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1.
Science ; 376(6588): 86-90, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35357926

RESUMO

Neuropathic pain is often caused by injury and diseases that affect the somatosensory system. Although pain development has been well studied, pain recovery mechanisms remain largely unknown. Here, we found that CD11c-expressing spinal microglia appear after the development of behavioral pain hypersensitivity following nerve injury. Nerve-injured mice with spinal CD11c+ microglial depletion failed to recover spontaneously from this hypersensitivity. CD11c+ microglia expressed insulin-like growth factor-1 (IGF1), and interference with IGF1 signaling recapitulated the impairment in pain recovery. In pain-recovered mice, the depletion of CD11c+ microglia or the interruption of IGF1 signaling resulted in a relapse in pain hypersensitivity. Our findings reveal a mechanism for the remission and recurrence of neuropathic pain, providing potential targets for therapeutic strategies.


Assuntos
Dor Crônica/fisiopatologia , Hiperalgesia/fisiopatologia , Microglia/fisiologia , Neuralgia/fisiopatologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Medula Espinal/fisiopatologia , Animais , Proteínas de Bactérias/genética , Antígenos CD11/genética , Antígenos CD11/metabolismo , Feminino , Proteínas Luminescentes/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Recidiva
2.
Dev Cell ; 57(4): 415-416, 2022 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-35231422

RESUMO

The capacity for long-distance axon regeneration and functional recovery after spinal cord injury in the adult has long been thought to be a unique feature of certain non-mammalian vertebrates. However, in this issue of Developmental Cell, Nogueira-Rodrigues et al. report an astonishingly high regenerative ability in the spiny mouse.


Assuntos
Axônios , Traumatismos da Medula Espinal , Animais , Modelos Animais de Doenças , Regeneração Nervosa , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia
3.
J Korean Med Sci ; 37(7): e52, 2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35191229

RESUMO

Acute transverse myelitis (ATM) has been reported as rare complication of vaccination. Herein, we report 2 cases of ATM after the administration of an mRNA vaccine for coronavirus disease 2019 (COVID-19). The first one is an 81-year-old man who received the BNT162b2 vaccine. He presented with bilateral hand weakness. Spine magnetic resonance imaging (MRI) showed high signal intensity from the C1 to C3 vertebrae. The second is a 23-year-old woman who received the BNT162b2 vaccine and experienced tingling in her legs. Spine MRI showed a high signal intensity lesion at the conus medullaris. These patients were treated with intravenous methylprednisolone and their symptoms improved slightly. Careful follow-up is needed to identify adverse events after the administration of mRNA vaccines for COVID-19.


Assuntos
/efeitos adversos , Mãos/fisiopatologia , Perna (Membro)/fisiopatologia , Mielite Transversa/patologia , Medula Espinal/fisiopatologia , Vacinação/efeitos adversos , Idoso de 80 Anos ou mais , COVID-19/imunologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Metilprednisolona/uso terapêutico , Mielite Transversa/diagnóstico , Mielite Transversa/tratamento farmacológico , SARS-CoV-2/imunologia , Coluna Vertebral/diagnóstico por imagem , Adulto Jovem
4.
Dev Cell ; 57(4): 440-450.e7, 2022 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-34986324

RESUMO

Regeneration of adult mammalian central nervous system (CNS) axons is abortive, resulting in inability to recover function after CNS lesion, including spinal cord injury (SCI). Here, we show that the spiny mouse (Acomys) is an exception to other mammals, being capable of spontaneous and fast restoration of function after severe SCI, re-establishing hind limb coordination. Remarkably, Acomys assembles a scarless pro-regenerative tissue at the injury site, providing a unique structural continuity of the initial spinal cord geometry. The Acomys SCI site shows robust axon regeneration of multiple tracts, synapse formation, and electrophysiological signal propagation. Transcriptomic analysis of the spinal cord following transcriptome reconstruction revealed that Acomys rewires glycosylation biosynthetic pathways, culminating in a specific pro-regenerative proteoglycan signature at SCI site. Our work uncovers that a glycosylation switch is critical for axon regeneration after SCI and identifies ß3gnt7, a crucial enzyme of keratan sulfate biosynthesis, as an enhancer of axon growth.


Assuntos
Axônios/fisiologia , Regeneração Nervosa/fisiologia , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/patologia , Animais , Axônios/patologia , Modelos Animais de Doenças , Glicosilação , Camundongos , Medula Espinal/fisiologia , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Coluna Vertebral/fisiopatologia
5.
PLoS One ; 17(1): e0262755, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35085322

RESUMO

Chronic spinal cord injury (SCI) is a highly debilitating and recalcitrant disease with limited treatment options. Although various stem cell types have shown some clinical efficacy for injury repair they have not for SCI. Hair-follicle-associated pluripotent (HAP) stem cells have been shown to differentiate into neurons, Schwan cells, beating cardiomyocytes and many other type of cells, and have effectively regenerated acute spinal cord injury in mouse models. In the present report, HAP stem cells from C57BL/6J mice, encapsulated in polyvinylidene fluoride membranes (PFM), were implanted into the severed thoracic spinal cord of C57BL/6J or athymic nude mice in the early chronic phase. After implantation, HAP stem cells differentiated to neurons, astrocytes and oligodendrocytes in the regenerated thoracic spinal cord of C57BL/6J and nude mice. Quantitative motor function analysis, with the Basso Mouse Scale for Locomotion (BMS) score, demonstrated a significant functional improvement in the HAP-stem-cell-implanted mice, compared to non-implanted mice. HAP stem cells have critical advantages over other stem cells: they do not develop teratomas; do not loose differentiation ability when cryopreserved and thus are bankable; are autologous, readily obtained from anyone; and do not require genetic manipulation. HAP stem cells therefore have greater clinical potential for SCI repair than induced pluripotent stem cells (iPSCs), neuronal stem cells (NSCs)/neural progenitor cells (NPCs) or embryonic stem cells (ESCs). The present report demonstrates future clinical potential of HAP-stem-cell repair of chronic spinal cord injury, currently a recalcitrant disease.


Assuntos
Folículo Piloso/citologia , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes/citologia , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia , Regeneração da Medula Espinal/fisiologia , Animais , Diferenciação Celular/fisiologia , Polímeros de Fluorcarboneto/metabolismo , Folículo Piloso/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos Transgênicos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Nestina/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Células-Tronco Pluripotentes/metabolismo , Polivinil/metabolismo , Medicina Regenerativa/métodos , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/metabolismo
6.
J Neurosci ; 42(3): 513-527, 2022 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-34880118

RESUMO

Long-term potentiation (LTP) and long-term depression (LTD) in the spinal dorsal horn reflect activity-dependent synaptic plasticity and central sensitization in chronic pain. Tetanic high-frequency stimulation is commonly used to induce LTP in the spinal cord. However, primary afferent nerves often display low-frequency, rhythmic bursting discharges in painful conditions. Here, we determined how theta-burst stimulation (TBS) of primary afferents impacts spinal cord synaptic plasticity and nociception in male and female mice. We found that TBS induced more LTP, whereas tetanic stimulation induced more LTD, in mouse spinal lamina II neurons. TBS triggered LTP, but not LTD, in 50% of excitatory neurons expressing vesicular glutamate transporter-2 (VGluT2). By contrast, TBS induced LTD and LTP in 12-16% of vesicular GABA transporter (VGAT)-expressing inhibitory neurons. Nerve injury significantly increased the prevalence of TBS-induced LTP in VGluT2-expressing, but not VGAT-expressing, lamina II neurons. Blocking NMDARs, inhibiting α2δ-1 with gabapentin, or α2δ-1 knockout abolished TBS-induced LTP in lamina II neurons. Also, disrupting the α2δ-1-NMDAR interaction with α2δ-1Tat peptide prevented TBS-induced LTP in VGluT2-expressing neurons. Furthermore, TBS of the sciatic nerve induced long-lasting allodynia and hyperalgesia in wild-type, but not α2δ-1 knockout, mice. TBS significantly increased the α2δ-1-NMDAR interaction and synaptic trafficking in the spinal cord. In addition, treatment with NMDAR antagonists, gabapentin, or α2δ-1Tat peptide reversed TBS-induced pain hypersensitivity. Therefore, TBS-induced primary afferent input causes a neuropathic pain-like phenotype and LTP predominantly in excitatory dorsal horn neurons via α2δ-1-dependent NMDAR activation. α2δ-1-bound NMDARs may be targeted for reducing chronic pain development at the onset of tissue/nerve injury.SIGNIFICANCE STATEMENT Spinal dorsal horn synaptic plasticity is a hallmark of chronic pain. Although sensory nerves display rhythmic bursting discharges at theta frequencies during painful conditions, the significance of this naturally occurring firing activity in the induction of spinal synaptic plasticity is largely unknown. In this study, we found that theta-burst stimulation (TBS) of sensory nerves induced LTP mainly in excitatory dorsal horn neurons and that the prevalence of TBS-induced LTP was potentiated by nerve injury. This TBS-driven synaptic plasticity required α2δ-1 and its interaction with NMDARs. Furthermore, TBS of sensory nerves induced persistent pain, which was maintained by α2δ-1-bound NMDARs. Thus, TBS-induced LTP at primary afferent-dorsal horn neuron synapses is an appropriate cellular model for studying mechanisms of chronic pain.


Assuntos
Potenciação de Longa Duração/fisiologia , Dor/fisiopatologia , Células do Corno Posterior/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Medula Espinal/fisiopatologia , Ritmo Teta/fisiologia , Animais , Feminino , Masculino , Camundongos , Camundongos Knockout , Dor/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Nervo Isquiático/metabolismo , Nervo Isquiático/fisiopatologia , Medula Espinal/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/genética , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo
7.
Brain Res Bull ; 178: 69-81, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34813897

RESUMO

Recent studies have revealed that glial sigma-1 receptor (Sig-1R) in the spinal cord may be a critical factor to mediate sensory function. However, the functional role of Sig-1R in astrocyte has not been clearly elucidated. Here, we determined whether Sig-1Rs modulate calcium responses in primary cultured astrocytes and pathological changes in spinal astrocytes, and whether they contribute to pain hypersensitivity in naïve mice and neuropathic pain following chronic constriction injury (CCI) of the sciatic nerve in mice. Sig-1R was expressed in glial fibrillary acidic protein (GFAP)-positive cultured astrocytes. Treatment with the Sig-1R agonist, PRE-084 or neurosteroid dehydroepiandrosterone (DHEA) increased intracellular calcium responses in cultured astrocytes, and this increase was blocked by the pretreatment with the Sig-1R antagonist, BD-1047 or neurosteroid progesterone. Intrathecal administration of PRE-084 or DHEA for 10 days induced mechanical and thermal hypersensitivity and increased the number of Sig-1R-immunostained GFAP-positive cells in the superficial dorsal horn (SDH) region of the spinal cord in naïve mice, and these changes were inhibited by administration with BD-1047 or progesterone. In CCI mice, intrathecal administration of BD-1047 or progesterone at post-operative day 14 suppressed the developed mechanical allodynia and the number of Sig-1R-immunostained GFAP-positive cells that were increased in the SDH region of the spinal cord following CCI of the sciatic nerve. These results demonstrate that Sig-1Rs play an important role in the modulation of intracellular calcium responses in cultured astrocytes and pathological changes in spinal astrocytes and that administration of BD-1047 or progesterone alleviates the Sig-1R-induced pain hypersensitivity and the peripheral nerve injury-induced mechanical allodynia.


Assuntos
Astrócitos/metabolismo , Cálcio/metabolismo , Hiperalgesia/metabolismo , Neuralgia/metabolismo , Neuroesteroides/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Receptores sigma/metabolismo , Medula Espinal/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Camundongos , Neuralgia/tratamento farmacológico , Neuralgia/fisiopatologia , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Traumatismos dos Nervos Periféricos/fisiopatologia , Progesterona/farmacologia , Receptores sigma/antagonistas & inibidores , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia
8.
J Neurophysiol ; 127(1): 99-115, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34851739

RESUMO

We explored the relationship between population interneuronal network activation and motor output in the adult, in vivo, air-stepping, spinal cat. By simultaneously measuring the activity of large numbers of spinal interneurons, we explored ensembles of coherently firing interneurons and their relation to motor output. In addition, the networks were analyzed in relation to their spatial distribution along the lumbar enlargement for evidence of localized groups driving particular phases of the locomotor step cycle. We simultaneously recorded hindlimb EMG activity during stepping and extracellular signals from 128 channels across two polytrodes inserted within lamina V-VII of two separate lumbar segments. Results indicated that spinal interneurons participate in one of two ensembles that are highly correlated with the flexor or the extensor muscle bursts during stepping. Interestingly, less than half of the isolated single units were significantly unimodally tuned during the step cycle whereas >97% of the single units of the ensembles were significantly correlated with muscle activity. These results show the importance of population scale analysis in neural studies of behavior as there is a much greater correlation between muscle activity and ensemble firing than between muscle activity and individual neurons. Finally, we show that there is no correlation between interneurons' rostrocaudal locations within the lumbar enlargement and their preferred phase of firing or ensemble participation. These findings indicate that spinal interneurons of lamina V-VII encoding for different phases of the locomotor cycle are spread throughout the lumbar enlargement in the adult spinal cord.NEW & NOTEWORTHY We report on the ensemble organization of interneuronal activity in the spinal cord during locomotor movements and show that lumbar intermediate zone interneurons organize in two groups related to the two major phases of walking: stance and swing. Ensemble organization is also shown to better correlate with muscular output than single-cell activity, although ensemble membership does not appear to be somatotopically organized within the spinal cord.


Assuntos
Interneurônios/fisiologia , Rede Nervosa/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Medula Espinal/fisiopatologia , Caminhada/fisiologia , Animais , Comportamento Animal/fisiologia , Gatos , Geradores de Padrão Central/fisiopatologia , Eletromiografia , Feminino , Membro Posterior/fisiopatologia , Vértebras Lombares
9.
Neurosci Lett ; 770: 136401, 2022 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-34929317

RESUMO

Psychological stress has been demonstrated to increase reports of pain in humans with pelvic pain of urologic origin. In rodent models, conditioning with acute footshock (AFS) has been demonstrated to increase measures of stress/anxiety as well as bladder hypersensitivity. The spinal neurochemical mechanisms of this pro-nociceptive process are unknown and so the present study administered antagonists for multiple receptors that have been associated with facilitatory mechanisms into the spinal intrathecal space. Bladder hypersensitivity was induced through use of an AFS paradigm in which female Sprague-Dawley rats received a 15-min intermittent shock treatment. Visceromotor responses (VMRs; abdominal muscle contractions) to air pressure-controlled urinary bladder distension (UBD) were used as nociceptive endpoints. Immediately following AFS treatments, rats were anesthetized (inhaled isoflurane, IP urethane) and surgically prepared. Pharmacological antagonists were administered via an intrathecal (IT) catheter onto the lumbosacral spinal cord and VMRs to graded UBD determined 15 min later. Administration of IT naloxone hydrochloride (10 µg) and IT phentolamine hydrochloride (10 µg) resulted in VMRs that were more robust than VMRs in rats that received AFS and IT normal saline whereas there was no significant effect of these drugs on VMRs in rats which underwent non-footshock procedures. In contrast, a low dose of the NMDA-receptor antagonist, MK-801 (30 µg), significantly reduced VMRs in rats made hypersensitive to UBD by AFS, but had no significant effect on rats that underwent non-footshock procedures. This study suggests that pro-nociceptive effects of AFS in otherwise healthy rats involve a spinal NMDA-linked mechanism. The effects of IT naloxone and IT phentolamine suggest the presence of inhibitory influences that are opioidergic and/or alpha-adrenergic and that are masked by the pro-nociceptive mechanisms. Other agents with no statistically significant effect on VMRs include methysergide (30 µg), ondansetron (10 µg), mecamylamine (50 µg), antalarmin (24 µg), aSVG30 (12 µg), and SSR149415 (50 µg).


Assuntos
Maleato de Dizocilpina/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Hiperalgesia/tratamento farmacológico , Medula Espinal/metabolismo , Bexiga Urinária/metabolismo , Animais , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia , Estresse Fisiológico , Bexiga Urinária/fisiopatologia
10.
Exp Neurol ; 349: 113962, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34953895

RESUMO

Propriospinal neurons (PSNs) play a crucial role in motor control and sensory processing and contribute to plastic reorganization of spinal circuits responsible for recovery from spinal cord injury (SCI). Due to their scattered distribution and various intersegmental projection patterns, it is challenging to dissect the function of PSNs within the neuronal network. New genetically encoded tools, particularly cell-type-specific transgene expression methods using recombinant viral vectors combined with other genetic, pharmacologic, and optogenetic approaches, have enormous potential for visualizing PSNs in the neuronal circuits and monitoring and manipulating their activity. Furthermore, recombinant viral tools have been utilized to promote the intrinsic regenerative capacities of PSNs, towards manipulating the 'hostile' microenvironment for improving functional regeneration of PSNs. Here we summarize the latest development in this fast-moving field and provide a perspective for using this technology to dissect PSN physiological role in contributing to recovery of function after SCI.


Assuntos
Técnicas de Transferência de Genes , Plasticidade Neuronal , Neurônios , Propriocepção , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia , Medula Espinal/fisiopatologia , Animais , Vetores Genéticos , Humanos , Rede Nervosa/fisiopatologia , Regeneração Nervosa , Vias Neurais/fisiopatologia , Traumatismos da Medula Espinal/genética
11.
Nat Commun ; 12(1): 7093, 2021 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-34876587

RESUMO

Spinal cord injury (SCI) interrupts long-projecting descending spinal neurons and disrupts the spinal central pattern generator (CPG) that controls locomotion. The intrinsic mechanisms underlying re-wiring of spinal neural circuits and recovery of locomotion after SCI are unclear. Zebrafish shows axonal regeneration and functional recovery after SCI making it a robust model to study mechanisms of regeneration. Here, we use a two-cut SCI model to investigate whether recovery of locomotion can occur independently of supraspinal connections. Using this injury model, we show that injury induces the localization of a specialized group of intraspinal serotonergic neurons (ISNs), with distinctive molecular and cellular properties, at the injury site. This subpopulation of ISNs have hyperactive terminal varicosities constantly releasing serotonin activating 5-HT1B receptors, resulting in axonal regrowth of spinal interneurons. Axon regrowth of excitatory interneurons is more pronounced compared to inhibitory interneurons. Knock-out of htr1b prevents axon regrowth of spinal excitatory interneurons, negatively affecting coordination of rostral-caudal body movements and restoration of locomotor function. On the other hand, treatment with 5-HT1B receptor agonizts promotes functional recovery following SCI. In summary, our data show an intraspinal mechanism where a subpopulation of ISNs stimulates axonal regrowth resulting in improved recovery of locomotor functions following SCI in zebrafish.


Assuntos
Axônios/fisiologia , Recuperação de Função Fisiológica , Neurônios Serotoninérgicos/fisiologia , Traumatismos da Medula Espinal , Animais , Eletrofisiologia , Interneurônios , Locomoção , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Neurônios Serotoninérgicos/patologia , Serotonina/metabolismo , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Peixe-Zebra
12.
Neural Plast ; 2021: 5607898, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34721569

RESUMO

Spinal cord stimulation (SCS) as an evidence-based interventional treatment has been used and approved for clinical use in a variety of pathological states including peripheral neuropathic pain; however, until now, it has not been used for the treatment of spinal cord injury- (SCI-) induced central neuropathic pain. This paper reviews the underlying mechanisms of SCS-induced analgesia and its clinical application in the management of peripheral and central neuropathic pain. Evidence from recent research publications indicates that nociceptive processing at peripheral and central sensory systems is thought to be modulated by SCS through (i) inhibition of the ascending nociceptive transmission by the release of analgesic neurotransmitters such as GABA and endocannabinoids at the spinal dorsal horn; (ii) facilitation of the descending inhibition by release of noradrenalin, dopamine, and serotonin acting on their receptors in the spinal cord; and (iii) activation of a variety of supraspinal brain areas related to pain perception and emotion. These insights into the mechanisms have resulted in the clinically approved use of SCS in peripheral neuropathic pain states like Complex Regional Pain Syndrome (CRPS) and Failed Back Surgery Syndrome (FBSS). However, the mechanisms underlying SCS-induced pain relief in central neuropathic pain are only partly understood, and more research is needed before this therapy can be implemented in SCI patients with central neuropathic pain.


Assuntos
Inibição Neural/fisiologia , Neuralgia/fisiopatologia , Neuralgia/terapia , Manejo da Dor/métodos , Estimulação da Medula Espinal/métodos , Humanos , Medula Espinal/fisiopatologia , Estimulação da Medula Espinal/tendências , Resultado do Tratamento
13.
Oxid Med Cell Longev ; 2021: 9577874, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34721761

RESUMO

BACKGROUND: Neuropathic pain is a debilitating disease with few effective treatments. Emerging evidence indicates the involvement of mitochondrial dysfunction and oxidative stress in neuropathic pain. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a potent regulator of the antioxidant response system. In this study, we investigated whether RTA-408 (RTA, a novel synthetic triterpenoid under clinical investigation) could activate Nrf2 and promote mitochondrial biogenesis (MB) to reverse neuropathic pain and the underlying mechanisms. METHODS: Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Pain behaviors were measured via the von Frey test and Hargreaves plantar test. The L4-6 spinal cord was collected to examine the activation of Nrf2 and MB. RESULTS: RTA-408 treatment significantly reversed mechanical allodynia and thermal hyperalgesia in CCI mice in a dose-dependent manner. Furthermore, RTA-408 increased the activity of Nrf2 and significantly restored MB that was impaired in CCI mice in an Nrf2-dependent manner. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) is the key regulator of MB. We found that the PGC-1α activator also induced a potent analgesic effect in CCI mice. Moreover, the antinociceptive effect of RTA-408 was reversed by the preinjection of the PGC-1α inhibitor. CONCLUSIONS: Nrf2 activation attenuates chronic constriction injury-induced neuropathic pain via induction of PGC-1α-mediated mitochondrial biogenesis in the spinal cord. Our results indicate that Nrf2 may be a potential therapeutic strategy to ameliorate neuropathic pain and many other disorders with oxidative stress and mitochondrial dysfunction.


Assuntos
Analgésicos/farmacologia , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/agonistas , Neuralgia/prevenção & controle , Biogênese de Organelas , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Neuropatia Ciática/tratamento farmacológico , Medula Espinal/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Doença Crônica , Constrição Patológica , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Neuralgia/metabolismo , Neuralgia/patologia , Neuralgia/fisiopatologia , Limiar da Dor/efeitos dos fármacos , Neuropatia Ciática/metabolismo , Neuropatia Ciática/patologia , Neuropatia Ciática/fisiopatologia , Transdução de Sinais , Medula Espinal/metabolismo , Medula Espinal/patologia , Medula Espinal/fisiopatologia
14.
PLoS One ; 16(11): e0252559, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34762669

RESUMO

Syringomyelia (SM) is a spinal cord disorder in which a cyst (syrinx) filled with fluid forms in the spinal cord post-injury/disease, in patients syrinx symptoms include loss of pain and temperature sensation or locomotion deficit. Currently, there are no small animal models and connected tools to help study the functional impacts of SM. The objective of this study was to determine the detectability of subtle locomotion deficits due to syrinx formation/expansion in post-traumatic syringomyelia (PTSM) rat model using the recently reported method of Gait Analysis Instrumentation, and Technology Optimized for Rodents (GAITOR) with Automated Gait Analysis Through Hues and Areas (AGATHA) technique. First videos of the rats were collected while walking in an arena (using GAITOR) followed by extracting meaningful locomotion information from collected videos using AGATHA protocol. PTSM injured rats demonstrated detectable locomotion deficits in terms of duty factor imbalance, paw placement accuracy, step contact width, stride length, and phase dispersion parameters compared to uninjured rats due to SM. We concluded that this technique could detect mild and subtle locomotion deficits associated with PTSM injury, which also in future work could be used further to monitor locomotion responses after different treatment strategies for SM.


Assuntos
Hiperalgesia/fisiopatologia , Locomoção/fisiologia , Medula Espinal/fisiopatologia , Siringomielia/fisiopatologia , Caminhada/fisiologia , Animais , Modelos Animais de Doenças , Análise da Marcha , Masculino , Medição da Dor , Ratos , Ratos Wistar
15.
Int J Mol Sci ; 22(21)2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34769048

RESUMO

(1) Background: Amyotrophic lateral sclerosis (ALS) is an incurable, neurodegenerative disease. In some cases, ALS causes behavioral disturbances and cognitive dysfunction. Swimming has revealed a neuroprotective influence on the motor neurons in ALS. (2) Methods: In the present study, a SOD1-G93A mice model of ALS were used, with wild-type B6SJL mice as controls. ALS mice were analyzed before ALS onset (10th week of life), at ALS 1 onset (first symptoms of the disease, ALS 1 onset, and ALS 1 onset SWIM), and at terminal ALS (last stage of the disease, ALS TER, and ALS TER SWIM), and compared with wild-type mice. Swim training was applied 5 times per week for 30 min. All mice underwent behavioral tests. The spinal cord was analyzed for the enzyme activities and oxidative stress markers. (3) Results: Pre-symptomatic ALS mice showed increased locomotor activity versus control mice; the swim training reduced these symptoms. The metabolic changes in the spinal cord were present at the pre-symptomatic stage of the disease with a shift towards glycolytic processes at the terminal stage of ALS. Swim training caused an adaptation, resulting in higher glutathione peroxidase (GPx) and protection against oxidative stress. (4) Conclusion: Therapeutic aquatic activity might slow down the progression of ALS.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/fisiopatologia , Glutationa Peroxidase/metabolismo , Locomoção/fisiologia , Neurônios Motores/fisiologia , Medula Espinal/metabolismo , Natação/fisiologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Masculino , Camundongos , Camundongos Transgênicos/metabolismo , Camundongos Transgênicos/fisiologia , Microglia/metabolismo , Microglia/fisiologia , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Neurônios Motores/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Estresse Oxidativo/fisiologia , Medula Espinal/fisiopatologia , Superóxido Dismutase/metabolismo
16.
Biomed Res Int ; 2021: 7254708, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34746308

RESUMO

Spinal cord ischemia/reperfusion (SCI/R) injury is a devastating complication usually occurring after thoracoabdominal aortic surgery. However, it remains unsatisfactory for its intervention by using pharmacological strategies. Oxidative stress is a main pharmacological process involved in SCI/R, which will elicit downstream programmed cell death such as the novel defined necroptosis. Astragalin is a bioactive natural flavonoid with a wide spectrum of pharmacological activities. Herein, we firstly evaluated the effect of astragalin to oxidative stress as well as the possible downstream necroptosis after SCI/R in mice. Our results demonstrated that astragalin improves the ethological score and histopathological deterioration of SCI/R mice. Astragalin mitigates oxidative stress and ameliorates inflammation after SCI/R. Astragalin blocks necroptosis induced by SCI/R. That is, the amelioration of astragalin to the motoneuron injury and histopathological changes. Indicators of oxidative stress, inflammation, and necroptosis after SCI/R were significantly blocked. Summarily, we firstly illustrated the protection of astragalin against SCI/R through its blockage to the necroptosis at downstream of oxidative stress.


Assuntos
Quempferóis/farmacologia , Necroptose/efeitos dos fármacos , Isquemia do Cordão Espinal/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Flavonoides/farmacologia , Inflamação/tratamento farmacológico , Quempferóis/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Necroptose/fisiologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Isquemia do Cordão Espinal/complicações , Isquemia do Cordão Espinal/fisiopatologia
17.
Cell Rep ; 37(8): 110019, 2021 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-34818559

RESUMO

In cell transplantation therapy for spinal cord injury (SCI), grafted human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) mainly differentiate into neurons, forming synapses in a process similar to neurodevelopment. In the developing nervous system, the activity of immature neurons has an important role in constructing and maintaining new synapses. Thus, we investigate how enhancing the activity of transplanted hiPSC-NS/PCs affects both the transplanted cells themselves and the host tissue. We find that chemogenetic stimulation of hiPSC-derived neural cells enhances cell activity and neuron-to-neuron interactions in vitro. In a rodent model of SCI, consecutive and selective chemogenetic stimulation of transplanted hiPSC-NS/PCs also enhances the expression of synapse-related genes and proteins in surrounding host tissues and prevents atrophy of the injured spinal cord, thereby improving locomotor function. These findings provide a strategy for enhancing activity within the graft to improve the efficacy of cell transplantation therapy for SCI.


Assuntos
Células-Tronco Pluripotentes Induzidas/transplante , Locomoção/fisiologia , Traumatismos da Medula Espinal/terapia , Animais , Diferenciação Celular/fisiologia , Linhagem Celular , Células Cultivadas , Modelos Animais de Doenças , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/fisiologia , Camundongos , Camundongos SCID , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/fisiologia , Células-Tronco Neurais/transplante , Neurônios/metabolismo , Recuperação de Função Fisiológica , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Transplante de Células-Tronco/métodos
18.
PLoS One ; 16(11): e0260166, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34793572

RESUMO

BACKGROUND: Transcutaneous spinal cord stimulation (tSCS) is a non-invasive modality in which electrodes can stimulate spinal circuitries and facilitate a motor response. This review aimed to evaluate the methodology of studies using tSCS to generate motor activity in persons with spinal cord injury (SCI) and to appraise the quality of included trials. METHODS: A systematic search for studies published until May 2021 was made of the following databases: EMBASE, Medline (Ovid) and Web of Science. Two reviewers independently screened the studies, extracted the data, and evaluated the quality of included trials. The electrical characteristics of stimulation were summarised to allow for comparison across studies. In addition, the surface electromyography (EMG) recording methods were evaluated. RESULTS: A total of 3753 articles were initially screened, of which 25 met the criteria for inclusion. Studies were divided into those using tSCS for neurophysiological investigations of reflex responses (n = 9) and therapeutic investigations of motor recovery (n = 16). The overall quality of evidence was deemed to be poor-to-fair (10.5 ± 4.9) based on the Downs and Black Quality Checklist criteria. The electrical characteristics were collated to establish the dosage range across stimulation trials. The methods employed by included studies relating to stimulation parameters and outcome measurement varied extensively, although some trends are beginning to appear in relation to electrode configuration and EMG outcomes. CONCLUSION: This review outlines the parameters currently employed for tSCS of the cervicothoracic and thoracolumbar regions to produce motor responses. However, to establish standardised procedures for neurophysiological assessments and therapeutic investigations of tSCS, further high-quality investigations are required, ideally utilizing consistent electrophysiological recording methods, and reporting common characteristics of the electrical stimulation administered.


Assuntos
Atividade Motora/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia , Estimulação da Medula Espinal/métodos , Medula Espinal/fisiopatologia , Animais , Estimulação Elétrica/métodos , Humanos
19.
Oxid Med Cell Longev ; 2021: 8186877, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34712387

RESUMO

Spinal cord injury (SCI) refers to a major worldwide cause of accidental death and disability. However, the complexity of the pathophysiological mechanism can result in less-effective clinical treatment. Growth differentiation factor 11 (GDF-11), an antiageing factor, was reported to affect the development of neurogenesis and exert a neuroprotective effect after cerebral ischaemic injury. The present work is aimed at investigating the influence of GDF-11 on functional recovery following SCI, in addition to the potential mechanisms involved. We employed a mouse model of spinal cord contusion injury and assessed functional outcomes via the Basso Mouse Scale and footprint analysis following SCI. Using western blot assays and immunofluorescence, we analysed the levels of pyroptosis, autophagy, necroptosis, and molecules related to the AMPK-TRPML1-calcineurin signalling pathway. The results showed that GDF-11 noticeably optimized function-related recovery, increased autophagy, inhibited pyroptosis, and alleviated necroptosis following SCI. Furthermore, the conducive influences exerted by GDF-11 were reversed with the application of 3-methyladenine (3MA), an autophagy suppressor, indicating that autophagy critically impacted the therapeutically related benefits of GDF-11 on recovery after SCI. In the mechanistic study described herein, GDF-11 stimulated autophagy improvement and subsequently inhibited pyroptosis and necroptosis, which were suggested to be mediated by TFE3; this effect resulted from the activity of TFE3 through the AMPK-TRPML1-calcineurin signalling cascade. Together, GDF-11 protects the injured spinal cord by suppressing pyroptosis and necroptosis via TFE3-mediated autophagy augmentation and is a potential agent for SCI therapy.


Assuntos
Autofagia/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Fatores de Diferenciação de Crescimento/farmacologia , Necroptose/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Medula Espinal/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Calcineurina/metabolismo , Modelos Animais de Doenças , Feminino , Camundongos Endogâmicos C57BL , Recuperação de Função Fisiológica , Transdução de Sinais , Medula Espinal/metabolismo , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Canais de Potencial de Receptor Transitório/metabolismo
20.
Stem Cell Reports ; 16(11): 2703-2717, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34653401

RESUMO

Functional recovery is still limited mainly due to several mechanisms, such as the activation of Nogo receptor-1 (NgR1) signaling, when human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PC) are transplanted for subacute spinal cord injury (SCI). We previously reported the neuroprotective and regenerative benefits of overexpression of lateral olfactory tract usher substance (LOTUS), an endogenous NgR1 antagonist, in the injured spinal cord using transgenic mice. Here, we evaluate the effects of lentiviral transduction of LOTUS gene into hiPSC-NS/PCs before transplantation in a mouse model of subacute SCI. The transduced LOTUS contributes to neurite extension, suppression of apoptosis, and secretion of neurotrophic factors in vitro. In vivo, the hiPSC-NS/PCs enhance the survival of grafted cells and enhance axonal extension of the transplanted cells, resulting in significant restoration of motor function following SCI. Therefore, the gene transduction of LOTUS in hiPSC-NS/PCs could be a promising adjunct for transplantation therapy for SCI.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Neurais/metabolismo , Traumatismos da Medula Espinal/terapia , Transplante de Células-Tronco/métodos , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Atividade Motora/fisiologia , Recuperação de Função Fisiológica/fisiologia , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Transdução Genética , Transplante Heterólogo
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