RESUMO
BACKGROUND AND PURPOSE: After repeat administration of gadolinium-based contrast agents (GBCAs), the association between gadolinium retention in the central and peripheral nervous systems and the main manifestations of myelopathy and progressive neurologic symptoms remains unclear. We investigated the effects of the repeat administration of GBCAs on gadolinium retention in the central and peripheral nervous systems and the sensory, cognitive, and athletic implications. MATERIALS AND METHODS: Forty-eight male Wistar rats (6 weeks of age) were randomly divided into 4 experimental groups (12 rats in each group): the gadodiamide group (linear and nonionic GBCAs), the gadopentetate dimeglumine group (linear and ionic GBCAs), the gadoterate meglumine group (macrocyclic and ionic GBCAs), and the control group (0.9% saline solution). The brains of the rats were scanned using 9.4T MRI. Sensory behavioral tests were performed to assess the effect of GBCAs on pain sensitivity function. Gadolinium deposition in the brain, spinal cord, and peripheral nerves was determined by inductively coupled plasma mass-spectrometry. Transmission electron microscopy was used to observe the microscopic distribution of gadolinium after deposition in the spinal cord. The histopathologic features in the spinal cord were analyzed by H&E staining, Nissl staining, glial fibrillary acidic protein staining, and neuron-specific enolase staining after administration of GBCAs. RESULTS: All GBCAs resulted in gadolinium deposition in the central and peripheral nerve tissues, with the highest deposition in the sciatic nerve tissue (mean, 62.86 [SD, 12.56] nmol/g). Decreased muscle power, impairment of spatial cognitive function power, and pain hypersensitivity to thermal and mechanical stimuli were observed after exposure to gadodiamide. At the spinal cord, transmission electron microscopy found that the region of gadolinium depositions had a spheric structure similar to "sea urchins" and was mainly located near the vascular basement membrane. CONCLUSIONS: Multiple injections of GBCAs caused gadolinium deposition in the brain, spinal cord, and peripheral nerves, especially in the spinal cords of the gadodiamide group. Gadodiamide led to pain hypersensitivity and decreased muscle power and cognitive ability. For the patients who are hypersensitive to pain and need multiple MRI examinations, we recommend using macrocyclic GBCAs and the lowest dose possible.
Assuntos
Meios de Contraste , Gadolínio , Ratos Wistar , Animais , Meios de Contraste/farmacocinética , Masculino , Ratos , Gadolínio/farmacocinética , Imageamento por Ressonância Magnética/métodos , Cognição/efeitos dos fármacos , Gadolínio DTPA/farmacocinética , Gadolínio DTPA/administração & dosagem , Sistema Nervoso Periférico/efeitos dos fármacos , Sistema Nervoso Periférico/diagnóstico por imagem , Medula Espinal/diagnóstico por imagem , Medula Espinal/metabolismo , Medula Espinal/efeitos dos fármacos , Sistema Nervoso Central/diagnóstico por imagem , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacosRESUMO
BACKGROUND: Prenatal nicotine exposure (PNE) has been documented to cause numerous deleterious effects on fetal development. However, the epigenetic changes promoted by nicotine exposure on germ cells are still not well understood. OBJECTIVES: In this study, we focused on elucidating the impact of prenatal nicotine exposure on regulatory epigenetic mechanisms important for germ cell development. METHODS: Sprague-Dawley rats were exposed to nicotine during pregnancy and male progeny was analyzed at 11 weeks of age. Testis morphology was analyzed using frozen testis sections and expression of germ cell markers was examined by RT-qPCR; histone modifications were assessed by Western Blot (WB). DNA methylation analysis was performed by methylation-specific PCR of bisulfite converted DNA. Genome-wide DNA methylation was analyzed using Methylated DNA immunoprecipitation (MeDIP)-seq. We also carried out transcriptomics analysis of pituitary glands by RNA-seq. RESULTS: We show that gestational exposure to nicotine reduces germ cell numbers, perturbs meiosis, affects the expression of germ line reprogramming responsive genes, and impacts the DNA methylation of nervous system genes in the testis. PNE also causes perturbation of gene expression in the pituitary gland of the brain. CONCLUSIONS: Our data demonstrate that PNE leads to perturbation of male spermatogenesis, and the observed effects are associated with changes of peripheral nervous system signaling pathways. Alterations in the expression of genes associated with diverse biological activities such as cell migration, cell adhesion and GABA signaling in the pituitary gland underscore the complexity of the effects of nicotine exposure during pregnancy.
Assuntos
Metilação de DNA , Epigênese Genética , Nicotina , Efeitos Tardios da Exposição Pré-Natal , Ratos Sprague-Dawley , Testículo , Animais , Masculino , Feminino , Gravidez , Ratos , Testículo/efeitos dos fármacos , Testículo/metabolismo , Epigênese Genética/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Transdução de Sinais/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Espermatogênese/genética , Sistema Nervoso Periférico/efeitos dos fármacos , Sistema Nervoso Periférico/metabolismoRESUMO
This special issue of the Journal of Neurochemistry, entitled "Cholinergic Mechanisms," presents 15 reviews and two original papers, which have been selected to cover the broad spectrum of topics and disciplines presented at the XVIth International Symposium on Cholinergic Mechanisms (ISCM-XVI), ranging from the molecular and the cellular to the clinical and the cognitive mechanisms of cholinergic transmission. The authors discuss recent developments in the field, for instance, the association of cholinergic transmission with a number of important neurological and neuromuscular diseases in the central and peripheral nervous systems.
Assuntos
Acetilcolina/metabolismo , Encéfalo/metabolismo , Neurônios Colinérgicos/metabolismo , Sistema Nervoso Periférico/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Colinérgicos/metabolismo , Colinérgicos/farmacologia , Neurônios Colinérgicos/efeitos dos fármacos , Humanos , Sistema Nervoso Periférico/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
Cholinesterases are fundamental players in the peripheral and central nervous systems [...].
Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Sistema Nervoso Central/enzimologia , Doenças Neurodegenerativas/enzimologia , Neurônios/enzimologia , Sistema Nervoso Periférico/enzimologia , Acetilcolinesterase/genética , Animais , Butirilcolinesterase/genética , Sistema Nervoso Central/citologia , Sistema Nervoso Central/efeitos dos fármacos , Inibidores da Colinesterase/uso terapêutico , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Expressão Gênica , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Sistema Nervoso Periférico/citologia , Sistema Nervoso Periférico/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/enzimologia , Transmissão SinápticaRESUMO
Chronic pain is a leading health and socioeconomic problem and an unmet need exists for long-lasting analgesics. SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) are required for neuropeptide release and noxious signal transducer surface trafficking, thus, selective expression of the SNARE-cleaving light-chain protease of botulinum neurotoxin A (LCA) in peripheral sensory neurons could alleviate chronic pain. However, a safety concern to this approach is the lack of a sensory neuronal promoter to prevent the expression of LCA in the central nervous system. Towards this, we exploit the unique characteristics of Pirt (phosphoinositide-interacting regulator of TRP), which is expressed in peripheral nociceptive neurons. For the first time, we identified a Pirt promoter element and cloned it into a lentiviral vector driving transgene expression selectively in peripheral sensory neurons. Pirt promoter driven-LCA expression yielded rapid and concentration-dependent cleavage of SNAP-25 in cultured sensory neurons. Moreover, the transcripts of pain-related genes (TAC1, tachykinin precursor 1; CALCB, calcitonin gene-related peptide 2; HTR3A, 5-hydroxytryptamine receptor 3A; NPY2R, neuropeptide Y receptor Y2; GPR52, G protein-coupled receptor 52; SCN9A, sodium voltage-gated channel alpha subunit 9; TRPV1 and TRPA1, transient receptor potential cation channel subfamily V member 1 and subfamily A member 1) in pro-inflammatory cytokines stimulated sensory neurons were downregulated by viral mediated expression of LCA. Furthermore, viral expression of LCA yielded long-lasting inhibition of pain mediator release. Thus, we show that the engineered Pirt-LCA virus may provide a novel means for long lasting pain relief.
Assuntos
Toxinas Botulínicas Tipo A/farmacologia , Neuropeptídeos/metabolismo , Dor/prevenção & controle , Sistema Nervoso Periférico/metabolismo , Células Receptoras Sensoriais/metabolismo , Proteína 25 Associada a Sinaptossoma/metabolismo , Animais , Animais Recém-Nascidos , Feminino , Humanos , Masculino , Fusão de Membrana , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Nociceptores/efeitos dos fármacos , Nociceptores/metabolismo , Dor/genética , Dor/metabolismo , Dor/patologia , Sistema Nervoso Periférico/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/efeitos dos fármacos , Proteína 25 Associada a Sinaptossoma/genéticaRESUMO
Reflex cardiorespiratory alterations elicited after instillation of nociceptive agents intra-arterially (i.a) are termed as 'vasosensory reflex responses'. The present study was designed to evaluate such responses produced after i.a. instillation of histamine (1 mM; 10 mM; 100 mM) and to delineate the pathways i.e. the afferents and efferents mediating these responses. Blood pressure, electrocardiogram and respiratory excursions were recorded before and after injecting saline/histamine, in a local segment of femoral artery in urethane anesthetized rats. Paw edema and latencies of responses were also estimated. Separate groups of experiments were conducted to demonstrate the involvement of somatic nerves in mediating histamine-induced responses after ipsilateral femoral and sciatic nerve sectioning (+NX) and lignocaine pre-treatment (+Ligno). In addition, another set of experiments was performed after bilateral vagotomy (+VagX) and the responses after histamine instillation were studied. Histamine produced concentration-dependent hypotensive, bradycardiac, tachypnoeic and hyperventilatory responses of shorter latencies (2-7 s) favouring the neural mechanisms in eliciting the responses. Instillation of saline (time matched control) in a similar fashion produced no response, excluding the possibilities of ischemic/stretch effects. Paw edema was absent in both hind limbs indicating that the histamine did not reach the paws and did not spill out into the systemic circulation. +NX, +VagX, +Ligno attenuated histamine-induced cardiorespiratory responses significantly. These observations conclude that instillation of 10 mM of histamine produces optimal vasosensory reflex responses originating from the local vascular bed; afferents and efferents of which are mostly located in ipsilateral somatic and vagus nerves respectively.
Assuntos
Endotélio Vascular/inervação , Histamina/farmacologia , Sistema Nervoso Periférico/efeitos dos fármacos , Reflexo/efeitos dos fármacos , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Bradicardia/induzido quimicamente , Bradicardia/fisiopatologia , Endotélio Vascular/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Hiperventilação/induzido quimicamente , Hiperventilação/fisiopatologia , Masculino , Sistema Nervoso Periférico/fisiologia , Ratos , Reflexo/fisiologia , Taquipneia/induzido quimicamente , Taquipneia/fisiopatologia , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
BACKGROUND: We recently reported that a 6-day continuous peripheral nerve block reduced established postamputation phantom pain 3 weeks after treatment ended. However, the immediate effects of perineural infusion (secondary outcomes) have yet to be reported. METHODS: Participants from 5 enrolling academic centers with an upper or lower limb amputation and established phantom pain received a single-injection ropivacaine peripheral nerve block(s) and perineural catheter insertion(s). They were subsequently randomized to receive a 6-day ambulatory perineural infusion of either ropivacaine 0.5% or normal saline in a double-masked fashion. Participants were contacted by telephone 1, 7, 14, 21, and 28 days after the infusion started, with pain measured using the Numeric Rating Scale. Treatment effects were assessed using the Wilcoxon rank-sum test at each time point. Adjusting for 4 time points (days 1, 7, 14, and 21), P < .0125 was deemed statistically significant. Significance at 28 days was reported using methods from the original, previously published article. RESULTS: Pretreatment average phantom and residual pain scores were balanced between the groups. The day after infusion initiation (day 1), average phantom, and residual limb pain intensity was lower in patients receiving local anesthetic (n = 71) versus placebo (n = 73): median [quartiles] of 0 [0-2.5] vs 3.3 [0-5.0], median difference (98.75% confidence interval [CI]) of -1.0 (-3.0 to 0) for phantom pain (P = .001) and 0 [0-0] vs 0 [0-4.3], and median difference 0.0 (-2.0 to 0.0) for residual limb pain (P < .001). Pain's interference with physical and emotional functioning as measured with the interference domain of the Brief Pain Inventory improved during the infusion on day 1 for patients receiving local anesthetic versus placebo: 0 [0-10] vs 10 [0-40], median difference (98.75% CI) of 0.0 (-16.0 to 0.0), P = .002. Following infusion discontinuation (day 6), a few differences were found between the active and placebo treatment groups between days 7 and 21. In general, sample medians for average phantom and residual limb pain scores gradually increased after catheter removal for both treatments, but to a greater degree in the control group until day 28, at which time the differences between the groups returned to statistical significance. CONCLUSIONS: This secondary analysis suggests that a continuous peripheral nerve block decreases phantom and residual limb pain during the infusion, although few improvements were again detected until day 28, 3 weeks following catheter removal.
Assuntos
Amputação Cirúrgica/efeitos adversos , Anestésicos Locais/administração & dosagem , Bloqueio Nervoso , Manejo da Dor , Dor Pós-Operatória/tratamento farmacológico , Sistema Nervoso Periférico/efeitos dos fármacos , Membro Fantasma/tratamento farmacológico , Ropivacaina/administração & dosagem , Humanos , Bloqueio Nervoso/efeitos adversos , Manejo da Dor/efeitos adversos , Medição da Dor , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Membro Fantasma/diagnóstico , Membro Fantasma/etiologia , Ropivacaina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: Peripheral nerve block (PNB) with perineural local anesthetic is used for anesthesia or analgesia with many benefits. To extend these benefits, various adjuvant drugs have been used to prolong the duration of analgesia. We aimed to evaluate the effectiveness of various adjuvants at prolonging the duration of sensory and motor blockade for PNB. METHODS: A network meta-analysis of placebo-controlled and active randomized controlled trials was performed comparing 10 adjuvants. Embase, PubMed, Web of Science, and Cochrane library were searched, with articles before May 21, 2020 included. Two authors independently selected studies and extracted data. The primary outcomes were sensory block (SB) and motor block (MB) time, and the secondary outcome was time of first analgesia rescue (FAR). Effect size measures were described as mean differences (MD) with 95% confidence intervals (CIs). Confidence in evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). The study protocol was preregistered with the prospectively registered systematic reviews in health and social care international database (PROSPERO), as number CRD42020187866. RESULTS: Overall 16,364 citations were identified, of which 53 studies were included with data for 3649 patients. In network meta-analyses, 4 of 7 included treatment strategies were associated with more efficacious analgesia compared with placebo therapy, including dexamethasone (SB time: 5.73 hours, 95% CI, 4.16-7.30; MB time: 4.20 hours, 95% CI, 2.51-5.89; time of FAR: 8.71 hours, 95% CI, 6.63-10.79), dexmedetomidine (SB time: 4.51 hours, 95% CI, 3.52-5.50; MB time: 4.04 hours, 95% CI, 2.98-5.11; time of FAR: 5.25 hours, 95% CI, 4.08-6.43), fentanyl (SB time: 3.59 hours, 95% CI, 0.11-7.06; MB time: 4.42 hours, 95% CI, 0.78-8.06), and clonidine (SB time: 2.75 hours, 95% CI, 1.46-4.04; MB time: 2.93 hours, 95% CI, 1.69-4.16; time of FAR: 3.35 hours, 95% CI, 1.82-4.87). In a subgroup analysis, addition of dexamethasone to ropivacaine significantly increased the time of FAR when compared to dexmedetomidine (time of FAR: 5.23 hours, 95% CI, 2.92-7.54) or clonidine (time of FAR: 6.61 hours, 95% CI, 4.29-8.92) with ropivacaine. CONCLUSIONS: These findings provide evidence for the consideration of dexmedetomidine, dexamethasone, and clonidine as adjuvants to prolong the duration of PNB. The addition of dexamethasone to ropivacaine has a longer time of FAR compared with clonidine or dexmedetomidine.
Assuntos
Adjuvantes Anestésicos/administração & dosagem , Anestésicos Locais/administração & dosagem , Atividade Motora/efeitos dos fármacos , Bloqueio Nervoso , Sistema Nervoso Periférico/efeitos dos fármacos , Limiar Sensorial/efeitos dos fármacos , Adjuvantes Anestésicos/efeitos adversos , Anestésicos Locais/efeitos adversos , Clonidina/administração & dosagem , Dexmedetomidina/administração & dosagem , Esquema de Medicação , Interações Medicamentosas , Humanos , Bloqueio Nervoso/efeitos adversos , Metanálise em Rede , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Ophiorrhiza rugosa var. prostrata is a traditional medicinal plant used by the indigenous and local tribes (Chakma, Marma and Tanchangya) of Bangladesh for the management of chest pain, body ache, and earache. However, the knowledge of anti-nociceptive and anti-inflammatory potentials of this plant is scarce. AIM OF THE STUDY: Therefore, we scrutinized the anti-nociceptive and anti-inflammatory properties of O. rugosa leaves along with its possible mechanism(s) of action using chemical and heat-induced pain models. METHODS AND MATERIALS: O. rugosa was extracted using 100% ethanol (EEOR) followed by exploring phytochemicals and assessing acute toxicity. To determine anti-nociceptive potentials, chemical-induced (acetic acid and formalin) and heat-induced (hot plate and tail immersion) nociceptive models were followed. To investigate the possible involvement of opioid receptors during formalin, hot plate, and tail immersion tests, naltrexone was administered whereas methylene blue and glibenclamide were used to explore cGMP involvement and ATP-sensitive K+ channel pathways, respectively. Moreover, the anti-inflammatory potential was assessed using the carrageenan-induced paw edema test model. Motor behaviours of EEOR were assessed by the open-field test. Finally, bioactive constituents (identified by GC-MS) from O. rugosa were subjected to molecular docking and ADME/t analysis to evaluate its potency and safety. RESULTS: During chemical-induced and heat-induced pain models, EEOR exhibited significant and effective nociception suppression at all experimental doses (200 and 400 mg/kg). Also, the administration of naltrexone corroborated the association of opioid receptors with the anti-nociceptive activity by EEOR. Similarly, cGMP and ATP-sensitive K+ channel pathways were also found to be involved in the anti-nociceptive mechanism. Furthermore, significant and dose-dependent inhibition of inflammation induced by carrageenan was recorded for EEOR. Both doses of EEOR did not affect the animal's locomotor capacity in the open-field test. Besides, in silico test identified the key compounds (loliolide, harman, squalene, vitamin E, and gamma-sitosterol) that inhibited some particular receptors regarding pain and inflammation. CONCLUSION: This research exposes central and peripheral pain intervention as well as anti-inflammatory activity of O. rugosa. Also, the identified compounds from this plant support its activities by effectively inhibiting anti-nociceptive and anti-inflammatory receptors. Overall, these outcomes valorize the ethnomedicinal efficacy of O. rugosa in managing various painful conditions.
Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Dor/tratamento farmacológico , Dor/metabolismo , Extratos Vegetais/farmacologia , Rubiaceae/química , Ácido Acético/toxicidade , Analgésicos/química , Analgésicos/isolamento & purificação , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Carragenina/toxicidade , Sistema Nervoso Central/efeitos dos fármacos , Modelos Animais de Doenças , Edema/induzido quimicamente , Edema/tratamento farmacológico , Feminino , Formaldeído/toxicidade , Temperatura Alta/efeitos adversos , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Nociceptividade/efeitos dos fármacos , Dor/etiologia , Sistema Nervoso Periférico/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Receptores Opioides/efeitos dos fármacosRESUMO
This case series describes three patients affected by severe acute respiratory syndrome coronavirus 2, who developed polyradiculoneuritis as a probable neurological complication of coronavirus disease 2019 (COVID-19). A diagnosis of Guillain Barré syndrome was made on the basis of clinical symptoms, cerebrospinal fluid analysis, and electroneurography. In all of them, the therapeutic approach included the administration of intravenous immunoglobulin (0.4 gr/kg for 5 days), which resulted in the improvement of neurological symptoms. Clinical neurophysiology revealed the presence of conduction block, absence of F waves, and in two cases, a significant decrease in amplitude of compound motor action potential cMAP. Due to the potential role of inflammation on symptoms development and prognosis, interleukin-6 (IL-6) and IL-8 levels were measured in serum and cerebrospinal fluid during the acute phase, while only serum was tested after recovery. Both IL-6 and IL-8 were found increased during the acute phase, both in the serum and cerebrospinal fluid, whereas 4 months after admission (at complete recovery), only IL-8 remained elevated in the serum. These results confirm the inflammatory response that might be linked to peripheral nervous system complications and encourage the use of IL-6 and IL-8 as prognostic biomarkers in COVID-19.
Assuntos
COVID-19/complicações , Síndrome de Guillain-Barré/complicações , Interleucina-6/líquido cefalorraquidiano , Interleucina-8/líquido cefalorraquidiano , Insuficiência Respiratória/complicações , SARS-CoV-2/patogenicidade , Potenciais de Ação/efeitos dos fármacos , Doença Aguda , Idoso , Antibacterianos/uso terapêutico , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , COVID-19/líquido cefalorraquidiano , COVID-19/virologia , Convalescença , Darunavir/uso terapêutico , Combinação de Medicamentos , Síndrome de Guillain-Barré/líquido cefalorraquidiano , Síndrome de Guillain-Barré/tratamento farmacológico , Síndrome de Guillain-Barré/virologia , Humanos , Hidroxicloroquina/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Interleucina-6/sangue , Interleucina-8/sangue , Lopinavir/uso terapêutico , Masculino , Condução Nervosa/efeitos dos fármacos , Sistema Nervoso Periférico/efeitos dos fármacos , Sistema Nervoso Periférico/patologia , Sistema Nervoso Periférico/virologia , Prognóstico , Insuficiência Respiratória/líquido cefalorraquidiano , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/virologia , Ritonavir/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Tratamento Farmacológico da COVID-19RESUMO
Monomethyl auristatin E (MMAE) is a potent anti-cancer microtubule-targeting agent (MTA) used as a payload in three approved MMAE-containing antibody drug conjugates (ADCs) and multiple ADCs in clinical development to treat different types of cancers. Unfortunately, MMAE-ADCs can induce peripheral neuropathy, a frequent adverse event leading to treatment dose reduction or discontinuation and subsequent clinical termination of many MMAE-ADCs. MMAE-ADC-induced peripheral neuropathy is attributed to non-specific uptake of the ADC in peripheral nerves and release of MMAE, disrupting microtubules (MTs) and causing neurodegeneration. However, molecular mechanisms underlying MMAE and MMAE-ADC effects on MTs remain unclear. Here, we characterized MMAE-tubulin/MT interactions in reconstituted in vitro soluble tubulin or MT systems and evaluated MMAE and vcMMAE-ADCs in cultured human MCF7 cells. MMAE bound to soluble tubulin heterodimers with a maximum stoichiometry of ~1:1, bound abundantly along the length of pre-assembled MTs and with high affinity at MT ends, introduced structural defects, suppressed MT dynamics, and reduced the kinetics and extent of MT assembly while promoting tubulin ring formation. In cells, MMAE and MMAE-ADC (via nonspecific uptake) suppressed proliferation, mitosis and MT dynamics, and disrupted the MT network. Comparing MMAE action to other MTAs supports the hypothesis that peripheral neuropathy severity is determined by the precise mechanism(s) of each individual drug-MT interaction (location of binding, affinity, effects on morphology and dynamics). This work demonstrates that MMAE binds extensively to tubulin and MTs and causes severe MT dysregulation, providing convincing evidence that MMAE-mediated inhibition of MT-dependent axonal transport leads to severe peripheral neuropathy.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Microtúbulos/efeitos dos fármacos , Oligopeptídeos/toxicidade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Sistema Nervoso Periférico/efeitos dos fármacos , Moduladores de Tubulina/toxicidade , Tubulina (Proteína)/metabolismo , Transporte Axonal/efeitos dos fármacos , Sítios de Ligação , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Microtúbulos/metabolismo , Microtúbulos/patologia , Mitose/efeitos dos fármacos , Oligopeptídeos/metabolismo , Sistema Nervoso Periférico/metabolismo , Sistema Nervoso Periférico/patologia , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Ligação Proteica , Medição de Risco , Fuso Acromático/efeitos dos fármacos , Fuso Acromático/metabolismo , Fuso Acromático/patologia , Moduladores de Tubulina/metabolismoRESUMO
The role of peripheral adenosine receptors in pain is a controversial issue and seems to be quite different from the roles of spinal and central adenosine receptors. The present study is aimed at clarifying the role of these receptors in peripheral nociception. To clarify this, studies were done on Swiss mice with adenosine receptor agonists and antagonists. Nociceptive behavior was induced by subcutaneous injection of glutamate (10 µmol) into the ventral surface of the hind paw of mice. Statistical analyses were performed by one-way ANOVA followed by the Student-Newman-Keuls post hoc test. Results showed that intraplantar (i.pl.) administration of N6-cyclohexyl-adenosine (CHA), an adenosine A1 receptor agonist, at 1 or 10 µg/paw significantly reduced glutamate-induced nociception (p<0.01 and p<0.001 vs. vehicle, respectively, n=8-10). In contrast, i.pl. injection of hydrochloride hydrate (CGS21680, an adenosine A2A receptor agonist) (1 µg/paw) induced a significant increase in glutamate-induced nociception compared to the vehicle (p<0.05, n=8), while 4-(-2-[7-amino-2-{2-furyl}{1,2,4}triazolo{2,3-a} {1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM241385, an adenosine A2A receptor antagonist) (20 µg/paw) caused a significant reduction (p<0.05, n=7-8). There were no significant effects on i.pl. administration of four additional adenosine receptor drugs-8-cyclopentyl-1,3-dipropylxanthine (DPCPX, an A1 antagonist, 1-10 µg/paw), N(6)-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine (DPMA, an A2B agonist, 1-100 µg/paw), alloxazine (an A2B antagonist, 0.1-3 µg/paw), and 2-hexyn-1-yl-N(6)-methyladenosine (HEMADO) (an A3 agonist, 1-100 µg/paw) (p>0.05 vs. vehicle for all tests). We also found that prior administration of DPCPX (3 µg/paw) significantly blocked the anti-nociceptive effect of CHA (1 µg/paw) (p<0.05, n=7-9). Similarly, ZM241385 (20 µg/paw) administered prior to CGS21680 (1 µg/paw) significantly blocked CGS21680-induced exacerbation of nociception (p<0.05, n=8). Finally, inosine (10 and 100 µg/paw), a novel endogenous adenosine A1 receptor agonist recently reported by our research group, was also able to reduce glutamate-induced nociception (p<0.001 vs. vehicle, n=7-8). Interestingly, as an A1 adenosine receptor agonist, the inosine effect was significantly blocked by the A1 antagonist DPCPX (3 µg/paw) (p<0.05, n=7-9) but not by the A2A antagonist ZM241385 (10 µg/paw, p>0.05). In summary, these results demonstrate for the first time that i.pl administration of inosine induces an anti-nociceptive effect, similar to that elicited by CHA and possibly mediated by peripheral adenosine A1 receptor activation. Moreover, our results suggest that peripheral adenosine A2A receptor activation presents a pro-nociceptive effect, exacerbating glutamate-induced nociception independent of inosine-induced anti-nociceptive effects.
Assuntos
Glutamatos , Nociceptividade/efeitos dos fármacos , Dor/induzido quimicamente , Dor/psicologia , Sistema Nervoso Periférico/efeitos dos fármacos , Receptores Purinérgicos P1/efeitos dos fármacos , Agonistas do Receptor A1 de Adenosina/farmacologia , Antagonistas do Receptor A1 de Adenosina/farmacologia , Agonistas do Receptor A2 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Feminino , Pé , Glutamatos/administração & dosagem , Injeções , Inosina/farmacologia , Masculino , Camundongos , Medição da Dor/efeitos dos fármacos , Receptor A2A de Adenosina/efeitos dos fármacosRESUMO
Akt (protein kinase B) signaling is frequently activated in diverse cancers. Akt inhibitors such as perifosine and MK-2206 have been evaluated as potential cancer chemotherapeutics. Although both drugs are generally well tolerated, among their most common side-effects vomiting is a major concern. Here we investigated whether these Akt inhibitors evoke emesis in the least shrew model of vomiting. Indeed, both perifosine and MK-2206 induced vomiting with maximal efficacies of 90% at 50 mg/kg (i.p.) and 100% at 10 mg/kg (i.p.), respectively. MK-2206 (10 mg/kg, i.p.) increased c-Fos immunoreactivity both centrally in the shrew brainstem dorsal vagal complex (DVC) emetic nuclei, and peripherally in the jejunum. MK-2206 also evoked phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in both the DVC emetic nuclei and the enteric nervous system in the jejunum. The ERK1/2 inhibitor U0126 suppressed MK-2206-induced emesis dose-dependently. We then evaluated the suppressive efficacy of diverse antiemetics against MK-2206-evoked vomiting including antagonists/inhibitors of the: L-type Ca2+ channel (nifedipine at 2.5 mg/kg, subcutaneously (s.c.)); glycogen synthase kinase 3 (GSK-3) (AR-A014418 at 10 mg/kg and SB216763 at 0.25 mg/kg, i.p.); 5-hydroxytryptamine 5-HT3 receptor (palonosetron at 0.5 mg/kg, s.c.); substance P neurokinin NK1 receptor (netupitant at 10 mg/kg, i.p.) and dopamine D2/3 receptor (sulpride at 8 mg/kg, s.c.). All tested antagonists/blockers attenuated emetic parameters to varying degrees. In sum, this is the first study to demonstrate how pharmacological inhibition of Akt evokes vomiting via both central and peripheral mechanisms, a process which involves multiple emetic receptors.
Assuntos
Antieméticos/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis , Proteína Oncogênica v-akt/antagonistas & inibidores , Sistema Nervoso Periférico/efeitos dos fármacos , Musaranhos/fisiologia , Vômito/induzido quimicamente , Vômito/fisiopatologia , Animais , Antieméticos/uso terapêutico , Tronco Encefálico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eméticos/farmacologia , Sistema Nervoso Entérico/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/antagonistas & inibidores , Jejuno/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosforilação , Proteínas Proto-Oncogênicas c-fos/metabolismo , Vômito/tratamento farmacológicoRESUMO
Hepatic encephalopathy (HE) is a debilitating and life-threatening disease. Results from acute or chronic liver failure and is characterized by abnormal cerebral and neurological alterations. This study aimed at investigating the effect of allicin, the major functional component in freshly crushed garlic extract, on thioacetamide (TAA)-induced HE in rats. Induction of HE by a single dose of TAA (300 mg/kg; I.P.) was associated with a marked elevation in the serum levels of alanine aminotransferase, aspartate aminotransferase, bilirubin, albumin, total protein, blood urea nitrogen and serum ammonia besides reduction in the serum level of albumin. Moreover, it was accompanied with an increase in the hepatic and brain levels of inflammatory mediators; TNF-α and IL-1ß as well as elevation of the hepatic and brain levels of oxidative stress biomarkers; reduced glutathione and lipid peroxidation evidenced by malondialdeyde. Oral administration of allicin (50, 100 and 200 mg/kg; P.O.) for 6 days prior to TAA injection restored the serum liver function, hepatic and brain levels of inflammatory mediators as well as oxidative stress biomarkers in a dose-dependent manner. From our results, it can be concluded that allicin has a protective effect on TAA-induced HE in rats in a dose-dependent manner due to its powerful antioxidant and anti-inflammatory properties.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/uso terapêutico , Sistema Nervoso Central/efeitos dos fármacos , Dissulfetos/uso terapêutico , Encefalopatia Hepática/induzido quimicamente , Encefalopatia Hepática/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Sistema Nervoso Periférico/efeitos dos fármacos , Ácidos Sulfínicos/uso terapêutico , Tioacetamida , Animais , Química Encefálica , Sistema Nervoso Central/patologia , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Encefalopatia Hepática/patologia , Testes de Função Hepática , Masculino , Estresse Oxidativo , Sistema Nervoso Periférico/patologia , RatosRESUMO
Interleukin-31 (IL-31) is involved in excessive development of cutaneous sensory nerves in atopic dermatitis (AD), leading to severe pruritus. We previously reported that PQA-18, a prenylated quinolinecarboxylic acid (PQA) derivative, is an immunosuppressant with inhibition of p21-activated kinase 2 (PAK2) and improves skin lesions in Nc/Nga mice as an AD model. In the present study, we investigate the effect of PQA-18 on sensory nerves in lesional skin. PQA-18 alleviates cutaneous nerve fiber density in the skin of Nc/Nga mice. PQA-18 also inhibits IL-31-induced sensory nerve fiber outgrowth in dorsal root ganglion cultures. Signaling analysis reveals that PQA-18 suppresses phosphorylation of PAK2, Janus kinase 2, and signal transducer and activator of transcription 3 (STAT3), activated by IL-31 receptor (IL-31R), resulting in inhibition of neurite outgrowth in Neuro2A cells. Gene silencing analysis for PAK2 confirms the requirement for STAT3 phosphorylation and neurite outgrowth elicited by IL-31R activation. LC/MS/MS analysis reveals that PQA-18 prevents the formation of PAK2 activation complexes induced by IL-31R activation. These results suggest that PQA-18 inhibits the IL-31 pathway through suppressing PAK2 activity, which suppresses sensory nerve outgrowth. PQA-18 may be a valuable lead for the development of a novel drug for pruritus of AD.
Assuntos
Ácidos Carboxílicos/farmacologia , Dermatite Atópica/tratamento farmacológico , Interleucinas/antagonistas & inibidores , Quinolinas/farmacologia , Células Receptoras Sensoriais/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Dermatite Atópica/metabolismo , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Interleucinas/metabolismo , Janus Quinase 2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/patologia , Fatores de Crescimento Neural/metabolismo , Sistema Nervoso Periférico/efeitos dos fármacos , Sistema Nervoso Periférico/metabolismo , Prenilação de Proteína , Fator de Transcrição STAT3/metabolismo , Células Receptoras Sensoriais/metabolismo , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/metabolismo , Quinases Ativadas por p21/metabolismoRESUMO
PURPOSE: Hypertensive lesions induce alterations at hemodynamic, peripheral, and central levels. Anandamide (N-arachidonoylethanolamine; AEA) protects neurons from inflammatory damage, but its free administration may cause central adverse effects. AEA controlled release by nanoformulations could reduce/eliminate its side effects. The present study aimed to evaluate the effects of nanoformulated AEA (nf-AEA) on systolic blood pressure (SBP), behavior, and central/peripheral inflammatory, oxidative, and apoptotic state in spontaneously hypertensive rats (SHR). MATERIALS/METHODS: Male rats were used, both Wistar Kyoto (WKY) and SHR (n â= â10 per group), with/without treatment with nf-AEA (obtained by electrospraying) at a weekly dose of 5 âmg/kg IP for 4 weeks. SBP was measured and behavioral tests were performed. Inflammatory/oxidative markers were quantified at the central (brain cortex) and peripheral (serum) level. RESULTS: SHR showed hyperactivity, low anxiety, and high concentrations of central/peripheral inflammatory/oxidative markers, also higher apoptosis of brain cortical cells compared to WKY. As opposed to this group, treatment with nf-AEA in SHR significantly reduced SBP, peripheral/central inflammatory/oxidative makers, and central apoptosis. Nf-AEA also increased neuroprotective mechanisms mediated by intracellular heat shock protein 70 (Hsp70), which were attenuated in untreated SHR. Additionally, nf-AEA reversed the abnormal behaviors observed in SHR without producing central adverse effects. CONCLUSIONS: Our results suggest protective properties of nf-AEA, both peripherally and centrally, through a signaling pathway that would involve the type I angiotensin II receptor, Wilms tumor transcription factor 1, Hsp70, and iNOS. Considering non-nf-AEA limitations, this nanoformulation could contribute to the development of new antihypertensive and behavioral disorder treatments associated with neuroinflammation.
Assuntos
Anti-Hipertensivos/farmacologia , Ácidos Araquidônicos/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Endocanabinoides/farmacologia , Hemodinâmica , Hipertensão/tratamento farmacológico , Nanopartículas/química , Sistema Nervoso Periférico/efeitos dos fármacos , Alcamidas Poli-Insaturadas/farmacologia , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/química , Ácidos Araquidônicos/administração & dosagem , Ácidos Araquidônicos/química , Pressão Sanguínea , Endocanabinoides/administração & dosagem , Endocanabinoides/química , Hipertensão/metabolismo , Hipertensão/patologia , Masculino , Nanopartículas/administração & dosagem , Estresse Oxidativo , Alcamidas Poli-Insaturadas/administração & dosagem , Alcamidas Poli-Insaturadas/química , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Transdução de SinaisRESUMO
Peripheral neuropathy (PN) refers to many conditions involving damage to the peripheral nervous system (PNS). Usually, PN causes weakness, numbness and pain and is the result of traumatic injuries, infections, metabolic problems, inherited causes, or exposure to chemicals. Despite the high prevalence of PN, available treatments are still unsatisfactory. Neuroactive steroids (i.e., steroid hormones synthesized by peripheral glands as well as steroids directly synthesized in the nervous system) represent important physiological regulators of PNS functionality. Data obtained so far and here discussed, indeed show that in several experimental models of PN the levels of neuroactive steroids are affected by the pathology and that treatment with these molecules is able to exert protective effects on several PN features, including neuropathic pain. Of note, the observations that neuroactive steroid levels are sexually dimorphic not only in physiological status but also in PN, associated with the finding that PN show sex dimorphic manifestations, may suggest the possibility of a sex specific therapy based on neuroactive steroids.
Assuntos
Neuroesteroides/metabolismo , Sistema Nervoso Periférico/fisiopatologia , Animais , Humanos , Modelos Biológicos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Neuroesteroides/química , Neuroesteroides/uso terapêutico , Sistema Nervoso Periférico/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/patologia , Doenças do Sistema Nervoso Periférico/fisiopatologiaRESUMO
Citicoline is a chemical compound involved in the synthesis of cell membranes. It also has other, not yet explained functions. Research on the use of citicoline is conducted in neurology, ophthalmology, and psychiatry. Citicoline is widely available as a dietary supplement. It is often used to enhance cognitive functions. In our article, accessible databases were searched for articles regarding citicoline use in neurological diseases. This article has a systemic review form. After rejecting non-eligible reports, 47 remaining articles were reviewed. The review found that citicoline has been proven to be a useful compound in preventing dementia progression. It also enhances cognitive functions among healthy individuals and improves prognosis after stroke. In an animal model of nerve damage and neuropathy, citicoline stimulated regeneration and lessened pain. Among patients who underwent brain trauma, citicoline has an unclear clinical effect. Citicoline has a wide range of effects and could be an essential substance in the treatment of many neurological diseases. Its positive impact on learning and cognitive functions among the healthy population is also worth noting.
Assuntos
Citidina Difosfato Colina/farmacologia , Doenças do Sistema Nervoso/tratamento farmacológico , Animais , Lesões Encefálicas Traumáticas/tratamento farmacológico , Cognição/efeitos dos fármacos , Demência/prevenção & controle , Modelos Animais de Doenças , Humanos , Metanálise como Assunto , Neuralgia/tratamento farmacológico , Neurotransmissores/sangue , Sistema Nervoso Periférico/efeitos dos fármacos , Sistema Nervoso Periférico/metabolismo , Acidente Vascular Cerebral/tratamento farmacológicoRESUMO
Recurrent laryngeal nerve (RLN) injury, in which hoarseness and dysphagia arise as a result of impaired vocal fold movement, is a serious complication. Misdirected regeneration is an issue for functional regeneration. In this study, we demonstrated the effect of TrkA inhibitors, which blocks the NGF-TrkA pathway that acts on the sensory/automatic nerves thus preventing misdirected regeneration among motor and sensory nerves, and thereby promoting the regeneration of motor neurons to achieve functional recovery. RLN axotomy rat models were used in this study, in which cut ends of the nerve were bridged with polyglycolic acid-collagen tube with and without TrkA inhibitor (TrkAi) infiltration. Our study revealed significant improvement in motor nerve fiber regeneration and function, in assessment of vocal fold movement, myelinated nerve regeneration, compound muscle action potential, and prevention of laryngeal muscle atrophy. Retrograde labeling demonstrated fewer labeled neurons in the vagus ganglion, which confirmed reduced misdirected regeneration among motor and sensory fibers, and a change in distribution of the labeled neurons in the nucleus ambiguus. Our study demonstrated that TrkAi have a strong potential for clinical application in the treatment of RLN injury.
Assuntos
Neurônios Motores/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Receptor trkA/antagonistas & inibidores , Traumatismos do Nervo Laríngeo Recorrente/tratamento farmacológico , Nervo Laríngeo Recorrente/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/metabolismo , Animais , Colágeno/metabolismo , Músculos Laríngeos/inervação , Masculino , Bulbo/efeitos dos fármacos , Bulbo/metabolismo , Neurônios Motores/metabolismo , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/metabolismo , Sistema Nervoso Periférico/efeitos dos fármacos , Sistema Nervoso Periférico/metabolismo , Ácido Poliglicólico/metabolismo , Ratos , Ratos Sprague-Dawley , Nervo Laríngeo Recorrente/metabolismo , Traumatismos do Nervo Laríngeo Recorrente/metabolismo , Células Receptoras Sensoriais/metabolismo , Prega Vocal/efeitos dos fármacos , Prega Vocal/metabolismoRESUMO
Remyelination of the peripheral and central nervous systems (PNS and CNS, respectively) is a prerequisite for functional recovery after lesion. However, this process is not always optimal and becomes inefficient in the course of multiple sclerosis. Here we show that, when acetylated, eukaryotic elongation factor 1A1 (eEF1A1) negatively regulates PNS and CNS remyelination. Acetylated eEF1A1 (Ac-eEF1A1) translocates into the nucleus of myelinating cells where it binds to Sox10, a key transcription factor for PNS and CNS myelination and remyelination, to drag Sox10 out of the nucleus. We show that the lysine acetyltransferase Tip60 acetylates eEF1A1, whereas the histone deacetylase HDAC2 deacetylates eEF1A1. Promoting eEF1A1 deacetylation maintains the activation of Sox10 target genes and increases PNS and CNS remyelination efficiency. Taken together, these data identify a major mechanism of Sox10 regulation, which appears promising for future translational studies on PNS and CNS remyelination.