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1.
J Vet Sci ; 25(3): e35, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38834505

RESUMO

IMPORTANCE: Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis characterized by inflammation within the central nervous system. However, inflammation in non-neuronal tissues, including the lungs, has not been fully evaluated. OBJECTIVE: This study evaluated the inflammatory response in lungs of EAE mice by immunohistochemistry and histochemistry. METHODS: Eight adult C57BL/6 mice were injected with myelin oligodendrocyte glycoprotein35-55 to induce the EAE. Lungs and spinal cords were sampled from the experimental mice at the time of sacrifice and used for the western blotting, histochemistry, and immunohistochemistry. RESULTS: Histopathological examination revealed inflammatory lesions in the lungs of EAE mice, characterized by infiltration of myeloperoxidase (MPO)- and galectin-3-positive cells, as determined by immunohistochemistry. Increased numbers of collagen fibers in the lungs of EAE mice were confirmed by histopathological analysis. Western blotting revealed significantly elevated level of osteopontin (OPN), cluster of differentiation 44 (CD44), MPO and galectin-3 in the lungs of EAE mice compared with normal controls (p < 0.05). Immunohistochemical analysis revealed both OPN and CD44 in ionized calcium-binding adapter molecule 1-positive macrophages within the lungs of EAE mice. CONCLUSIONS AND RELEVANCE: Taken together, these findings suggest that the increased OPN level in lungs of EAE mice led to inflammation; concurrent increases in proinflammatory factors (OPN and galectin-3) caused pulmonary impairment.


Assuntos
Encefalomielite Autoimune Experimental , Pulmão , Camundongos Endogâmicos C57BL , Animais , Encefalomielite Autoimune Experimental/patologia , Camundongos , Pulmão/patologia , Feminino , Imuno-Histoquímica , Osteopontina/metabolismo , Galectina 3/metabolismo , Peroxidase/metabolismo , Receptores de Hialuronatos/metabolismo , Medula Espinal/patologia , Inflamação/patologia , Western Blotting
2.
Int J Mol Sci ; 25(11)2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38891920

RESUMO

Cancer-related cognitive impairment (CRCI) is a consequence of chemotherapy and extracranial radiation therapy (ECRT). Our prior work demonstrated gliosis in the brain following ECRT in SKH1 mice. The signals that induce gliosis were unclear. Right hindlimb skin from SKH1 mice was treated with 20 Gy or 30 Gy to induce subclinical or clinical dermatitis, respectively. Mice were euthanized at 6 h, 24 h, 5 days, 12 days, and 25 days post irradiation, and the brain, thoracic spinal cord, and skin were collected. The brains were harvested for spatial proteomics, immunohistochemistry, Nanostring nCounter® glial profiling, and neuroinflammation gene panels. The thoracic spinal cords were evaluated by immunohistochemistry. Radiation injury to the skin was evaluated by histology. The genes associated with neurotransmission, glial cell activation, innate immune signaling, cell signal transduction, and cancer were differentially expressed in the brains from mice treated with ECRT compared to the controls. Dose-dependent increases in neuroinflammatory-associated and neurodegenerative-disease-associated proteins were measured in the brains from ECRT-treated mice. Histologic changes in the ECRT-treated mice included acute dermatitis within the irradiated skin of the hindlimb and astrocyte activation within the thoracic spinal cord. Collectively, these findings highlight indirect neuronal transmission and glial cell activation in the pathogenesis of ECRT-related CRCI, providing possible signaling pathways for mitigation strategies.


Assuntos
Medula Espinal , Animais , Camundongos , Medula Espinal/efeitos da radiação , Medula Espinal/metabolismo , Medula Espinal/patologia , Encéfalo/efeitos da radiação , Encéfalo/patologia , Encéfalo/metabolismo , Pele/efeitos da radiação , Pele/patologia , Pele/metabolismo , Neuroglia/metabolismo , Neuroglia/efeitos da radiação , Neuroglia/patologia , Gliose/patologia , Gliose/etiologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/metabolismo , Radioterapia/efeitos adversos
3.
J Neuroinflammation ; 21(1): 154, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38851724

RESUMO

Extracellular vesicles (EVs) are released by all cells, can cross the blood-brain barrier, and have been shown to play an important role in cellular communication, substance shuttling, and immune modulation. In recent years EVs have shifted into focus in multiple sclerosis (MS) research as potential plasma biomarkers and therapeutic vehicles. Yet little is known about the disease-associated changes in EVs in the central nervous system (CNS). To address this gap, we characterized the physical and proteomic changes of mouse spinal cord-derived EVs before and at 16 and 25 days after the induction of experimental autoimmune encephalomyelitis (EAE), a neuroinflammatory model of MS. Using various bioinformatic tools, we found changes in inflammatory, glial, and synaptic proteins and pathways, as well as a shift in the predicted contribution of immune and glial cell types over time. These results show that EVs provide snapshots of crucial disease processes such as CNS-compartmentalized inflammation, re/de-myelination, and synaptic pathology, and might also mediate these processes. Additionally, inflammatory plasma EV biomarkers previously identified in people with MS were also altered in EAE spinal cord EVs, suggesting commonalities of EV-related pathological processes during EAE and MS and overlap of EV proteomic changes between CNS and circulating EVs.


Assuntos
Encefalomielite Autoimune Experimental , Vesículas Extracelulares , Camundongos Endogâmicos C57BL , Medula Espinal , Vesículas Extracelulares/metabolismo , Animais , Medula Espinal/metabolismo , Medula Espinal/patologia , Camundongos , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Proteômica
4.
Acta Neuropathol ; 147(1): 100, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38884646

RESUMO

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with average lifespan of 2-5 years after diagnosis. The identification of novel prognostic and pharmacodynamic biomarkers are needed to facilitate therapeutic development. Metalloprotein human superoxide dismutase 1 (SOD1) is known to accumulate and form aggregates in patient neural tissue with familial ALS linked to mutations in their SOD1 gene. Aggregates of SOD1 have also been detected in other forms of ALS, including the sporadic form and the most common familial form linked to abnormal hexanucleotide repeat expansions in the Chromosome 9 open reading frame 72 (C9ORF72) gene. Here, we report the development of a real-time quaking-induced conversion (RT-QuIC) seed amplification assay using a recombinant human SOD1 substrate to measure SOD1 seeding activity in postmortem spinal cord and motor cortex tissue from persons with different ALS etiologies. Our SOD1 RT-QuIC assay detected SOD1 seeds in motor cortex and spinal cord dilutions down to 10-5. Importantly, we detected SOD1 seeding activity in specimens from both sporadic and familial ALS cases, with the latter having mutations in either their SOD1 or C9ORF72 genes. Analyses of RT-QuIC parameters indicated similar lag phases in spinal cords of sporadic and familial ALS patients, but higher ThT fluorescence maxima by SOD1 familial ALS specimens and sporadic ALS thoracic cord specimens. For a subset of sporadic ALS patients, motor cortex and spinal cords were examined, with seeding activity in both anatomical regions. Our results suggest SOD1 seeds are in ALS patient neural tissues not linked to SOD1 mutation, suggesting that SOD1 seeding activity may be a promising biomarker, particularly in sporadic ALS cases for whom genetic testing is uninformative.


Assuntos
Esclerose Lateral Amiotrófica , Medula Espinal , Superóxido Dismutase-1 , Humanos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/metabolismo , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Medula Espinal/patologia , Medula Espinal/metabolismo , Córtex Motor/patologia , Córtex Motor/metabolismo , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Proteína C9orf72/genética , Mutação/genética
5.
CNS Neurosci Ther ; 30(6): e14692, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38872258

RESUMO

AIM: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease characterized by progressive death of upper and lower motor neurons, leading to generalized muscle atrophy, paralysis, and even death. Mitochondrial damage and neuroinflammation play key roles in the pathogenesis of ALS. In the present study, the efficacy of A-1, a derivative of arctigenin with AMP-activated protein kinase (AMPK) and silent information regulator 1 (SIRT1) activation for ALS, was investigated. METHODS: A-1 at 33.3 mg/kg was administrated in SOD1G93A transgenic mice orally from the 13th week for a 6-week treatment period. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes, and microglia in the spinal cord were evaluated by H&E, Masson, Sirius Red, Nissl, and immunohistochemistry staining. Protein expression was detected with proteomics analysis, Western blotting, and ELISA. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit. RESULTS: A-1 administration in SOD1G93A mice enhanced mobility, decreased skeletal muscle atrophy and fibrosis, mitigated loss of spinal motor neurons, and reduced glial activation. Additionally, A-1 treatment improved mitochondrial function, evidenced by elevated ATP levels and increased expression of key mitochondrial-related proteins. The A-1 treatment group showed decreased levels of IL-1ß, pIκBα/IκBα, and pNF-κB/NF-κB. CONCLUSIONS: A-1 treatment reduced motor neuron loss, improved gastrocnemius atrophy, and delayed ALS progression through the AMPK/SIRT1/PGC-1α pathway, which promotes mitochondrial biogenesis. Furthermore, the AMPK/SIRT1/IL-1ß/NF-κB pathway exerted neuroprotective effects by reducing neuroinflammation. These findings suggest A-1 as a promising therapeutic approach for ALS.


Assuntos
Proteínas Quinases Ativadas por AMP , Esclerose Lateral Amiotrófica , Furanos , Interleucina-1beta , Camundongos Transgênicos , NF-kappa B , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Sirtuína 1 , Animais , Sirtuína 1/metabolismo , Camundongos , NF-kappa B/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Furanos/farmacologia , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/metabolismo , Interleucina-1beta/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Lignanas/farmacologia , Lignanas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Masculino , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/patologia , Neurônios Motores/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Medula Espinal/metabolismo
6.
PLoS One ; 19(6): e0305173, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38875300

RESUMO

Chlorpyrifos is an organophosphate pesticide associated with numerous health effects including motor performance decrements. While many studies have focused on the health effects following acute chlorpyrifos poisonings, almost no studies have examined the effects on motoneurons following occupational-like exposures. The main objective of this study was to examine the broad effects of repeated occupational-like chlorpyrifos exposures on spinal motoneuron soma size relative to motor activity. To execute our objective, adult rats were exposed to chlorpyrifos via oral gavage once a day, five days a week for two weeks. Chlorpyrifos exposure effects were assessed either three days or two months following the last exposure. Three days following the last repeated chlorpyrifos exposure, there were transient effects in open-field motor activity and plasma cholinesterase activity levels. Two months following the chlorpyrifos exposures, there were delayed effects in sensorimotor gating, pro-inflammatory cytokines and spinal lumbar motoneuron soma morphology. Overall, these results offer support that subacute repeated occupational-like chlorpyrifos exposures have both short-term and longer-term effects in motor activity, inflammation, and central nervous system mechanisms.


Assuntos
Clorpirifos , Atividade Motora , Neurônios Motores , Animais , Clorpirifos/toxicidade , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/patologia , Ratos , Masculino , Atividade Motora/efeitos dos fármacos , Inseticidas/toxicidade , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Ratos Sprague-Dawley , Região Lombossacral , Colinesterases/metabolismo , Colinesterases/sangue , Inibidores da Colinesterase/toxicidade
7.
J Neuroinflammation ; 21(1): 146, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824594

RESUMO

T cells play an important role in the acquired immune response, with regulatory T cells (Tregs) serving as key players in immune tolerance. Tregs are found in nonlymphoid and damaged tissues and are referred to as "tissue Tregs". They have tissue-specific characteristics and contribute to immunomodulation, homeostasis, and tissue repair through interactions with tissue cells. However, important determinants of Treg tissue specificity, such as antigen specificity, tissue environment, and pathology, remain unclear. In this study, we analyzed Tregs in the central nervous system of mice with ischemic stroke and experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. The gene expression pattern of brain Tregs in the EAE model was more similar to that of ischemic stroke Tregs in the brain than to that of spinal cord Tregs. In addition, most T-cell receptors (TCRs) with high clonality were present in both the brain and spinal cord. Furthermore, Gata3+ and Rorc+ Tregs expressed TCRs recognizing MOG in the spinal cord, suggesting a tissue environment conducive to Rorc expression. Tissue-specific chemokine/chemokine receptor interactions in the spinal cord and brain influenced Treg localization. Finally, spinal cord- or brain-derived Tregs had greater anti-inflammatory capacities in EAE mice, respectively. Taken together, these findings suggest that the tissue environment, rather than pathogenesis or antigen specificity, is the primary determinant of the tissue-specific properties of Tregs. These findings may contribute to the development of novel therapies to suppress inflammation through tissue-specific Treg regulation.


Assuntos
Encéfalo , Encefalomielite Autoimune Experimental , Camundongos Endogâmicos C57BL , Medula Espinal , Linfócitos T Reguladores , Animais , Linfócitos T Reguladores/imunologia , Camundongos , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Medula Espinal/imunologia , Medula Espinal/patologia , Medula Espinal/metabolismo , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Modelos Animais de Doenças
8.
Genes (Basel) ; 15(5)2024 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-38790244

RESUMO

BACKGROUND: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is an inherited disease caused by pathogenic biallelic variants in the gene DARS2, which encodes mitochondrial aspartyl-tRNA synthetase. This disease is characterized by slowly progressive spastic gait, cerebellar symptoms, and leukoencephalopathy with brainstem and spinal cord involvement. CASE PRESENTATION: Peripheral blood samples were collected from four patients from four unrelated families to extract genomic DNA. All patients underwent partial exon analysis of the DARS2 gene using Sanger sequencing, which detected the c.228-21_228-20delinsC variant in a heterozygous state. Further DNA from three patients was analyzed using a next-generation sequencing-based custom AmpliSeq™ panel for 59 genes associated with leukodystrophies, and one of the patients underwent whole genome sequencing. We identified a novel pathogenic variant c.1675-1256_*115delinsGCAACATTTCGGCAACATTCCAACC in the DARS2 gene. Three patients (patients 1, 2, and 4) had slowly progressive cerebellar ataxia, and two patients (patients 1 and 2) had spasticity. In addition, two patients (patients 2 and 4) showed signs of axonal neuropathy, such as decreased tendon reflexes and loss of distal sensitivity. Three patients (patients 1, 2, and 3) also had learning difficulties. It should be noted the persistent presence of characteristic changes in brain MRI in all patients, which emphasizes its importance as the main diagnostic tool for suspicion and subsequent confirmation of LBSL. Conclusions: We found a novel indel variant in the DARS2 gene in four patients with LBSL and described their clinical and genetic characteristics. These results expand the mutational spectrum of LBSL and aim to improve the laboratory diagnosis of this form of leukodystrophy.


Assuntos
Aspartato-tRNA Ligase , Mutação INDEL , Leucoencefalopatias , Humanos , Aspartato-tRNA Ligase/genética , Aspartato-tRNA Ligase/deficiência , Masculino , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Feminino , Tronco Encefálico/patologia , Tronco Encefálico/diagnóstico por imagem , Criança , Ácido Láctico/sangue , Federação Russa , Adulto , Medula Espinal/patologia , Medula Espinal/diagnóstico por imagem , Adolescente , Doenças Mitocondriais
9.
PLoS One ; 19(5): e0303235, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38728287

RESUMO

Excitotoxicity represents the primary cause of neuronal death following spinal cord injury (SCI). While autophagy plays a critical and intricate role in SCI, the specific mechanism underlying the relationship between excitotoxicity and autophagy in SCI has been largely overlooked. In this study, we isolated primary spinal cord neurons from neonatal rats and induced excitotoxic neuronal injury by high concentrations of glutamic acid, mimicking an excitotoxic injury model. Subsequently, we performed transcriptome sequencing. Leveraging machine learning algorithms, including weighted correlation network analysis (WGCNA), random forest analysis (RF), and least absolute shrinkage and selection operator analysis (LASSO), we conducted a comprehensive investigation into key genes associated with spinal cord neuron injury. We also utilized protein-protein interaction network (PPI) analysis to identify pivotal proteins regulating key gene expression and analyzed key genes from public datasets (GSE2599, GSE20907, GSE45006, and GSE174549). Our findings revealed that six genes-Anxa2, S100a10, Ccng1, Timp1, Hspb1, and Lgals3-were significantly upregulated not only in vitro in neurons subjected to excitotoxic injury but also in rats with subacute SCI. Furthermore, Hspb1 and Lgals3 were closely linked to neuronal autophagy induced by excitotoxicity. Our findings contribute to a better understanding of excitotoxicity and autophagy, offering potential targets and a theoretical foundation for SCI diagnosis and treatment.


Assuntos
Autofagia , Galectina 3 , Aprendizado de Máquina , Neurônios , Animais , Ratos , Galectina 3/metabolismo , Galectina 3/genética , Ácido Glutâmico/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/genética , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Neurônios/metabolismo , Mapas de Interação de Proteínas , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/genética
10.
Neurobiol Dis ; 197: 106534, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38759931

RESUMO

Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, yet effective treatment is lacking. Moreover, the underlying pathomechanisms of ALS remain unclear, with impaired mitophagy function being increasingly recognized as a contributing factor. FUN14 domain-containing protein 1 (FUNDC1) is an autophagy receptor localized to the outer mitochondrial membrane and a mitochondrial membrane protein that mediates mitophagy and therefore considered as important factor in neurodegenerative diseases. However, its specific role in ALS is not yet clear. Therefore, this study aimed to investigate the regulatory role of FUNDC1 in ALS and determine its regulatory mechanisms. ALS transgenic mice were obtained and maintained under standard conditions. Cell lines were generated by stable transfection with hSOD1G93A or control vectors. Mice received intrathecal injections of AAV9 vectors expressing FUNDC1 or EGFP. Motor function was assessed through behavioral tests, and histological and immunostaining analyses were performed. Colocalization analysis was conducted in transfected cells, and protein expression was evaluated via western blotting. We first observed that FUNDC1 was significantly downregulated in the spinal cord tissues of SOD1G93A mice. FUNDC1 overexpression considerably improved locomotor activity and prolonged survival time in SOD1G93A mice. Mechanistically, reduced expression of FUNDC1 resulted in decreased mitophagy, as indicated by decreased recruitment through LC3 in SOD1G93A mice and cellular models. Consequently, this led to increased mitochondrial accumulation and cell apoptosis, exacerbating the ALS phenotype. Furthermore, we identified transcription factor FOXD3 as an essential upstream factor of FUNDC1, resulting in reduced transcription of FUNDC1 in ALS lesions. This study suggests a novel strategy of targeting FUNDC1-mediated mitophagy for developing therapeutic interventions to mitigate disease progression and improve outcomes for ALS patients.


Assuntos
Esclerose Lateral Amiotrófica , Modelos Animais de Doenças , Camundongos Transgênicos , Proteínas Mitocondriais , Mitofagia , Neurônios Motores , Animais , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/genética , Mitofagia/fisiologia , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Camundongos , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Humanos , Medula Espinal/metabolismo , Medula Espinal/patologia
11.
Turk J Med Sci ; 54(1): 1-15, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38812654

RESUMO

Background/aim: This study aims to determine the possible embryotoxic effects of propofol on the cerebellum and spinal cord using fertile chicken eggs. Materials and methods: A total of 430 fertile eggs were divided into 5 groups: control, saline, 2.5 mg.kg-1, 12.5 mg.kg-1, and 37.5 mg.kg-1 propofol. Injections were made immediately before incubation via the air chamber. On the 15th, 18th, and 21st day of incubation, 6 embryos from each group were evaluated. Serial paraffin sections taken from the cerebellum and spinal cord were stained with hematoxylin-eosin, Kluver-Barrera, toluidine blue, and periodic acid-Schiff's reaction. The outer granular layer and total cortex thickness were measured, and the linear density of the Purkinje cells was determined. The ratios of the substantia grisea surface area to the total surface area of the spinal cord were calculated. The transverse and longitudinal diameters of the canalis centralis were also assessed. Results: No structural malformation was observed in any embryos examined macroscopically. No significant difference was observed between the groups in terms of development and histologic organization of the cerebellum and spinal cord. However, on the 15th, 18th, and 21st day, the outer granular layer (p < 0.001 for all days) and the total cortex thickness (p < 0.01, p < 0.001, and p < 0.001, respectively) decreased significantly in different propofol dose groups in varying degrees in the cerebellum. Similarly, in the spinal cord, there were significant changes in the ratios of the substantia grisea surface area to the total surface area (p < 0.01 and p < 0.001, respectively). Conclusion: It was concluded that the in-ovo-administered propofol given immediately before incubation has adverse effects on the developing cerebellum and spinal cord. Therefore, it is important for anesthesiologists always to remain vigilant when treating female patients of childbearing age.


Assuntos
Cerebelo , Propofol , Medula Espinal , Animais , Propofol/toxicidade , Propofol/administração & dosagem , Cerebelo/efeitos dos fármacos , Cerebelo/patologia , Cerebelo/embriologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Medula Espinal/embriologia , Embrião de Galinha/efeitos dos fármacos , Anestésicos Intravenosos/toxicidade , Anestésicos Intravenosos/administração & dosagem
12.
Biomed Pharmacother ; 175: 116677, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38701570

RESUMO

The current pharmacological approaches to multiple sclerosis (MS) target its inflammatory and autoimmune components, but effective treatments to foster remyelination and axonal repair are still lacking. We therefore selected two targets known to be involved in MS pathogenesis: N-acylethanolamine-hydrolyzing acid amidase (NAAA) and glycogen synthase kinase-3ß (GSK-3ß). We tested whether inhibiting these targets exerted a therapeutic effect against experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The combined inhibition of NAAA and GSK-3ß by two selected small-molecule compounds, ARN16186 (an NAAA inhibitor) and AF3581 (a GSK-3ß inhibitor), effectively mitigated disease progression, rescuing the animals from paralysis and preventing a worsening of the pathology. The complementary activity of the two inhibitors reduced the infiltration of immune cells into the spinal cord and led to the formation of thin myelin sheaths around the axons post-demyelination. Specifically, the inhibition of NAAA and GSK-3ß modulated the over-activation of NF-kB and STAT3 transcription factors in the EAE-affected mice and induced the nuclear translocation of ß-catenin, reducing the inflammatory insult and promoting the remyelination process. Overall, this work demonstrates that the dual-targeting of key aspects responsible for MS progression could be an innovative pharmacological approach to tackle the pathology.


Assuntos
Amidoidrolases , Encefalomielite Autoimune Experimental , Glicogênio Sintase Quinase 3 beta , Camundongos Endogâmicos C57BL , Esclerose Múltipla , Animais , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Encefalomielite Autoimune Experimental/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Camundongos , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Feminino , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia , NF-kappa B/metabolismo , Inibidores Enzimáticos/farmacologia , Bainha de Mielina/metabolismo , Bainha de Mielina/efeitos dos fármacos
13.
Int Immunopharmacol ; 134: 112246, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38759372

RESUMO

BACKGROUND: A wide array of histone deacetylase (HDAC) inhibitors and aryl hydrocarbon receptor (AHR) agonists commonly arrest experimental autoimmune encephalomyelitis (EAE). However, it is not known whether HDAC inhibition is linked to the AHR signaling pathway in EAE. METHODS: We investigated how the pan-HDAC inhibitor SB939 (pracinostat) exerted immunoregulatory action in the myelin oligodendrocyte glycoprotein 35-55 (MOG35-55)-induced EAE mouse model by evaluating changes in of signal transducer and activator of transcription 3 (STAT3) acetylation and the expression of indoleamine 2,3-dioxygenase 1 (IDO1) and AHR in inflamed spinal cords during EAE evolution. We proved the involvement of IDO1 and the AHR in SB939-mediated immunosuppression using Ido1-/- and Ahr-/- mice. RESULTS: Administration with SB939 halted EAE progression, which depended upon IDO1 expression in neurons of the central nervous system (CNS). Our in vitro and in vivo studies demonstrated that SB939 sustained the interleukin-6-induced acetylation of STAT3, resulting in the stable transcriptional activation of Ido1. The therapeutic effect of SB939 also required the AHR, which is expressed mainly in CD4+ T cells and macrophages in CNS disease lesions. Finally, SB939 was shown to markedly reduce the proliferation of CD4+ T cells in inflamed neuronal tissues but not in the spleen or draining lymph nodes. CONCLUSIONS: Overall, our results suggest that IDO1 tryptophan metabolites produced by neuronal cells may act on AHR in pathogenic CD4+ T cells in a paracrine fashion in the CNS and that the specific induction of IDO1 expression in neurons at disease-afflicted sites can be considered a therapeutic approach to block the progression of multiple sclerosis without affecting systemic immunity.


Assuntos
Encefalomielite Autoimune Experimental , Inibidores de Histona Desacetilases , Indolamina-Pirrol 2,3,-Dioxigenase , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios , Fator de Transcrição STAT3 , Animais , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/metabolismo , Camundongos , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Feminino , Medula Espinal/patologia , Medula Espinal/metabolismo , Medula Espinal/imunologia , Medula Espinal/efeitos dos fármacos , Glicoproteína Mielina-Oligodendrócito/imunologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Progressão da Doença , Histona Desacetilases/metabolismo , Histona Desacetilases/genética , Fragmentos de Peptídeos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Interleucina-6/metabolismo , Interleucina-6/genética
14.
Tissue Cell ; 88: 102420, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38795506

RESUMO

Peripheral and central neuropathies frequently complicate worldwide diabetes. Compared to peripheral neuropathy, central neuropathy didn`t gain a major research interest. Angiotensin II is reported to be involved in diabetic neuropathic pain but its role in the central pathological changes in the spinal cord is not clear. Here, we study the role of Losartan; an Angiotensin II receptor 1 (AT1) antagonist in suppression of the diabetes-induced changes in the spinal cord. Three groups of rats were applied; a negative control group, a streptozotocin (STZ) diabetic group, and a group receiving STZ and Losartan. After two months, the pathological alteration in the spinal cord was investigated, and an immunohistochemical study was performed for neuronal, astrocytic, and microglial markers; nuclear protein (NeuN), Glial fibrillary acidic protein (GFAP), and Ionized calcium-binding adaptor molecule 1 (Iba1), respectively, and for an apoptosis marker; caspase-3, and the inflammatory marker; nuclear factor kappa B (NF-kB) signaling, heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2); physiological antioxidant system. The results showed that Losartan caused recovery of spinal cord changes, by inhibiting the microglial and astrocytic activation, suppressing neuronal apoptosis and NF-kB expression with activation of Nrf2/HO-1 (P<0.0005). It is suggested, herein, that Losartan can suppress diabetes-induced glial activation, inflammation, neuronal apoptosis, and oxidative stress in the spinal cord; the mechanisms that may underlie the role of AT1 antagonism in suppressing diabetic neuropathic pain.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II , Diabetes Mellitus Experimental , Losartan , Fator 2 Relacionado a NF-E2 , Medula Espinal , Animais , Medula Espinal/patologia , Medula Espinal/metabolismo , Medula Espinal/efeitos dos fármacos , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Fator 2 Relacionado a NF-E2/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Ratos , Masculino , Losartan/farmacologia , Heme Oxigenase-1/metabolismo , Neuropatias Diabéticas/patologia , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Ratos Wistar , Apoptose/efeitos dos fármacos , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos
15.
Neurosci Lett ; 833: 137829, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38788796

RESUMO

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that has been reported to be affected by inflammatory cells, such as microglia and macrophages, through the concept of non-cell autonomous neuronal death. Resident microglia in the human brain and monocyte-derived macrophages (MoDM) infiltrating in tissues are difficult to distinguish. Therefore, the effects of microglia and MoDMs in ALS remain poorly understood. This study aimed to investigate the role of resident microglia and MoDMs in the pathogenesis of ALS using postmortem brain and spinal cord samples. The samples used for immunohistochemical analysis included 11 cases of sporadic ALS and 11 age-matched controls. We stained the cells with TMEM119 to detect resident microglia and CCR2 to detect MoDMs. In ALS cases, TMEM119-immunopositive resident microglia were abundant in the motor cortex and subcortical white matter (SWM) of the motor area, whereas CCR2-immunopositive MoDM was similar to control cases. In addition, the mean density of CD68-immunopositive cells in the SWM significantly correlated with the mean density of pTDP-43-positive GCIs. These results suggest that resident microglial activation plays an important role in the cerebral pathogenesis of ALS and may provide novel therapeutic strategies to target excessive activation of resident microglia in ALS.


Assuntos
Esclerose Lateral Amiotrófica , Encéfalo , Proteínas de Membrana , Microglia , Humanos , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Microglia/metabolismo , Microglia/patologia , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Proteínas de Membrana/metabolismo , Encéfalo/patologia , Encéfalo/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Receptores CCR2/metabolismo , Substância Branca/patologia , Substância Branca/metabolismo , Medula Espinal/metabolismo , Medula Espinal/patologia , Idoso de 80 Anos ou mais
16.
Sci Adv ; 10(22): eadk3229, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38820149

RESUMO

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of somatic motor neurons. A major focus has been directed to motor neuron intrinsic properties as a cause for degeneration, while less attention has been given to the contribution of spinal interneurons. In the present work, we applied multiplexing detection of transcripts and machine learning-based image analysis to investigate the fate of multiple spinal interneuron populations during ALS progression in the SOD1G93A mouse model. The analysis showed that spinal inhibitory interneurons are affected early in the disease, before motor neuron death, and are characterized by a slow progressive degeneration, while excitatory interneurons are affected later with a steep progression. Moreover, we report differential vulnerability within inhibitory and excitatory subpopulations. Our study reveals a strong interneuron involvement in ALS development with interneuron specific degeneration. These observations point to differential involvement of diverse spinal neuronal circuits that eventually may be determining motor neuron degeneration.


Assuntos
Esclerose Lateral Amiotrófica , Modelos Animais de Doenças , Interneurônios , Camundongos Transgênicos , Neurônios Motores , Medula Espinal , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Animais , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Camundongos , Interneurônios/metabolismo , Interneurônios/patologia , Medula Espinal/patologia , Medula Espinal/metabolismo , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Humanos , Progressão da Doença , Degeneração Neural/patologia
17.
Clin Nucl Med ; 49(7): e321-e323, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38775827

RESUMO

ABSTRACT: Diffuse midline glioma, H3K27-altered, is a relatively new entity, characterized by H3K27M histone mutation. This rare pediatric disease with severe prognosis has recently been identified as a new subtype of diffuse astrocytoma due to major breakthrough in histopathological and molecular characterization of gliomas. We report a case of H3K27-altered diffuse midline glioma in a 30-year-old woman.


Assuntos
Fluordesoxiglucose F18 , Glioma , Histonas , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Medula Espinal , Humanos , Feminino , Adulto , Glioma/diagnóstico por imagem , Glioma/patologia , Medula Espinal/diagnóstico por imagem , Medula Espinal/patologia , Histonas/metabolismo , Tomografia Computadorizada por Raios X , Imagem Multimodal
18.
Biomed Pharmacother ; 176: 116792, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38795645

RESUMO

BACKGROUND: Mounting experimental evidence has underscored the remarkable role played by the Wnt family of proteins in the spinal cord functioning and therapeutic potential in spinal cord injury (SCI). We aim to provide a therapeutic prospect associated with the modulation of canonical Wnt signaling, examining the spatio-temporal expression pattern of Dickkopf-1 (Dkk1) and its neutralization after SCI. We employ an intraparenchymal injection of the clinically validated Dkk1-blocking antibody, BHQ880, to elucidate its effects in SCI. METHODS: A rat model of contusion SCI was used. Histological analyses were performed, wherein Dkk1 protein was sought, and ELISA analyses were employed for Dkk1 detection in cerebrospinal fluid and serum. To ascertain the BHQ880 therapeutic effect, rats were subjected to SCI and then injected with the antibody in the lesion epicenter 24 hours post-injury (hpi). Subsequent evaluation of motor functional recovery extended up to 56 days post-injury (dpi). qRT-PCR and histological analyses were conducted. RESULTS: We demonstrate the presence of Dkk1 in the healthy rat spinal cord, with pronounced alterations observed following injury, primarily concentrated in the epicenter regions. Notably, a significative upregulation of Dkk1 was detected at 24 hpi, peaking at 3 dpi and remaining elevated until 42 dpi. Moreover, we revealed that early administration of BHQ880 considerably improved motor functional recovery, promoted preservation of myelinated tissue, and reduced astroglial and microglia/macrophage reactivity. Furthermore, there was a decrease in the acute expression of different inflammatory genes. CONCLUSIONS: Collectively, our findings highlight the therapeutic potential of BHQ880 treatment in the context of SCI.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal , Animais , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Ratos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia , Masculino , Ratos Sprague-Dawley , Modelos Animais de Doenças , Atividade Motora/efeitos dos fármacos
19.
Mult Scler Relat Disord ; 87: 105666, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38749352

RESUMO

BACKGROUND: Spinal cord is one of the prominent targets of autoimmune mechanisms in Neuromyelitis Optica Spectrum Disorder (NMOSD). Rarely, NMOSD causes damage to the entire length of the spinal cord, from cervical segments to conus medullaris, which has not been characterized in the existing literature. MATERIAL AND METHOD: We reviewed medical records, demographic information, and magnetic resonance imaging (MRI) sequences of 174 NMOSD patients from January 2011 to January 2023 who were admitted to Isfahan Multiple Sclerosis center to find patients with whole spinal transverse myelitis (TM). RESULTS: Whole spinal TM was present in five patients (2.9 %). Three patients were seropositive for Aquaporin-4 (AQP4) antibody; Myelin Oligodendrocyte Glycoprotein antibody (MOG IgG) tested negative for all of them. Lower limb weakness was the most frequent clinical complaint. Two patients presented with optic neuritis; One patient reported having episodes of nausea and vomiting. These patients, overall, yielded a higher expanded disability status scale (EDSS) score than the other NMOSD patients. CONCLUSION: Whole spinal TM is a rare finding in NMOSD, which is strongly associated with a higher severity and a worse outcome of the disease. The role of anti-AQP4 antibodies in the extent of myelitis in NMOSD has yet to be investigated.


Assuntos
Aquaporina 4 , Mielite Transversa , Neuromielite Óptica , Humanos , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/complicações , Neuromielite Óptica/imunologia , Mielite Transversa/diagnóstico por imagem , Mielite Transversa/imunologia , Feminino , Adulto , Masculino , Pessoa de Meia-Idade , Aquaporina 4/imunologia , Imageamento por Ressonância Magnética , Adulto Jovem , Estudos Retrospectivos , Medula Espinal/diagnóstico por imagem , Medula Espinal/patologia , Autoanticorpos/sangue
20.
Toxicon ; 245: 107780, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38821321

RESUMO

We reported thirteen cases of bilateral stringhalt associated with Hypochaeris radicata that occurred in horses in Uruguay during a severe drought in the summer of 2023. All horses were affected chronically and progressively by bilateral hyperflexion of hindlimbs. In two severely affected horses, the main histological lesions included neuronal chromatolysis and axonal spheroids in the ventral gray horn in the lumbar and sacral spinal cord and axonal degeneration and digestion chambers in ventral roots fibers and long peripheral nerves. We suggest that in addition to injuries to peripheral nerves, lesions in the spinal cord play an important role in the clinical signs of stringhalt in horses.


Assuntos
Doenças dos Cavalos , Animais , Cavalos , Uruguai , Medula Espinal/patologia , Masculino , Feminino
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