espinal , Idoso , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Tratos Piramidais/diagnóstico por imagem , Tratos Piramidais/patologia , Degeneração Retrógrada/patologia , Medula Espinal/patologia , Neoplasias da Medula Espinal/diagnóstico por imagem , Neoplasias da Medula Espinal/patologiaRESUMO
INTRODUCTION: Pituitary adenomas comprise approximately 10% of all intracranial tumors. Initially, subtle changes occur in the field of vision, which are difficult to assess clinically. It has been seen that following surgery of pituitary macroadenoma, total recovery of normal vision occurs in 35% of the patients, improvement of vision occurs in 60%, and in the rest there is no change in vision. Retinal nerve fiber layer thickness (RNFLT) undergoes retrograde degeneration following compression of optic apparatus by pituitary tumor. We planned a study to evaluate RNFLT before and after pituitary adenoma surgery and its correlation with visual acuity. MATERIAL AND METHODS: Twenty patients (40 eyes) with diagnosed pituitary adenoma were included in the study. Preoperative visual acuity, fundus and RNFL thickness were calculated using spectral-domain OCT Optovue, Heidelberg Engineering, Heidelberg, Germany (RT 100 version 5.1), and postoperative measurement was done after 1 and 3 months. Four-quadrant mean of RNFLT was calculated. Results were tabulated and analyzed. STATISTICAL ANALYSIS: Results of the study were analyzed using IBM SPSS Statistics version 19.0. RESULTS: There was no significant change in RNFLT after pituitary adenoma surgery, and it was found that patients with RNFLT within normal range preoperatively showed improvement in visual acuity after pituitary surgery. On the other hand, patients who had thinned-out RNFLT preoperatively showed no improvement in visual acuity. It was also found that once optic disc pallor sets due to chronic compression, then chances of its reversion to normal depend on its grading: only mild pallor disc has some chance to revert to normal, whereas moderate and severe pallor do not revert to normal. CONCLUSION: RNFLT and optic disc can be used as prognostic factors for evaluation of visual outcome in pituitary adenoma surgery.
Assuntos
Adenoma/cirurgia , Fibras Nervosas/patologia , Neoplasias Hipofisárias/cirurgia , Retina/diagnóstico por imagem , Neurônios Retinianos/patologia , Degeneração Retrógrada/diagnóstico por imagem , Transtornos da Visão/fisiopatologia , Acuidade Visual , Adenoma/complicações , Adenoma/fisiopatologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/fisiopatologia , Período Pré-Operatório , Retina/patologia , Degeneração Retrógrada/etiologia , Degeneração Retrógrada/patologia , Degeneração Retrógrada/fisiopatologia , Tomografia de Coerência Óptica , Resultado do Tratamento , Transtornos da Visão/etiologia , Adulto JovemRESUMO
BACKGROUND: Hypertrophic olivary degeneration (HOD) is very rare type of degeneration that causes hypertrophy rather than atrophy. The classical presentation of HOD is palatal myoclonus. However, HOD may rarely present with Holmes tremor (HT). HT is unusual symptomatic tremor characterized by combination of rest and intention tremor. It has been reported in small case series, so far. CASE DESCRIPTION: In this study, a man aged 62 years with HOD and HT spreading to the upper and lower extremities after pontine-midbrain hemorrhage due to cavernoma was presented. CONCLUSIONS: Although pontine-midbrain hemorrhage may cause HT in the late period, HOD can be revealed on magnetic resonance imaging. Tract anatomy, especially the Guillain-Mollaret triangle, should be considered to explain the relationship between HT and HOD.
Assuntos
Neoplasias do Tronco Encefálico/complicações , Hemangioma Cavernoso do Sistema Nervoso Central/complicações , Hemorragias Intracranianas/etiologia , Núcleo Olivar/diagnóstico por imagem , Degeneração Retrógrada/etiologia , Tremor/etiologia , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico por imagem , Humanos , Hipertrofia , Hemorragias Intracranianas/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Pedúnculo Cerebelar Médio/diagnóstico por imagem , Núcleo Olivar/patologia , Ponte/diagnóstico por imagem , Núcleo Rubro/diagnóstico por imagem , Degeneração Retrógrada/diagnóstico por imagem , Degeneração Retrógrada/patologia , Tomografia Computadorizada por Raios X , Tremor/diagnóstico por imagemRESUMO
BACKGROUND: Retinal thinning after a retrogeniculate lesion (transsynaptic retrograde degeneration) was first described 50 years ago, but has long been a controversial issue. It is now possible to use OCT for the in vivo measurement of retinal thickness. MATERIAL AND METHODS: This was a retrospective study of patients with homonymous visual field loss, with SD-OCT assessment (RNFL and RGCL measurements) in isolated retrogeniculate lesions, subsequently confirmed by a neuroradiologist. RESULTS: Nine patients with vascular, inflammatory or tumour brain lesions were included in the study. Homonymous RGCL thinning was found in all patients, and correlated with the visual field defect. No correlation was found with RNFL. CONCLUSIONS: The homonymous defect of RGCL in patients with retrogeniculate lesions demonstrates the presence of transsynaptic retrograde degeneration. RGCL is a better predictor of visual field defects than RNFL measurement.
Assuntos
Retina/patologia , Degeneração Retiniana/patologia , Células Ganglionares da Retina/patologia , Degeneração Retrógrada/patologia , Tomografia de Coerência Óptica/métodos , Vias Visuais/patologia , Adulto , Idoso , Diagnóstico Diferencial , Medicina Baseada em Evidências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: Retrograde trans-synaptic degeneration of retinal ganglion cell layer (GCL) has been proposed as one of the mechanisms contributing to permanent disability after visual pathway damage. We set out to test this mechanism taking advantage of the new methods for imaging the macula with high resolution by optical coherence tomography (OCT) in patients with lesions in the posterior visual pathway. Additionally, we explored the association between thinning of GCL as an imaging marker of visual impairment such as visual field defects. METHODS: Retrospective case note review of patients with retrogeniculate lesions studied by spectral domain OCT of the macula and quadrant pattern deviation (PD) of the visual fields. RESULTS: We analysed 8 patients with either hemianopia or quadrantanopia due to brain lesions (stroke â=â5; surgery â=â2; infection â=â1). We found significant thinning of the GCL in the projecting sector of the retina mapping to the brain lesion. Second, we found strong correlation between the PD of the visual field quadrant and the corresponding macular GCL sector for the right (Râ=â0.792, p<0.001) and left eyes (Râ=â0.674, p<0.001). CONCLUSIONS: The mapping between lesions in the posterior visual pathway and their projection in the macula GCL sector corroborates retrograde trans-synaptic neuronal degeneration after brain injury as a mechanism of damage with functional consequences. This finding supports the use of GCL thickness as an imaging marker of trans-synaptic degeneration in the visual pathway after brain lesions.
Assuntos
Células Ganglionares da Retina/patologia , Degeneração Retrógrada/patologia , Sinapses/patologia , Vias Visuais/patologia , Adolescente , Adulto , Idoso , Atrofia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Degeneração Retrógrada/fisiopatologia , Estudos Retrospectivos , Campos Visuais , Imagens com Corantes Sensíveis à Voltagem , Adulto JovemRESUMO
Atrophy of upper motor neurons hampers axonal regeneration and functional recovery following spinal cord injury (SCI). Apart from the severity of primary injury, a series of secondary pathological damages including spinal cord edema and glial scar formation affect the fate of injured upper motor neurons. The aquaporin-4 (AQP4) water channel plays a critical role in water homeostasis and migration of astrocytes in the central nervous system, probably offering a new therapeutic target for protecting against upper motor neuron degeneration after SCI. To test this hypothesis, we examined the effect of AQP4 deficiency on atrophy of rubrospinal neurons after unilateral rubrospinal tract transection at the fourth cervical level in mice. AQP4 gene knockout (AQP4-/-) mice exhibited high extent of spinal cord edema at 72 h after lesion compared with wild-type littermates. AQP4-/- mice showed impairments in astrocyte migration toward the transected site with a greater lesion volume at 1 week after surgery and glial scar formation with a larger cyst volume at 6 weeks. More severe atrophy and loss of axotomized rubrospinal neurons as well as axonal degeneration in the rubrospinal tract rostral to the lesion were observed in AQP4-/- mice at 6 weeks after SCI. AQP4 expression was downregulated at the lesioned spinal segment at 3 days and 1 week after injury, but upregulated at 6 weeks. These results demonstrated that AQP4 not only mitigates spinal cord damage but also ameliorates retrograde degeneration of rubrospinal neurons by promoting edema clearance and glial scar formation after laceration SCI. This finding supports the notion that AQP4 may be a promising therapeutic target for SCI.
Assuntos
Aquaporina 4/deficiência , Cicatriz/metabolismo , Edema/metabolismo , Neuroglia/metabolismo , Degeneração Retrógrada/metabolismo , Traumatismos da Medula Espinal/metabolismo , Animais , Vértebras Cervicais/metabolismo , Vértebras Cervicais/patologia , Cicatriz/patologia , Edema/patologia , Feminino , Camundongos , Camundongos Knockout , Neuroglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Núcleo Rubro/metabolismo , Núcleo Rubro/patologia , Degeneração Retrógrada/patologia , Traumatismos da Medula Espinal/patologiaRESUMO
BACKGROUND: Optic radiation (OR) damage occurs in multiple sclerosis (MS). OBJECTIVES: The purpose of this study was to explore the contribution of local and distant mechanisms associated with OR damage in MS. METHODS: Diffusion tensor (DT) magnetic resonance imaging (MRI) tractography probability maps of the ORs were derived from 102 MS patients and 11 controls. Between-group differences of OR normal-appearing white matter (NAWM) damage and topographical distribution of OR damage were assessed using quantitative and voxel-wise analyses, considering the influence of previous optic neuritis (ON+) and T2 OR lesions (T2 OR+). RESULTS: OR NAWM diffusivity abnormalities were more severe in ON+ patients vs patients without previous optic neuritis (ON-) and T2 OR+ vs T2 OR- patients. Damage to the anterior portions of the ORs was more severe in ON+ vs ON- patients. Compared to controls and T2 OR- patients, T2 OR+ patients experienced a more distributed pattern of DT MRI abnormalities along the ORs, with an increased axial diffusivity limited to the anterior portions of the ORs. In T2 OR+ group, ON+ vs ON- patients showed DT MRI abnormalities in the middle portion of the ORs, in correspondence with focal lesions. OR damage correlated with OR T2 lesion volume, visual dysfunction and optic nerve atrophy. CONCLUSIONS: Both trans-synaptic degeneration secondary to optic nerve damage and Wallerian degeneration due to local T2 lesions contribute to OR damage in MS.
Assuntos
Esclerose Múltipla/complicações , Esclerose Múltipla/patologia , Degeneração Retrógrada/etiologia , Degeneração Retrógrada/patologia , Vias Visuais/patologia , Degeneração Walleriana/etiologia , Degeneração Walleriana/patologia , Adulto , Atrofia , Mapeamento Encefálico , Imagem de Tensor de Difusão , Avaliação da Deficiência , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Nervo Óptico/patologia , Neurite Óptica/etiologia , Neurite Óptica/patologia , Adulto JovemRESUMO
Atrophy, the wasting or shrinkage of tissue, of the nervous system is the main feature of neurodegeneration, i.e. the umbrella term for the progressive loss of structure or function of neurons. Loss of neurons due to cell death and axonal degeneration characterize neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease or amyotrophic lateral sclerosis. In these illnesses, it still has to be elucidated to which extent inflammation is part of the pathology. Conversely, in chronic inflammation of the central nervous system (CNS), atrophy has previously also been described and neurodegeneration is discussed as a pathologic feature. The most frequent chronic inflammatory disease of the CNS is multiple sclerosis (MS), which leads to devastating relapsing-remitting symptoms and disability during the relapses, increasingly during the course of disease in patients. Meanwhile it became clear that axons already reveal pathology early in the disease and neurons are affected in the cortex and the spinal cord, albeit to a different extent. The broadening of understanding neurodegenerative aspects of MS pathology demands and creates new therapeutic strategies. Current medication used in MS treatment as well as medications about to be approved are primarily anti-inflammatory therapies. By modulating the immune system and thereby blocking key steps of the pathology, the immunomodulation therapies in MS have a slight impact on disability progression. There is, however, clinical and experimental data concerning the potential neuroprotective properties of novel therapies. Combining anti-inflammatory and direct neuroprotective or even neuroregenerative therapy strategies would be a step forward in the treatment of multiple sclerosis.
Assuntos
Esclerose Múltipla/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Alemtuzumab , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Axônios/efeitos dos fármacos , Axônios/imunologia , Axônios/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/patologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Progressão da Doença , Humanos , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Regeneração Nervosa/efeitos dos fármacos , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/patologia , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios/patologia , Prognóstico , Degeneração Retrógrada/tratamento farmacológico , Degeneração Retrógrada/imunologia , Degeneração Retrógrada/patologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/patologiaRESUMO
Axon degeneration is a hallmark of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Such degeneration is not a passive event but rather an active process mediated by mechanisms that are distinct from the canonical pathways of programmed cell death that mediate destruction of the cell soma. Little is known of the diverse mechanisms involved, particularly those of retrograde axon degeneration. We have previously observed in living animal models of degeneration in the nigrostriatal projection that a constitutively active form of the kinase, myristoylated Akt (Myr-Akt), demonstrates an ability to suppress programmed cell death and preserve the soma of dopamine neurons. Here, we show in both neurotoxin and physical injury (axotomy) models that Myr-Akt is also able to preserve dopaminergic axons due to suppression of acute retrograde axon degeneration. This cellular phenotype is associated with increased mammalian target of rapamycin (mTor) activity and can be recapitulated by a constitutively active form of the small GTPase Rheb, an upstream activator of mTor. Axon degeneration in these models is accompanied by the occurrence of macroautophagy, which is suppressed by Myr-Akt. Conditional deletion of the essential autophagy mediator Atg7 in adult mice also achieves striking axon protection in these acute models of retrograde degeneration. The protection afforded by both Myr-Akt and Atg7 deletion is robust and lasting, because it is still observed as protection of both axons and dopaminergic striatal innervation weeks after injury. We conclude that acute retrograde axon degeneration is regulated by Akt/Rheb/mTor signaling pathways.
Assuntos
Autofagia/fisiologia , Axônios/metabolismo , Dopamina/metabolismo , Neurônios/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Degeneração Retrógrada/metabolismo , Degeneração Retrógrada/patologia , Animais , Autofagia/efeitos dos fármacos , Proteína 7 Relacionada à Autofagia , Axônios/efeitos dos fármacos , Axônios/ultraestrutura , Dependovirus/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Proteínas de Fluorescência Verde/genética , Feixe Prosencefálico Mediano/patologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Microscopia Eletrônica de Transmissão/métodos , Proteínas Associadas aos Microtúbulos/metabolismo , Oxidopamina/efeitos adversos , Proteínas Proto-Oncogênicas c-akt/genética , Degeneração Retrógrada/etiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Substância Negra/patologia , Serina-Treonina Quinases TOR/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Although retrograde transsynaptic degeneration in the visual pathway of monkeys has been described since 1963, data in humans are sparse. The authors present a 24-year-old female referred to a neuro-ophthalmology consult for assessment before neurosurgery for a right occipital ependymoma. Clinical examination was unremarkable, including visual fields evaluated by computerised static perimetry. Four years after tumour extraction, the patient showed a left homonymous haemianopia documented by computerised static perimetry and a bow-tie like atrophy on the left on funduscopy. MRI revealed right occipital cortex lobectomy and optic tract atrophy. The presence of left homonymous haemianopia, the characteristic pattern of optic disc atrophy and right optic tract atrophy 4 years after right occipital tumour excision, strongly suggest the presence of retrograde transsynaptic degeneration. To our knowledge, this is the first time that retrograde transsynaptic degeneration-associated optic tract atrophy is clearly demonstrated by MRI.
Assuntos
Imageamento por Ressonância Magnética , Atrofia Óptica/diagnóstico , Degeneração Retrógrada/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Atrofia Óptica/patologia , Degeneração Retrógrada/patologia , Tomografia de Coerência Óptica , Adulto JovemRESUMO
The mechanism underlying axotomy-induced motoneuron loss is not fully understood, but appears to involve molecular changes within the injured motoneuron and the surrounding local microenvironment (neuropil). The mouse facial nucleus consists of six subnuclei which respond differentially to facial nerve transection at the stylomastoid foramen. The ventromedial (VM) subnucleus maintains virtually full facial motoneuron (FMN) survival following axotomy, whereas the ventrolateral (VL) subnucleus results in significant FMN loss with the same nerve injury. We hypothesized that distinct molecular phenotypes of FMN existed within the two subregions, one responsible for maintaining cell survival and the other promoting cell death. In this study, we used laser microdissection to isolate VM and VL facial subnuclear regions for molecular characterization. We discovered that, regardless of neuronal fate after injury, FMN in either subnuclear region respond vigorously to injury with a characteristic "regenerative" profile and additionally, the surviving VL FMN appear to compensate for the significant FMN loss. In contrast, significant differences in the expression of pro-inflammatory cytokine mRNA in the surrounding neuropil response were found between the two subnuclear regions of the facial nucleus that support a causative role for glial and/or immune-derived molecules in directing the contrasting responses of the FMN to axonal transection.
Assuntos
Nervo Facial/patologia , Nervo Facial/fisiopatologia , Terapia a Laser/métodos , Microdissecção/métodos , Neurônios Motores/metabolismo , Neurópilo/metabolismo , Fenótipo , Animais , Axotomia/instrumentação , Axotomia/métodos , Modelos Animais de Doenças , Nervo Facial/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Microdissecção/instrumentação , Neurônios Motores/patologia , Neurópilo/patologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Degeneração Retrógrada/metabolismo , Degeneração Retrógrada/patologia , Degeneração Retrógrada/fisiopatologia , Núcleos Ventrais do Tálamo/metabolismo , Núcleos Ventrais do Tálamo/patologia , Núcleos Ventrais do Tálamo/fisiopatologiaRESUMO
STUDY DESIGN: This study was aimed at investigating changes in the dorsal horn of the lumbar cord induced by mechanical compression using an in vivo model. OBJECTIVE: To determine the effect of axonal flow disturbance in the dorsal horns induced by nerve root compression. SUMMARY OF BACKGROUND DATA: Few studies have looked at changes of synapses within the dorsal horn caused by disturbance of axonal flow and the axon reaction as a result of mechanical compression of the dorsal root. METHODS: In mongrel dogs, the 7th lumbar nerve root was compressed for 1 week, or 3 weeks using a clip. After intravenous injection of Evans blue albumin, they were observed under a fluorescence microscope for the purpose of clarifying the function of the blood-spinal cord barrier. Morphologic changes of the synapses in the dorsal horns secondary to the nerve fiber degeneration were examined by light and electron microscope. Changes on immuno-staining for substance P, calcitonin gene-related peptide, and somatostatin in the dorsal horn were also examined. RESULTS: Light microscope observation conducted 1 week after compression of the nerve roots revealed Wallerian degeneration of the myelinated nerve in the dorsal horn, and fluorescence microscope observation of these areas demonstrated edema formation resulting from damage of the blood-spinal cord barrier. Three weeks after the compression, electron microscope observation revealed shrinkage of the axon terminals, ubiquitous presence of high electron density degeneration and presence of synapses whose contact with synapses was disrupted. Immuno-histochemical studies showed a marked decrease of substance P, calcitonin gene-related peptide, and somatostatin staining in substance gelatinosa with Wallerian degeneration after compression of nerve root. CONCLUSION: It is important to recognize that compressive disturbance of the nerve roots caused Wallerian degeneration not only at the site of compression of nerve roots but also at the synapses of spinal cord dorsal horns.
Assuntos
Células do Corno Anterior/ultraestrutura , Síndromes de Compressão Nervosa/patologia , Síndromes de Compressão Nervosa/fisiopatologia , Raízes Nervosas Espinhais/ultraestrutura , Animais , Células do Corno Anterior/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Modelos Animais de Doenças , Cães , Técnicas Imunoenzimáticas , Vértebras Lombares , Microscopia Eletrônica , Síndromes de Compressão Nervosa/metabolismo , Radiculopatia/metabolismo , Radiculopatia/patologia , Radiculopatia/fisiopatologia , Degeneração Retrógrada/patologia , Somatostatina/metabolismo , Estatísticas não Paramétricas , Substância P/metabolismoRESUMO
We have performed intrastriatal injection of thrombin and searched for distant effects in the cell body region. In striatum, thrombin produced a slight loss of striatal neurons as demonstrated by neural nuclei immunostaining - a non-specific neuronal marker - and the expression of glutamic acid decarboxylase 67 mRNA, a specific marker for striatal GABAergic interneurons, the most abundant phenotype in this brain area. Interestingly, striatal neuropil contained many boutons immunostained for synaptic vesicle protein 2 and synaptophysin which colocalize with tyrosine hydroxylase (TH), suggesting a degenerative process with pre-synaptic accumulation of synaptic vesicles. When we studied the effects on substantia nigra, we found the disappearance of dopaminergic neurons, shown by loss of TH immunoreactivity, loss of expression of TH and dopamine transporter mRNAs, and disappearance of FluoroGold-labelled nigral neurons. The degeneration of substantia nigra dopaminergic neurons was produced through up-regulation of cFos mRNA, apoptosis and accumulation of alpha-synuclein shown by colocalization experiments. Thrombin effects could be mediated by protease-activated receptor 4 activation, as protease-activated receptor 4-activating peptide mimicked thrombin effects. Our results point out the possible relationship between synapse elimination and retrograde degeneration in the nigral dopaminergic system.
Assuntos
Apoptose/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Degeneração Retrógrada/induzido quimicamente , Substância Negra/fisiopatologia , Sinapses/efeitos dos fármacos , Trombina/toxicidade , Animais , Apoptose/fisiologia , Corpo Estriado/patologia , Corpo Estriado/fisiopatologia , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Feminino , Glutamato Descarboxilase/metabolismo , Glicoproteínas de Membrana/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Vias Neurais/efeitos dos fármacos , Vias Neurais/patologia , Vias Neurais/fisiopatologia , Neurotoxinas/toxicidade , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Terminações Pré-Sinápticas/patologia , Proteínas Proto-Oncogênicas c-fos/genética , Ratos , Ratos Wistar , Receptores de Trombina/efeitos dos fármacos , Receptores de Trombina/metabolismo , Degeneração Retrógrada/patologia , Degeneração Retrógrada/fisiopatologia , Estilbamidinas , Substância Negra/metabolismo , Substância Negra/patologia , Sinapses/metabolismo , Sinapses/patologia , Vesículas Sinápticas/efeitos dos fármacos , Vesículas Sinápticas/metabolismo , Sinaptofisina/efeitos dos fármacos , Sinaptofisina/metabolismo , Tirosina 3-Mono-Oxigenase/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
STUDY DESIGN: The aim of this study is to investigate changes in lumbar motor neurons induced by mechanical nerve root compression using an in vivo model. This study is to investigate the changes of lumbar motor neuron induced by mechanical nerve root compression using in vivo model. OBJECTIVES: The effect of axonal flow disturbance induced by nerve root compression was determined in lumbar motor neuron. SUMMARY OF BACKGROUND DATA: The lumbar motor neuron should not be overlooked when considering the mechanism of weakness, so it is important to understand the morphologic and functional changes that occur in motor neurons of the spinal cord as a result of nerve root compression. However, few studies have looked at changes of neurons within the caused by disturbance of axonal flow, the axon reaction, chromatolysis, and cell death as a result of mechanical compression of the ventral root. METHODS: In mongrel dogs, the seventh lumbar nerve root was compressed for 1 week, or 3 weeks using a clip. Morphologic changes of the motor neurons secondary to the axon reaction were examined by light and electron microscopy. RESULTS: Light and electron microscopy showed central chromatolysis of motor neurons in the lumbar cord from 1 week after the start of compression. After 3 weeks, some neurons undergoing apoptosis were seen in the ventral horn. CONCLUSION: It is important to be aware that, in patients with nerve root compression due to lumbar disc herniation or lumbar canal stenosis, dysfunction is not confined to degeneration at the site of compression but also extends to the motor neurons within the lumbar cord as a result of the axon reaction. Patients with weakness of lower leg should therefore be fully informed of the fact that these symptoms will not resolve immediately after surgery.
Assuntos
Células do Corno Anterior/ultraestrutura , Neurônios Motores/ultraestrutura , Radiculopatia/patologia , Animais , Apoptose , Modelos Animais de Doenças , Cães , Retículo Endoplasmático/ultraestrutura , Vértebras Lombares , Microscopia Eletrônica , Mitocôndrias/ultraestrutura , Corpos de Nissl/ultraestrutura , Radiculopatia/fisiopatologia , Degeneração Retrógrada/patologia , Raízes Nervosas Espinhais/cirurgia , Fatores de TempoRESUMO
Nerve transection induces complex changes in gene regulation and expression that can have profound phenotypic effects on the fate of axotomized neurons. The transcription factors c-Jun and ATF-2 (activating transcription factor-2) are components of a regulatory network that mediates survival, regeneration, and apoptosis following axotomy in rodents. The activation and function of c-Jun and ATF-2 after nerve injury have not been examined in primates. Using a novel model of cranial nerve injury in baboons, we have examined the temporality of c-Jun activation (phosphorylation) in cranial nerve (CN) III and CN VI neurons and ATF-2 activation in CN VI neurons at 2, 4, and 9 days post-injury by immunohistochemistry. Furthermore, we have addressed whether the activation of these factors is associated with apoptosis by the TUNEL assay. We report that activated c-Jun is present in CN III and CN VI neurons ipsilateral to axotomy at 2, 4, and 9 days post-injury, but not in neurons contralateral to injury. Additionally, CN VI neurons ipsilateral to injury at 4 and 9 days contain activated ATF-2. Furthermore, no evidence of TUNEL reactivity was observed in either nucleus, regardless of laterality, at any of the examined time points. These findings suggest that activation of both c-Jun and ATF-2 does not mediate apoptosis in axotomized primate CN III and CN VI neurons at time points up to 9 days. This report serves as a basic inquiry into the neuronal response to cranial nerve injury in primates.
Assuntos
Apoptose/fisiologia , Traumatismos dos Nervos Cranianos/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Neurônios Motores/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Degeneração Retrógrada/metabolismo , Fatores de Transcrição/metabolismo , Nervo Abducente/citologia , Nervo Abducente/metabolismo , Traumatismo do Nervo Abducente/metabolismo , Traumatismo do Nervo Abducente/fisiopatologia , Fator 2 Ativador da Transcrição , Animais , Axotomia , Tronco Encefálico/metabolismo , Tronco Encefálico/patologia , Traumatismos dos Nervos Cranianos/patologia , Traumatismos dos Nervos Cranianos/fisiopatologia , Modelos Animais de Doenças , Progressão da Doença , Lateralidade Funcional/fisiologia , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Masculino , Neurônios Motores/patologia , Nervo Oculomotor/citologia , Nervo Oculomotor/metabolismo , Traumatismos do Nervo Oculomotor , Papio anubis , Fosforilação , Degeneração Retrógrada/patologia , Degeneração Retrógrada/fisiopatologia , Fatores de Tempo , Ativação Transcricional/fisiologiaRESUMO
Lumbosacral cord motoneurons innervating the pubococcygeus muscle (Pcm) at the pelvic floor of male rats were analyzed. We showed previously that these motoneurons participate in sexual functions and are sensitive to fluctuations of systemic androgen and estrogen. Though estrogen receptors have not been identified in Lamina IX at these spinal areas, the release of oxytocin from the paraventricular nucleus of the hypothalamus (PvN) has been found to control pelvic sexual physiology. We therefore worked on the hypothesis that steroid hormones in the PvN induce the release of oxytocin at the lumbosacral level to modulate the function of Pcm motoneurons. Four experiments were developed, and results were observed with the retrograde staining of motoneurons with horseradish peroxidase. Data indicated that morphometric parameters of Pcm motoneurons were significantly reduced after castration or blocking of the steroids at the PvN site, or following complete transection of the spinal cord at the T8 level. In each case, the reduction of the stain was recovered after intrathecal treatment with oxytocin. Thus, present results show that Pcm motoneurons respond to spinal oxytocin. The conclusive model that we propose is that steroids stimulate the PvN, causing the nucleus to release oxytocin at the level of the lumbosacral spinal cord, and the release of the peptide regulates the spread of the stain of Pcm motoneurons. This work also shows that motoneurons distal to a transected area in the spinal cord could respond to exogenous oxytocin, an important finding for the research of spinal cord lesioned subjects.
Assuntos
Neurônios Motores/citologia , Músculo Esquelético/inervação , Ocitocina/metabolismo , Núcleo Hipotalâmico Paraventricular/citologia , Diafragma da Pelve/inervação , Animais , Aromatase/fisiologia , Castração , Hormônios Esteroides Gonadais/fisiologia , Região Lombossacral/anatomia & histologia , Masculino , Neurônios Motores/fisiologia , Músculo Esquelético/fisiologia , Vias Neurais/citologia , Vias Neurais/fisiologia , Ocitocina/fisiologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/fisiologia , Diafragma da Pelve/fisiologia , Ratos , Degeneração Retrógrada/patologia , Comportamento Sexual Animal/fisiologia , Medula Espinal/citologia , Medula Espinal/fisiologia , Coloração e RotulagemRESUMO
Complete stopping of tremor or its essential reduction have been achieved in 55 of 66 patients with Parkinson's disease. In 3 cases, there was a fatal outcome. The microstructural changes of nigrostriatal, thalamus and neocortex neurons are presented, and biopotentials led from these structures, along with clinical and neurophysiological effects of electrostimulation of thalamic and subthalamic regions, are evaluated. The results obtained in the study are used for explanation of tremor mechanism.