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1.
Int J Mol Sci ; 22(19)2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34638645

RESUMO

Leptin has been suggested to play a role in amyotrophic lateral sclerosis (ALS), a fatal progressive neurodegenerative disease. This adipokine has previously been shown to be associated with a lower risk of ALS and to confer a survival advantage in ALS patients. However, the role of leptin in the progression of ALS is unknown. Indeed, our understanding of the mechanisms underlying leptin's effects in the pathogenesis of ALS is very limited, and it is fundamental to determine whether alterations in leptin's actions take place in this neurodegenerative disease. To characterize the association between leptin signaling and the clinical course of ALS, we assessed the mRNA and protein expression profiles of leptin, the long-form of the leptin receptor (Ob-Rb), and leptin-related signaling pathways at two different stages of the disease (onset and end-stage) in TDP-43A315T mice compared to age-matched WT littermates. In addition, at selected time-points, an immunoassay analysis was conducted to characterize plasma levels of total ghrelin, the adipokines resistin and leptin, and metabolic proteins (plasminogen activator inhibitor type 1 (PAI-1), gastric inhibitory peptide (GIP), glucagon-like peptide 1 (GLP-1), insulin and glucagon) in TDP-43A315T mice compared to WT controls. Our results indicate alterations in leptin signaling in the spinal cord and the hypothalamus on the backdrop of TDP-43-induced deficits in mice, providing new evidence about the pathways that could link leptin signaling to ALS.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Leptina/metabolismo , Transdução de Sinais/fisiologia , Adipocinas/metabolismo , Animais , Humanos , Masculino , Camundongos , Neurônios Motores/metabolismo , Doenças Neurodegenerativas/metabolismo , Medula Espinal/metabolismo
2.
Int J Mol Sci ; 22(19)2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34638701

RESUMO

Male sexual function in mammals is controlled by the brain neural circuits and the spinal cord centers located in the lamina X of the lumbar spinal cord (L3-L4). Recently, we reported that hypothalamic oxytocin neurons project to the lumbar spinal cord to activate the neurons located in the dorsal lamina X of the lumbar spinal cord (dXL) via oxytocin receptors, thereby facilitating male sexual activity. Sexual experiences can influence male sexual activity in rats. However, how this experience affects the brain-spinal cord neural circuits underlying male sexual activity remains unknown. Focusing on dXL neurons that are innervated by hypothalamic oxytocinergic neurons controlling male sexual function, we examined whether sexual experience affects such neural circuits. We found that >50% of dXL neurons were activated in the first ejaculation group and ~30% in the control and intromission groups in sexually naïve males. In contrast, in sexually experienced males, ~50% of dXL neurons were activated in both the intromission and ejaculation groups, compared to ~30% in the control group. Furthermore, sexual experience induced expressions of gastrin-releasing peptide and oxytocin receptors in the lumbar spinal cord. This is the first demonstration of the effects of sexual experience on molecular expressions in the neural circuits controlling male sexual activity in the spinal cord.


Assuntos
Ejaculação , Peptídeo Liberador de Gastrina/biossíntese , Regulação da Expressão Gênica , Ereção Peniana , Receptores de Ocitocina/biossíntese , Medula Espinal/metabolismo , Animais , Feminino , Masculino , Ratos , Ratos Long-Evans
3.
Int J Mol Sci ; 22(17)2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34502460

RESUMO

Amyotrophic lateral sclerosis (ALS) is a multifactorial and complex fatal degenerative disorder. A number of pathological mechanisms that lead to motor neuron death have been identified, although there are many unknowns in the disease aetiology of ALS. Alterations in lipid metabolism are well documented in the progression of ALS, both at the systemic level and in the spinal cord of mouse models and ALS patients. The origin of these lipid alterations remains unclear. This study aims to identify early lipid metabolic pathways altered before systemic metabolic symptoms in the spinal cord of mouse models of ALS. To do this, we performed a transcriptomic analysis of the spinal cord of SOD1G93A mice at an early disease stage, followed by a robust transcriptomic meta-analysis using publicly available RNA-seq data from the spinal cord of SOD1 mice at early and late symptomatic disease stages. The meta-analyses identified few lipid metabolic pathways dysregulated early that were exacerbated at symptomatic stages; mainly cholesterol biosynthesis, ceramide catabolism, and eicosanoid synthesis pathways. We present an insight into the pathological mechanisms in ALS, confirming that lipid metabolic alterations are transcriptionally dysregulated and are central to ALS aetiology, opening new options for the treatment of these devastating conditions.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Metabolismo dos Lipídeos , Medula Espinal/metabolismo , Transcriptoma , Esclerose Amiotrófica Lateral/etiologia , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Esteroide Hidroxilases/genética , Esteroide Hidroxilases/metabolismo
4.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502405

RESUMO

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS commonly affects the cerebellum causing acute and chronic symptoms. Cerebellar signs significantly contribute to clinical disability, and symptoms such as tremor, ataxia, and dysarthria are difficult to treat. Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies such as MS. In autopsy tissue from patients with MS, increased expression of FGF1, FGF2, FGF9, and FGFR1 was found in lesion areas. Recent research using mouse models has focused on regions such as the spinal cord, and data on the expression of FGF/FGFR in the cerebellum are not available. In recent EAE studies, we detected that oligodendrocyte-specific deletion of FGFRs results in a milder disease course, less cellular infiltrates, and reduced neurodegeneration in the spinal cord. The objective of this study was to characterize the role of FGFR1 in oligodendrocytes in the cerebellum. Conditional deletion of FGFR1 in oligodendrocytes (Fgfr1ind-/-) was achieved by tamoxifen application, EAE was induced using the MOG35-55 peptide. The cerebellum was analyzed by histology, immunohistochemistry, and western blot. At day 62 p.i., Fgfr1ind-/- mice showed less myelin and axonal degeneration compared to FGFR1-competent mice. Infiltration of CD3(+) T cells, Mac3(+) cells, B220(+) B cells and IgG(+) plasma cells in cerebellar white matter lesions (WML) was less in Fgfr1ind-/-mice. There were no effects on the number of OPC or mature oligodendrocytes in white matter lesion (WML). Expression of FGF2 and FGF9 associated with less myelin and axonal degeneration, and of the pro-inflammatory cytokines IL-1ß, IL-6, and CD200 was downregulated in Fgfr1ind-/- mice. The FGF/FGFR signaling protein pAkt, BDNF, and TrkB were increased in Fgfr1ind-/- mice. These data suggest that cell-specific deletion of FGFR1 in oligodendrocytes has anti-inflammatory and neuroprotective effects in the cerebellum in the EAE disease model of MS.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Oligodendroglia/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Animais , Cerebelo/metabolismo , Cerebelo/patologia , Doenças Desmielinizantes/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/fisiopatologia , Fatores de Crescimento de Fibroblastos/metabolismo , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esclerose Múltipla/metabolismo , Esclerose Múltipla/fisiopatologia , Bainha de Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito/farmacologia , Oligodendroglia/patologia , Fosforilação , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/fisiologia , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/metabolismo , Substância Branca/metabolismo
5.
Anesth Analg ; 133(5): 1321-1330, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34524124

RESUMO

BACKGROUND: The maternal pain threshold gradually increases during pregnancy, especially in late pregnancy. A series of mechanisms underlying pregnancy-induced analgesia have been reported. However, these mechanisms are still not completely clear, and the underlying molecular mechanisms need further investigation. We examined the relationship between the antinociceptive effect and the expression level of programmed cell death ligand-1 (PD-L1) during pregnancy and further observed the changes in pain thresholds and expression levels of cytokines in late-pregnant mice before and after blockade of PD-L1 or programmed cell death-1 (PD-1). METHODS: Part 1: Female mice were assigned to 3 groups (nonpregnant, late-pregnant, and postpartum). Part 2: Late-pregnant mice were assigned to 3 treatment groups (control [phosphate buffer solution], RMP1-14 [mouse anti-PD-1 antibody], and soluble PD-1 [sPD-1]). Behavioral testing (mechanical and thermal) and tissue (serum and spinal cord) analysis were performed on all groups. PD-L1, interleukin (IL)-10, tumor necrosis factor-α (TNF-α), and IL-6 expression levels in tissue were examined via reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and Western blot analysis. RESULTS: The mechanical and thermal pain thresholds were significantly increased in late pregnancy and decreased after delivery. PD-L1 expression was also elevated in late pregnancy and decreased after delivery. In addition, in the late stage of gestation, the maternal inflammatory microenvironment was dominated by anti-inflammatory factors. After administration of RMP1-14 or sPD-1, the pain thresholds of late-pregnant mice were significantly reduced. In late-pregnant mice, the high level of IL-10 was obviously reduced, and the low levels of TNF-α and IL-6 were elevated. CONCLUSIONS: The PD-L1/PD-1 pathway mediates pregnancy-induced analgesia, partially via the regulation of cytokines.


Assuntos
Antígeno B7-H1/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Limiar da Dor , Dor/prevenção & controle , Receptor de Morte Celular Programada 1/metabolismo , Medula Espinal/metabolismo , Animais , Comportamento Animal , Feminino , Camundongos , Dor/metabolismo , Dor/fisiopatologia , Gravidez , Transdução de Sinais , Medula Espinal/fisiopatologia
6.
Zhongguo Zhong Yao Za Zhi ; 46(16): 4175-4186, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34467730

RESUMO

Excitatory toxicity(ET) is an important factor of neuropathic pain(NPP) induced by central sensitization(CS), and the association of pannexin-1(Panx1)-Src-N-methyl-D-aspartate receptor subunit 2 B(NMDAR-2 B) is an important new pathway for ET to initiate CS. The present study confirmed whether the central analgesic effect of Chuanxiong Rhizoma extract(CRE) was achieved through the synchronous regulation of the brain and spinal pathways of Panx1-Src-NMDAR-2 B. In this study, dynamic and simulta-neo-us microdialysis of the brain and spinal cord in vivo combined with behavioristics, high performance liquid chromatography(HPLC)-fluorescence detection, microdialysis analysis(ISCUS~(flex)), ultrasensitive multifactorial electrochemiluminescence immunoassay, ELISA, and Western blot was employed to investigate the protein expression of NMDAR-2 B, Src, and Panx1, extracellular excitatory amino acids, cytokines, energy metabolites, and substance P in spinal dorsal horn(SDH) and anterior cingulate cortex(ACC) after CRE intervention with the rat model of spared sciatic nerve injury(SNI) as the experimental tool. Compared with the sham group, the SNI group exhibited diminished mechanical withdrawal threshold(MWT)(P<0.01), increased cold spray scores(P<0.01), glutamate(Glu), D-serine(D-Ser), and glycine(Gly) in extracellular fluids of ACC, and Glu, D-Ser, interleukin-1ß(IL-1ß), and lactic acid(Lac) in extracellular fluids of SDH(P<0.05), dwindled tumor necrosis factor(TNF-α)(P<0.05), and elevated protein levels of NMDAR-2 B, Src, and Panx1 in ACC(P<0.05). Compared with the SNI model rats, high-and medium-dose CRE(CRE-H/M) could potentiate the analgesic activity as revealed by the MWT test(P<0.05) and CRE-M enabled the decrease in cold spray scores(P<0.05). CRE-H/M could inhibit the levels of Glu, D-Ser and Gly in the extracellular fluids of ACC(P<0.05), and the levels of Glu in the extracellular fluids of SDH(P<0.05) in SNI rats. CRE-M significantly increased the levels of glucose(Gluc), Lac, interferon-gamma(IFN-γ), keratinocyte chemoattractant/human growth-regulated oncogenes(KC/GRO), and IL-4 in extracellular fluids of SDH in SNI rats(P<0.05). CRE-H/M/L could also inhibit the levels of NMDAR-2 B, Src and Panx1 in ACC and SDH in SNI rats(P<0.05). The central analgesic effect of CRE is presumedly related to the inhibited release of excitatory amino acid transmitters(Glu, D-Ser and Gly) in ACC and SDH of SNI rats, decreased protein expression of NMDAR-2 B, Src and Panx1 in the two regions, and the regulation of the Panx1-Src-NMDAR-2 B pathway in the spinal cord and brain. The above findings partially clarified the scientific basis of clinical analgesic effect of Chuanxiong Rhizoma.


Assuntos
Neuralgia , Receptores de N-Metil-D-Aspartato , Animais , Sensibilização do Sistema Nervoso Central , Neuralgia/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais , Medula Espinal/metabolismo
7.
Mol Pain ; 17: 17448069211042117, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34505815

RESUMO

BACKGROUND: Pain is an unpleasant sensory experience that usually plays a protective role. Inflammatory pain is often severe and stubborn, which has a great impact on the quality of life of patients. However, there has been no breakthrough in the treatment strategy and mechanism of inflammatory pain. METHODS: This study investigated the analgesic effect of tetrahydropalmatine (THP) in rats injected with complete Freund's adjuvant (CFA)-induced inflammatory pain. Allodynia and gait analysis of rats were used to evaluate the analgesic effect at different time points before and after operation. THP (2.5, 5, and 10 mg/kg) was administered intraperitoneally once daily for 7 days post Day 3. The expression levels of TNF-α and IL-1ß in the spinal cord were measured by enzyme-linked immunosorbent assay. The activation of astrocytes and microglial cells in the spinal cord was tested by western blot before and after THP treatment. The apoptosis of glial cells was tested by flow cytometry after treatment with THP in the primary cultured glial cell model. RESULTS: CFA treatment induced significant allodynia and caused abnormal gait in rats. Administration of THP at 10 mg/kg significantly alleviated CFA-induced inflammatory pain behaviors. Moreover, CFA-induced activation of glial cells and the increased levels of TNF-α and IL-1ß were inhibited by THP administration. In addition, THP promotes apoptosis in primary cultured glial cells. This study suggests the possible clinical utility of THP in the treatment of inflammatory pain. CONCLUSION: THP plays an analgesic role by inhibiting the activation of glial cells and promoting apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Alcaloides de Berberina/farmacologia , Inflamação/tratamento farmacológico , Neuroglia/efeitos dos fármacos , Dor/tratamento farmacológico , Animais , Astrócitos/metabolismo , Modelos Animais de Doenças , Adjuvante de Freund/efeitos adversos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Masculino , Microglia/efeitos dos fármacos , Neuroglia/metabolismo , Dor/metabolismo , Ratos Sprague-Dawley , Medula Espinal/metabolismo
8.
Cells ; 10(9)2021 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-34571884

RESUMO

In species that regenerate the injured spinal cord, the ependymal region is a source of new cells and a prominent coordinator of regeneration. In mammals, cells at the ependymal region proliferate in normal conditions and react after injury, but in humans, the central canal is lost in the majority of individuals from early childhood. It is replaced by a structure that does not proliferate after damage and is formed by large accumulations of ependymal cells, strong astrogliosis and perivascular pseudo-rosettes. We inform here of two additional mammals that lose the central canal during their lifetime: the Naked Mole-Rat (NMR, Heterocephalus glaber) and the mutant hyh (hydrocephalus with hop gait) mice. The morphological study of their spinal cords shows that the tissue substituting the central canal is not similar to that found in humans. In both NMR and hyh mice, the central canal is replaced by tissue reminiscent of normal lamina X and may include small groups of ependymal cells in the midline, partially resembling specific domains of the former canal. However, no features of the adult human ependymal remnant are found, suggesting that this structure is a specific human trait. In order to shed some more light on the mechanism of human central canal closure, we provide new data suggesting that canal patency is lost by delamination of the ependymal epithelium, in a process that includes apical polarity loss and the expression of signaling mediators involved in epithelial to mesenchymal transitions.


Assuntos
Epêndima/citologia , Medula Espinal/citologia , Adolescente , Adulto , Animais , Biomarcadores/metabolismo , Proliferação de Células , Epêndima/metabolismo , Feminino , Humanos , Macaca mulatta , Masculino , Camundongos Mutantes , Pessoa de Meia-Idade , Ratos-Toupeira , Pan troglodytes , Mutação Puntual , Proteínas de Ligação a Fator Solúvel Sensível a N-Etilmaleimida/genética , Especificidade da Espécie , Canal Medular/citologia , Canal Medular/metabolismo , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Adulto Jovem
9.
Cell Mol Life Sci ; 78(19-20): 6605-6630, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34476545

RESUMO

Motor neurone disease (MND) is a neurodegenerative disorder characterised by progressive destruction of motor neurons, muscle paralysis and death. The amyloid precursor protein (APP) is highly expressed in the central nervous system and has been shown to modulate disease outcomes in MND. APP is part of a gene family that includes the amyloid precursor-like protein 1 (APLP1) and 2 (APLP2) genes. In the present study, we investigated the role of APLP2 in MND through the examination of human spinal cord tissue and by crossing APLP2 knockout mice with the superoxide dismutase 1 (SOD1-G37R) transgenic mouse model of MND. We found the expression of APLP2 is elevated in the spinal cord from human cases of MND and that this feature of the human disease is reproduced in SOD1-G37R mice at the End-stage of their MND-like phenotype progression. APLP2 deletion in SOD1-G37R mice significantly delayed disease progression and increased the survival of female SOD1-G37R mice. Molecular and biochemical analysis showed female SOD1-G37R:APLP2-/- mice displayed improved innervation of the neuromuscular junction, ameliorated atrophy of muscle fibres with increased APP protein expression levels in the gastrocnemius muscle. These results indicate a sex-dependent role for APLP2 in mutant SOD1-mediated MND and further support the APP family as a potential target for further investigation into the cause and regulation of MND.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Doença dos Neurônios Motores/metabolismo , Superóxido Dismutase-1/metabolismo , Esclerose Amiotrófica Lateral/metabolismo , Animais , Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neurônios Motores/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Junção Neuromuscular/metabolismo , Fenótipo , Medula Espinal/metabolismo
10.
Int J Mol Sci ; 22(18)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34575871

RESUMO

The pathobiology of traumatic and nontraumatic spinal cord injury (SCI), including degenerative myelopathy, is influenced by neuroinflammation. The neuroinflammatory response is initiated by a multitude of injury signals emanating from necrotic and apoptotic cells at the lesion site, recruiting local and infiltrating immune cells that modulate inflammatory cascades to aid in the protection of the lesion site and encourage regenerative processes. While peripheral immune cells are involved, microglia, the resident immune cells of the central nervous system (CNS), are known to play a central role in modulating this response. Microglia are armed with numerous cell surface receptors that interact with neurons, astrocytes, infiltrating monocytes, and endothelial cells to facilitate a dynamic, multi-faceted injury response. While their origin and essential nature are understood, their mechanisms of action and spatial and temporal profiles warrant extensive additional research. In this review, we describe the role of microglia and the cellular network in SCI, discuss tools for their investigation, outline their spatiotemporal profile, and propose translationally-relevant therapeutic targets to modulate neuroinflammation in the setting of SCI.


Assuntos
Inflamação/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Traumatismos da Medula Espinal/metabolismo , Animais , Astrócitos/metabolismo , Membrana Celular/metabolismo , Células Endoteliais/metabolismo , Humanos , Imunidade Inata , Inflamação/fisiopatologia , Macrófagos/metabolismo , Monócitos/metabolismo , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia
11.
J Neurochem ; 159(3): 618-628, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34478561

RESUMO

Kappa free light chain (KFLC) index, a measure for intrathecal production of free kappa chains, has been increasingly recognized for its diagnostic potential in multiple sclerosis (MS) as a quantitative alternative to IgG oligoclonal bands (OCBs). Our objective was to investigate the sensitivity, specificity, and overall diagnostic accuracy of KFLC index in MS. KFLC index was prospectively determined as part of the diagnostic workup in patients with suspected MS (n = 327) between May 2013 and February 2020. Patients with clinically isolated syndrome (CIS), radiologically isolated syndrome (RIS), and MS had markedly higher KFLC index (44.6, IQR 16-128) compared with subjects with other neuro-inflammatory disorders (ONID) and symptomatic controls (SC) (2.19, IQR 1.68-2.98, p < 0.001). KFLC index had a sensitivity of 0.93 (95% CI 0.88-0.95) and specificity of 0.87 (95% CI 0.8-0.92) to discriminate CIS/RIS/MS from ONID and SC (AUC 0.94, 95% CI 0.91-0.97, p < 0.001). KFLC index and intrathecal fraction (IF) KFLC had similar accuracies to detect MS. Treatment with disease-modifying therapy (DMT) did not influence the level of KFLC index and it was not affected by demographic factors or associated with degenerative or inflammatory biomarkers in cerebrospinal fluid (CSF). KFLC index in MS diagnostics has methodological advantages compared to OCB and is independent to subjective interpretation. Moreover, it is an attractive diagnostic tool since the diagnostic specificity and sensitivity of KFLC index are similar with that of OCBs and KFLCIF and better than for IgG index. We show that KFLC index was influenced neither by DMT nor by demographic factors or other inflammatory or degenerative processes in MS as determined by biomarkers in CSF.


Assuntos
Cadeias Leves de Imunoglobulina/análise , Esclerose Múltipla/diagnóstico , Adulto , Biomarcadores , Doenças Desmielinizantes/diagnóstico , Diagnóstico Diferencial , Progressão da Doença , Feminino , Humanos , Imunoglobulina G/análise , Inflamação/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla/diagnóstico por imagem , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Medula Espinal/química , Medula Espinal/metabolismo
12.
Cells ; 10(7)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34360008

RESUMO

Ischemia reperfusion injury (IRI) is associated with a broad array of life-threatening medical conditions including myocardial infarct, cerebral stroke, and organ transplant. Although the pathobiology and clinical manifestations of IRI are well reviewed by previous publications, IRI-related transcriptomic alterations are less studied. This study aimed to reveal a transcriptomic hallmark for IRI by using the RNA-sequencing data provided by several studies on non-human preclinical experimental models. In this regard, we focused on the transcriptional responses of IRI in an acute time-point up to 48 h. We compiled a list of highly reported genes in the current literature that are affected in the context of IRI. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses and found many of the up-regulated genes to be involved in cell survival, cell surface signaling, response to oxidative stress, and inflammatory response, while down-regulated genes were predominantly involved in ion transport. Furthermore, by GO analysis, we found that multiple inflammatory and stress response processes were affected after IRI. Tumor necrosis factor alpha (TNF) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways were also highlighted in the Kyoto Encyclopedia of Genes and Genomes enrichment analysis. In the last section, we discuss the treatment approaches and their efficacy for IRI by comparing RNA sequencing data from therapeutic interventions with the results of our cross-comparison of differentially expressed genes and pathways across IRI.


Assuntos
Redes e Vias Metabólicas/genética , NF-kappa B/genética , Traumatismo por Reperfusão/genética , Transcriptoma , Fator de Necrose Tumoral alfa/genética , Animais , Fármacos Cardiovasculares/uso terapêutico , Terapia Baseada em Transplante de Células e Tecidos/métodos , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Pós-Condicionamento Isquêmico/métodos , Precondicionamento Isquêmico/métodos , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Anotação de Sequência Molecular , Miocárdio/metabolismo , Miocárdio/patologia , NF-kappa B/metabolismo , Ratos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/terapia , Análise de Sequência de RNA , Transdução de Sinais , Medula Espinal/irrigação sanguínea , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia , Fator de Necrose Tumoral alfa/metabolismo
13.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445680

RESUMO

Amyotrophic Lateral Sclerosis (ALS) is the most common degenerative motor neuron disease in adults. About 97% of ALS patients present TDP-43 aggregates with post-translational modifications, such as hyperphosphorylation, in the cytoplasm of affected cells. GSK-3ß is one of the protein kinases involved in TDP-43 phosphorylation. Up-regulation of its expression and activity is reported on spinal cord and cortex tissues of ALS patients. Here, we propose the repurposing of Tideglusib, an in-house non-ATP competitive GSK-3ß inhibitor that is currently in clinical trials for autism and myotonic dystrophy, as a promising therapeutic strategy for ALS. With this aim we have evaluated the efficacy of Tideglusib in different experimental ALS models both in vitro and in vivo. Moreover, we observed that GSK-3ß activity is increased in lymphoblasts from sporadic ALS patients, with a simultaneous increase in TDP-43 phosphorylation and cytosolic TDP-43 accumulation. Treatment with Tideglusib decreased not only phospho-TDP-43 levels but also recovered its nuclear localization in ALS lymphoblasts and in a human TDP-43 neuroblastoma model. Additionally, we found that chronic oral treatment with Tideglusib is able to reduce the increased TDP-43 phosphorylation in the spinal cord of Prp-hTDP-43A315T mouse model. Therefore, we consider Tideglusib as a promising drug candidate for ALS, being proposed to start a clinical trial phase II by the end of the year.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Tiadiazóis/farmacologia , Idoso , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/metabolismo , Animais , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Proteínas de Ligação a DNA/fisiologia , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Glicogênio Sintase Quinase 3 beta/fisiologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Neurônios Motores/metabolismo , Preparações Farmacêuticas/metabolismo , Fosforilação , Proteínas Quinases/metabolismo , Medula Espinal/metabolismo
14.
J Neurosci ; 41(39): 8163-8180, 2021 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-34385359

RESUMO

Sox10 is a well known factor to control oligodendrocyte (OL) differentiation, and its expression is regulated by Olig2. As an important protein kinase, Akt has been implicated in diseases with white matter abnormalities. To study whether and how Akt may regulate OL development, we generated OL lineage cell-specific Akt1/Akt2/Akt3 triple conditional knock-out (Akt cTKO) mice. Both male and female mice were used. These mutants exhibit a complete loss of mature OLs and unchanged apoptotic cell death in the CNS. We show that the deletion of Akt three isoforms causes downregulation of Sox10 and decreased levels of phosphorylated FoxO1 in the brain. In vitro analysis reveals that the expression of FoxO1 with mutations on phosphorylation sites for Akt significantly represses the Sox10 promoter activity, suggesting that phosphorylation of FoxO1 by Akt is important for Sox10 expression. We further demonstrate that mutant FoxO1 without Akt phosphorylation epitopes is enriched in the Sox10 promoter. Together, this study identifies a novel FoxO1 phosphorylation-dependent mechanism for Sox10 expression and OL differentiation.SIGNIFICANCE STATEMENT Dysfunction of Akt is associated with white matter diseases including the agenesis of the corpus callosum. However, it remains unknown whether Akt plays an important role in oligodendrocyte differentiation. To address this question, we generated oligodendrocyte lineage cell-specific Akt1/Akt2/Akt3 triple-conditional knock-out mice. Akt mutants exhibit deficient white matter development, loss of mature oligodendrocytes, absence of myelination, and unchanged apoptotic cell death in the CNS. We demonstrate that deletion of Akt three isoforms leads to downregulation of Sox10, and that phosphorylation of FoxO1 by Akt is critical for Sox10 expression. Together, these findings reveal a novel mechanism to regulate Sox10 expression. This study may provide insights into molecular mechanisms for neurodevelopmental diseases caused by dysfunction of protein kinases.


Assuntos
Encéfalo/metabolismo , Diferenciação Celular/fisiologia , Oligodendroglia/citologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição SOXE/metabolismo , Medula Espinal/metabolismo , Animais , Apoptose/fisiologia , Feminino , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Masculino , Camundongos , Camundongos Knockout , Oligodendroglia/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Fatores de Transcrição SOXE/genética , Substância Branca/metabolismo
15.
Ann Clin Lab Sci ; 51(4): 529-534, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34452891

RESUMO

OBJECTIVE: Multiple sclerosis (MS) is a progressive autoimmune-mediated inflammation of the central nervous system (CNS), and experimental autoimmune encephalomyelitis (EAE) is a suitable model to study the pathogenesis of MS. IL-2 has been considered as both a T cell growth factor and an anti-inflammatory cytokine. In the present study, we investigated the effects of a low dose IL-2 treatment on mouse EAE therapy. METHOD: The expression of IL-2 and IL-2 receptor were predicted using public microarray data and verified by real-time PCR and ELISA in mouse EAE model. Mice were injected with Myelin Oligodendrocyte Glycoprotein (35-55)(MOG35-55) subcutaneously to induce EAE model. IL-2 treatment was initiated during 5 consecutive days from day 15 post MOG35-55 immunization. Flow cytometry was applied to investigate the proportions of Th17 and Treg cells. ELISA was used to detect the concentrations of IL-17a, IFNr, IL-10 and TGFb. RESULTS: In this study, we showed that the IL-2 treatment ameliorates the clinical severity of EAE. Flow cytometry results indicated that the therapeutic effect was related to a reduction of Th17 cells and an expansion of Treg cells in the EAE spinal cord. In vitro experiments also confirmed the anti-inflammatory effect of IL-2 in EAE-reactivated T cells. CONCLUSION: Low-dose IL-2 is a potential therapeutic strategy for EAE and MS.


Assuntos
Anti-Inflamatórios/administração & dosagem , Encefalomielite Autoimune Experimental/tratamento farmacológico , Interleucina-2/administração & dosagem , Medula Espinal/efeitos dos fármacos , Células Th17/imunologia , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Medula Espinal/imunologia , Medula Espinal/metabolismo , Medula Espinal/patologia
16.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445312

RESUMO

"Neuroplasticity" is often evoked to explain adaptation and compensation after acute lesions of the Central Nervous System (CNS). In this study, we investigated the modification of 80 genes involved in synaptic plasticity at different times (24 h, 8 and 45 days) from the traumatic spinal cord injury (SCI), adopting a bioinformatic analysis. mRNA expression levels were analyzed in the motor cortex, basal ganglia, cerebellum and in the spinal segments rostral and caudal to the lesion. The main results are: (i) a different gene expression regulation is observed in the Spinal Cord (SC) segments rostral and caudal to the lesion; (ii) long lasting changes in the SC includes the extracellular matrix (ECM) enzymes Timp1, transcription regulators (Egr, Nr4a1), second messenger associated proteins (Gna1, Ywhaq); (iii) long-lasting changes in the Motor Cortex includes transcription regulators (Cebpd), neurotransmitters/neuromodulators and receptors (Cnr1, Gria1, Nos1), growth factors and related receptors (Igf1, Ntf3, Ntrk2), second messenger associated proteins (Mapk1); long lasting changes in Basal Ganglia and Cerebellum include ECM protein (Reln), growth factors (Ngf, Bdnf), transcription regulators (Egr, Cebpd), neurotransmitter receptors (Grin2c). These data suggest the molecular mapping as a useful tool to investigate the brain and SC reorganization after SCI.


Assuntos
Encéfalo/metabolismo , Plasticidade Neuronal/genética , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/metabolismo , Transcriptoma , Animais , Feminino , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Neurotransmissores/genética , Neurotransmissores/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/genética , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
17.
J Neurochem ; 159(3): 512-524, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34338322

RESUMO

Studies have verified that Fragile X mental retardation protein (FMRP), an RNA-binding protein, plays a potential role in the pathogenesis of formalin- and (RS)-3,5-dihydroxyphenylglycine-induced abnormal pain sensations. However, the role of FMRP in inflammatory pain has not been reported. Here, we showed an increase in FMRP expression in the spinal dorsal horn (SDH) in a rat model of inflammatory pain induced by complete Freund's adjuvant (CFA). Double immunofluorescence staining revealed that FMRP was mainly expressed in spinal neurons and colocalized with proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)]. After consecutive intrathecal injection of fragile X mental retardation 1 small interfering RNA for 3 days post-CFA injection, FMRP expression in the SDH was reduced, and CFA-induced hyperalgesia was decreased. In addition, the CFA-induced increase in spinal TNF-α and IL-6 production was significantly suppressed by intrathecal administration of fragile X mental retardation 1 small interfering RNA. Together, these results suggest that FMRP regulates TNF-α and IL-6 levels in the SDH and plays an important role in inflammatory pain.


Assuntos
Citocinas/biossíntese , Proteína do X Frágil de Retardo Mental/fisiologia , Inflamação/genética , Inflamação/patologia , Dor/patologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Animais , Proteína do X Frágil de Retardo Mental/genética , Adjuvante de Freund , Hiperalgesia/induzido quimicamente , Hiperalgesia/patologia , Injeções Espinhais , Interleucina-6/metabolismo , Masculino , Dor/induzido quimicamente , Dor/genética , Células do Corno Posterior/metabolismo , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
18.
Anesth Analg ; 133(5): 1311-1320, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34347648

RESUMO

BACKGROUND: Visceral and parietal peritoneum layers have different sensory innervations. Most visceral peritoneum sensory information is conveyed via the vagus nerve to the nucleus of the solitary tract (NTS). We already showed in animal models that intramuscular (i.m.) injection of local anesthetics decreases acute somatic and visceral pain and general inflammation induced by aseptic peritonitis. The goal of the study was to compare the effects of parietal block, i.m. bupivacaine, and vagotomy on spinal cord and NTS stimulation induced by a chemical peritonitis. METHODS: We induced peritonitis in rats using carrageenan and measured cellular activation in spinal cord and NTS under the following conditions, that is, a parietal nerve block with bupivacaine, a chemical right vagotomy, and i.m. microspheres loaded with bupivacaine. Proto-oncogene c-Fos (c-Fos), cluster of differentiation protein 11b (CD11b), and tumor necrosis factor alpha (TNF-α) expression in cord and NTS were studied. RESULTS: c-Fos activation in the cord was inhibited by nerve block 2 hours after peritoneal insult. Vagotomy and i.m. bupivacaine similarly inhibited c-Fos activation in NTS. Forty-eight hours after peritoneal insult, the number of cells expressing CD11b significantly increased in the cord (P = .010). The median difference in the effect of peritonitis compared to control was 30 cells (CI95, 13.5-55). TNF-α colocalized with CD11b. Vagotomy inhibited this microglial activation in the NTS, but not in the cord. This activation was inhibited by i.m. bupivacaine both in cord and in NTS. The median difference in the effect of i.m. bupivacaine added to peritonitis was 29 cells (80% increase) in the cord and 18 cells (75% increase) in the NTS. Our study underlines the role of the vagus nerve in the transmission of an acute visceral pain message and confirmed that systemic bupivacaine prevents noxious stimuli by inhibiting c-Fos and microglia activation. CONCLUSIONS: In rats receiving intraperitoneal carrageenan, i.m. bupivacaine similarly inhibited c-Fos and microglial activation both in cord and in the NTS. Vagal block inhibited activation only in the NTS. Our study underlines the role of the vagus nerve in the transmission of an acute visceral pain message and confirmed that systemic bupivacaine prevents noxious stimuli. This emphasizes the effects of systemic local anesthetics on inflammation and visceral pain.


Assuntos
Dor Aguda/prevenção & controle , Anestésicos Locais/administração & dosagem , Bupivacaína/administração & dosagem , Manejo da Dor , Núcleo Solitário/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Vagotomia , Nervo Vago/cirurgia , Dor Visceral/prevenção & controle , Dor Aguda/induzido quimicamente , Dor Aguda/metabolismo , Dor Aguda/fisiopatologia , Animais , Antígeno CD11b/metabolismo , Carragenina , Modelos Animais de Doenças , Injeções Intramusculares , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Peritonite/induzido quimicamente , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Sprague-Dawley , Núcleo Solitário/metabolismo , Núcleo Solitário/fisiopatologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Fator de Necrose Tumoral alfa/metabolismo , Nervo Vago/fisiopatologia , Dor Visceral/induzido quimicamente , Dor Visceral/metabolismo , Dor Visceral/fisiopatologia
19.
J Cell Biol ; 220(9)2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34347016

RESUMO

Cholesterol metabolism operates autonomously within the central nervous system (CNS), where the majority of cholesterol resides in myelin. We demonstrate that TDP-43, the pathological signature protein for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), influences cholesterol metabolism in oligodendrocytes. TDP-43 binds directly to mRNA of SREBF2, the master transcription regulator for cholesterol metabolism, and multiple mRNAs encoding proteins responsible for cholesterol biosynthesis and uptake, including HMGCR, HMGCS1, and LDLR. TDP-43 depletion leads to reduced SREBF2 and LDLR expression, and cholesterol levels in vitro and in vivo. TDP-43-mediated changes in cholesterol levels can be restored by reintroducing SREBF2 or LDLR. Additionally, cholesterol supplementation rescues demyelination caused by TDP-43 deletion. Furthermore, oligodendrocytes harboring TDP-43 pathology from FTD patients show reduced HMGCR and HMGCS1, and coaggregation of LDLR and TDP-43. Collectively, our results indicate that TDP-43 plays a role in cholesterol homeostasis in oligodendrocytes, and cholesterol dysmetabolism may be implicated in TDP-43 proteinopathies-related diseases.


Assuntos
Colesterol/metabolismo , Proteínas de Ligação a DNA/genética , Demência Frontotemporal/genética , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Animais , Proteínas de Ligação a DNA/deficiência , Modelos Animais de Doenças , Feminino , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Hidroximetilglutaril-CoA Sintase/genética , Hidroximetilglutaril-CoA Sintase/metabolismo , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Bainha de Mielina/patologia , Oligodendroglia/patologia , Organoides/metabolismo , Organoides/patologia , Cultura Primária de Células , Receptores de LDL/genética , Receptores de LDL/metabolismo , Transdução de Sinais , Medula Espinal/metabolismo , Medula Espinal/patologia , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Lobo Temporal/metabolismo , Lobo Temporal/patologia
20.
Cells ; 10(8)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34440641

RESUMO

Spinal cord injury (SCI) is a debilitating condition, often leading to severe motor, sensory, or autonomic nervous dysfunction. As the holy grail of regenerative medicine, promoting spinal cord tissue regeneration and functional recovery are the fundamental goals. Yet, effective regeneration of injured spinal cord tissues and promotion of functional recovery remain unmet clinical challenges, largely due to the complex pathophysiology of the condition. The transplantation of various cells, either alone or in combination with three-dimensional matrices, has been intensively investigated in preclinical SCI models and clinical trials, holding translational promise. More recently, a new paradigm shift has emerged from cell therapy towards extracellular vesicles as an exciting "cell-free" therapeutic modality. The current review recapitulates recent advances, challenges, and future perspectives of cell-based spinal cord tissue engineering and regeneration strategies.


Assuntos
Vesículas Extracelulares/transplante , Regeneração Nervosa , Células-Tronco Neurais/transplante , Traumatismos da Medula Espinal/cirurgia , Medula Espinal/fisiopatologia , Transplante de Células-Tronco , Engenharia Tecidual , Animais , Vesículas Extracelulares/metabolismo , Humanos , Células-Tronco Neurais/metabolismo , Neurogênese , Fenótipo , Recuperação de Função Fisiológica , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Transplante de Células-Tronco/efeitos adversos , Transplante de Células-Tronco/instrumentação , Tecidos Suporte
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