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1.
AAPS PharmSciTech ; 22(3): 95, 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33686480

RESUMO

Vulvodynia is a chronic clinical condition associated with vulvar pain that can impair the sexual, social, and psychological life of women. There is a need for more research to develop novel strategies and therapies for the treatment of vulvodynia. Vulvodynia in experimental animal models induced via infections, allergens, and diabetes are tedious and with lessor induction rate. The objective of the study was to explore the possibility of inducing vulvodynia using a chemotherapeutic agent in a rodent model. Paclitaxel is commonly used in treating breast and ovarian cancer, whose dose-limiting side effect is peripheral neuropathy. Studies have shown that peripheral neuropathy is one of the etiologies for vulvodynia. Following paclitaxel administration (2 mg/kg i.p.), the intensity of vulvar hypersensitivity was assessed using a series of von Frey filaments (0.008 to 1 g) to ensure the induction of vulvodynia. Vulvodynia was induced from day 2 and was well sustained for 11 days. Furthermore, the induced vulvodynia was validated by investigating the potentiation of a flinch response threshold, upon topical application and systemic administration of gabapentin, a commonly used medication for treating neuropathic pain. The results demonstrate that vulvodynia was induced due to administration of paclitaxel. The fact that chemotherapeutic agent-induced vulvodynia was responsive to topical and parenterally administered gabapentin provides validity to the model. The study establishes a new, relatively simple and reliable animal model for screening drug molecules for vulvar hypersensitivity.


Assuntos
Antineoplásicos/efeitos adversos , Vulvodinia/induzido quimicamente , Analgésicos/uso terapêutico , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Modelos Animais de Doenças , Feminino , Gabapentina/uso terapêutico , Neuralgia/induzido quimicamente , Neuralgia/psicologia , Paclitaxel/efeitos adversos , Medição da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
2.
J Med Chem ; 64(1): 890-904, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33372782

RESUMO

The sigma 1 receptor (S1R) is a molecular chaperone protein located in the endoplasmic reticulum and plasma membranes and has been shown to play important roles in various pathological disorders including pain and, as recently discovered, COVID-19. Employing structure- and QSAR-based drug design strategies, we rationally designed, synthesized, and biologically evaluated a series of novel triazole-based S1R antagonists. Compound 10 exhibited potent binding affinity for S1R, high selectivity over S2R and 87 other human targets, acceptable in vitro metabolic stability, slow clearance in liver microsomes, and excellent blood-brain barrier permeability in rats. Further in vivo studies in rats showed that 10 exhibited negligible acute toxicity in the rotarod test and statistically significant analgesic effects in the formalin test for acute inflammatory pain and paclitaxel-induced neuropathic pain models during cancer chemotherapy. These encouraging results promote further development of our triazole-based S1R antagonists as novel treatments for pain of different etiologies.


Assuntos
Manejo da Dor/métodos , Receptores sigma/antagonistas & inibidores , Triazóis/química , Animais , Sítios de Ligação , Barreira Hematoencefálica/metabolismo , Desenho de Fármacos , Cobaias , Meia-Vida , Humanos , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Estrutura Terciária de Proteína , Relação Quantitativa Estrutura-Atividade , Ratos , Receptores sigma/metabolismo , Triazóis/metabolismo , Triazóis/uso terapêutico
3.
BMJ Case Rep ; 13(12)2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33334741

RESUMO

A 23-year-old woman diagnosed with type 1 diabetes mellitus in 2011 came to our outpatient office because of an inability to walk correctly. She was under a basal bolus insulin regimen. In the summer of 2016, she experienced a rapid improvement in her glycaemic control. A few weeks later, she started to complain of a severe burning pain in the soles of her feet (pain score 10/10). Neither macrovascular nor microvascular complications were detected. The patient was forced to walk barefoot due to an intense pain using shoes or socks and used to soak her feet in water for several hours daily. She also developed severe intolerance to environmental heat, both indoors and outdoors. A diagnosis of treatment-induced diabetic neuropathy was made. The patient was admitted to a general ward to start pain therapy. After a 6-month course of different neuropathic pain drugs, the patient was able to walk autonomously again.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Neuropatias Diabéticas/diagnóstico , Insulina/efeitos adversos , Neuralgia/diagnóstico , Diabetes Mellitus Tipo 1/complicações , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/tratamento farmacológico , Dibenzazepinas/administração & dosagem , Quimioterapia Combinada/métodos , Eletromiografia , Feminino , , Gabapentina/administração & dosagem , Humanos , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Tramadol/administração & dosagem , Resultado do Tratamento , Teste de Caminhada , Adulto Jovem
4.
PLoS One ; 15(10): e0239758, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33057367

RESUMO

OBJECTIVE: People with HIV (PWH) continue to experience sensory neuropathy and neuropathic pain in the combination antiretroviral therapy (cART) era for unclear reasons. This study evaluated the role of iron in a previously reported association of iron-loading hemochromatosis (HFE) gene variants with reduced risk of neuropathy in PWH who received more neurotoxic cART, since an iron-related mechanism also might be relevant to neuropathic symptoms in PWH living in low-resource settings today. DESIGN: This time-to-event analysis addressed the impact of systemic iron levels on the rapidity of neuropathy onset in PWH who initiated cART. METHODS: Soluble transferrin receptor (sTFR), the sTFR-ferritin index of iron stores, and high-sensitivity C-reactive protein (hsCRP) levels were determined in stored baseline sera from participants of known HFE genotype from AIDS Clinical Trials Group (ACTG) Study 384, a multicenter randomized clinical trial that evaluated cART strategies. Associations with incident neuropathy were evaluated in proportional-hazards, time-to-event regression models, adjusting for potential confounders. RESULTS: Of 151 eligible participants with stored serum who were included in the original genetic study, 43 had cART-associated neuropathy; 108 had sufficient serum for analysis, including 30 neuropathy cases. Carriers of HFE variants had higher systemic iron (lower sTFR and sTFR-ferritin index) and lower hsCRP levels than non-carriers (all p<0.05). Higher sTFR or iron stores, the HFE 187C>G variant, and lower baseline hsCRP were associated with significantly delayed neuropathy in self-reported whites (n = 28; all p-values<0.05), independent of age, CD4+ T-cell count, plasma HIV RNA, and cART regimen. CONCLUSIONS: Higher iron stores, the HFE 187C>G variant, and lower hsCRP predicted delayed onset of neuropathy among self-reported white individuals initating cART. These findings require confirmation but may have implications for cART in HIV+ populations in areas with high endemic iron deficiency, especially those PWH in whom older, more neurotoxic antiretroviral drugs are occasionally still used.


Assuntos
Antirretrovirais/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Variação Genética/genética , Proteína da Hemocromatose/genética , Ferro/metabolismo , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Adulto , Antirretrovirais/uso terapêutico , Feminino , Ferritinas/genética , Genótipo , Infecções por HIV/tratamento farmacológico , Hemocromatose/genética , Heterozigoto , Humanos , Masculino , Neuralgia/induzido quimicamente , Neuralgia/genética , Receptores da Transferrina/genética
5.
J Neuroimmunol ; 345: 577261, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32570135

RESUMO

The development and maintenance of neuropathic pain is now given far more attention in the clinic work. Increasing evidence has shown that colony-stimulating factor 1 (CSF1) is involved in microglial activation and may further induce pain. Here, we observed the signaling events that link the CSF1-induced microglial activated and consequences for pain processing. For the in vitro study, flow cytometry showed the microglial activity was markedly increased after CSF1 stimulation. Western blot showed the increased expression of p-PRKAA1/PRKAA1, p-AMPK/AMPK, p-ULK1/ULK1, p-S6k/S6k and LC3-II/LC3-I. QRT-PCR showed the IL-1, TNF-α and BDNF were simultaneously upregulated in the activated microglia cells, whereas the specific AMPK inhibitor compound C exhibited reverse effects in microglia. Using immunofluorescence staining and electron microscopy, we found CSF1 decreased microglial p62 expression and induced the number of autophagosomes, whereas compound C significantly exhibited the reverse effects. For the in vivo study, compared with the control and AMPK-siRNA transfection, the mice under CSF1 intrathecal injection increased CSF1 receptor and LC3 expressed in the activated spinal microglia. More importantly, qRT-PCR showed CSF1 intrathecal injection substantially upregulated BDNF and c-Fos mRNA expression as well as the ensuing neuropathic pain. Our findings demonstrated that CSF1 induced a significant upregulation of microglial activation via the AMPK signaling pathway and resulted in an increasing microglial autophagic level. An increasing CSF1 level in the central nervous system can mimic and cause pain syndromes by up-regulation of AMPK-depended autophagy, thus offering a new target for the therapy of neuropathic pain.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/fisiologia , Fator Estimulador de Colônias de Macrófagos/administração & dosagem , Microglia/metabolismo , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Animais , Autofagia/efeitos dos fármacos , Células Cultivadas , Injeções Espinhais , Fator Estimulador de Colônias de Macrófagos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/patologia , Neuralgia/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
6.
J Med Chem ; 63(11): 6107-6133, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32368909

RESUMO

Voltage-gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of NaV1.7 inhibitors with all of the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic structure-activity relationship (SAR) studies carried out to identify novel sulfonamide derivatives as potent, selective, and state-dependent NaV1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over NaV1.5, and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43, and 51 showed a favorable pharmacokinetics (PK) profile across different species and robust efficacy in veratridine and formalin-induced inflammatory pain models in mice. Compound 51 also showed significant effects on the CCI-induced neuropathic pain model. The profile of 51 indicated that it has the potential for further evaluation as a therapeutic for pain.


Assuntos
Cromanos/química , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Animais , Cromanos/farmacocinética , Cromanos/uso terapêutico , Citocromo P-450 CYP2C9/química , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Modelos Animais de Doenças , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Canal de Sódio Disparado por Voltagem NAV1.7/química , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/patologia , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico
7.
J Cancer Res Ther ; 16(1): 34-39, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362607

RESUMO

Background and Objective: Metformin (MET) has been used as an antidiabetic agent for type II diabetes. At the same time, recent researches have shown that the clinical improvement of MET is useful for nerve damage. In this study, we investigated the analgesic effect of MET in paclitaxel (PAC)-induced neuropathic pain. Materials and Methods: Forty-two adult, female rats, Wistar strain weighing 220 ± 10 g were randomly divided into 5 experimental groups. PAC was intraperitoneally (IP) administered (2.0 mg/kg) for 4 groups every other day (0, 2, 4, and 6 days). By the 30th day, MET (100, 200, and 400 mg/kg) was administered to 4 groups. Before and after treatment, basal pain threshold values were measured with Randall-Selitto analgesiometer test. At the end of experiment, pathological values were measured in selected regions including brain (motor cortex, M1), spinal cord (L4-L5), sciatic nerve, and muscle. Results: According to our results, PAC-induced neuropathic pain reached to highest level at 14th day. Four hundred milligram/kilogram concentration of MET remarkably decreased PAC-induced neuropathic pain. On the other hand, pathologic features have shown that PAC had significant pathological change in the brain and spinal cord while in the peripheral nerves and muscles had not shown any pathological change. Conclusion: The pathological results of the current study for the first time demonstrated that MET beside of its antidiabetic effects reversed neuropathic pain induced by PAC. Consequently, this research can be promising for cancer patients that suffering from neuropathic pain induced by anticancer drugs.


Assuntos
Analgésicos/farmacologia , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Neoplasias/complicações , Neuralgia/prevenção & controle , Paclitaxel/efeitos adversos , Limiar da Dor/efeitos dos fármacos , Animais , Antineoplásicos Fitogênicos/efeitos adversos , Modelos Animais de Doenças , Feminino , Neoplasias/patologia , Neuralgia/induzido quimicamente , Neuralgia/patologia , Ratos , Ratos Wistar
8.
J Med Chem ; 63(10): 5185-5200, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32364386

RESUMO

Human carbonic anhydrase (CA; EC 4.2.1.1) isoforms II and VII are implicated in neuronal excitation, seizures, and neuropathic pain (NP). Their selective inhibition over off-target CAs is expected to produce an anti-NP action devoid of side effects due to promiscuous CA modulation. Here, a drug design strategy based on the observation of (dis)similarities between the target CA active sites was planned with benzenesulfonamide derivatives and, for the first time, a phosphorus-based linker. Potent and selective CA II/VII inhibitors were identified among the synthesized phenyl(thio)phosphon(amid)ates 3-22. X-ray crystallography depicted the binding mode of phosphonic acid 3 to both CAs II and VII. The most promising derivatives, after evaluation of their stability in acidic media, were tested in a mouse model of oxaliplatin-induced neuropathy. The most potent compound racemic mixture was subjected to HPLC enantioseparation, and the identification of the eutomer, the (S)-enantiomer, allowed to halve the dose totally relieving allodynia in mice.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/uso terapêutico , Anidrases Carbônicas/metabolismo , Hiperalgesia/tratamento farmacológico , Oxaliplatina/toxicidade , Animais , Antineoplásicos/toxicidade , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Temperatura Baixa/efeitos adversos , Cristalografia por Raios X/métodos , Modelos Animais de Doenças , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/enzimologia , Masculino , Camundongos , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/enzimologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
9.
Arch Biochem Biophys ; 685: 108330, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32156533

RESUMO

Switching microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype represents a novel therapeutic strategy for diabetic neuropathic pain (DNP). This study aims to determine the role and mechanism of interleukin (IL)-35 in regulating microglial M1/M2 polarization in DNP. A rat model of DNP was induced by a single streptozocin injection and recombinant IL-35 (rIL-35) was then intrathecally administered to the rats for 14 days. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured to assess the therapeutic effect of IL-35. Highly aggressive proliferating immortalized (HAPI), a rat microglia cell line, was treated with lipopolysaccharide (LPS) for M1 polarization or IL-4 for M2 polarization. The M1 markers (CD68, iNOS, TNF-α, IL-6) and M2 markers (CD206, Arg-1, IL-10) were examined. rIL-35 administration in DNP model rats elevated MWT and TWL, induced microglial polarization toward the M2 phenotype, suppressed JNK signaling and activated JAK2/STAT6 signaling. In vitro assay confirmed that rIL-35 induced microglial M2 polarization in HAPI cells through inhibiting JNK signaling and activating JAK2/STAT6 signaling. Collectively, the mechanism underlying therapeutic effect of IL-35 on DNP may relate to its promotion of microglial M2 polarization by regulating JNK signaling and JAK2/STAT6 signaling.


Assuntos
Neuropatias Diabéticas/metabolismo , Subunidade p35 da Interleucina-12/metabolismo , Microglia/metabolismo , Neuralgia/metabolismo , Animais , Linhagem Celular , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/complicações , Janus Quinase 2/metabolismo , MAP Quinase Quinase 4/metabolismo , Masculino , Neuralgia/induzido quimicamente , Neuralgia/complicações , Ratos Sprague-Dawley , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais/fisiologia , Estreptozocina
10.
Am J Chin Med ; 48(2): 407-428, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32138533

RESUMO

Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication of cisplatin, which is characterized by intolerable paresthesia, burning, and hyperalgesia, and severely impacts the life quality of patients. However, no clearly potent drug has been found for clinical medication due to its undefined mechanism. Corydalis Saxicola Bunting, a traditional Chinese medicine, has been proven to work well in anti-inflammation, blood circulations improvement, hemostasis, and analgesia. This study was designed to observe the effects of Corydalis saxicola Bunting total alkaloids (CSBTA) on cisplatin-induced neuropathic pain and to explore its potential mechanisms. In this study, the rats received intraperitoneal injection of 2mg/kg cisplatin twice a week for five weeks. Meanwhile, oral administration of low (30mg/kg)-, medium (60mg/kg)- and high (120mg/kg)-dose CSBTA were given daily for five weeks. By using Von-frey hair, heat radiant and -80∘C cold acetone, we found that CSBTA could obviously relieve cisplatin-induced mechanical, heat, and cold hyperalgesia. It has been verified that cisplatin-induced peripheral neuropathy is related to intraepidermal nerve fibers loss and activation of inflammation downstream. Our research found that Tumor necrosis factor-alpha (TNF-α), Interleukin-1beta (IL-1ß), and Prostaglandin E2 (PGE2) were significantly increased by 10 intraperitoneal injections of cisplatin, and such pro-inflammation cytokines could be reduced via CSBTA administration. Besides, in the cisplatin model group, the neuronal structures of dorsal root ganglia (DRG) were severely damaged and the loss of intraepidermal nerve fibers occurred; but in the CSBTA administration groups, all above pathological changes were improved. Moreover, CSBTA could normalize the overexpression levels of p-p38 and Transient receptor potential vanilloid receptor (TRPV1) induced by cisplatin in DRG, trigeminal ganglion (TG), spinal cord, and foot of rats. In summary, we considered that CSBTA exerted its therapeutic effects by ameliorating neuronal damages, improving intraepidermal nerve fiber (IENF) loss, and inhibiting inflammation-induced p38 phosphorylation to block TRPV1 activation. These findings were the first to confirm the analgesic effect of CSBTA on CIPN and suggested a novel strategy for treating CIPN in clinic.


Assuntos
Alcaloides/farmacologia , Alcaloides/uso terapêutico , Analgésicos , Cisplatino/efeitos adversos , Corydalis/química , Neuralgia/induzido quimicamente , Neuralgia/genética , Fitoterapia , Canais de Cátion TRPV/metabolismo , Alcaloides/isolamento & purificação , Animais , Neuralgia/tratamento farmacológico , Ratos
11.
J Clin Neurosci ; 73: 101-107, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32063448

RESUMO

OBJECTIVE: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the intractable long-term side effects of anticancer medications and results in pain and dysesthesia. Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex has been demonstrated to provide effective relief for intractable neuropathic pain. The objective of this study was to investigate the effects of rTMS treatment on CIPN in cancer patients. MATERIALS AND METHODS: Eleven female patients with breast cancer or gynecologic cancer (mean age 64.8 [standard deviation 7.8]) who had neuropathic pain and/or peripheral sensory neuropathy, with a minimum two grade severity based on the scale of the National Cancer Institutes' Common Terminology Criteria for Adverse Events (version 4.0) were enrolled. Patients received rTMS (5-Hz; 500 pulses/session; figure-8 coil) on their primary motor cortex corresponding to the target extremity. The intensity of pain and dysesthesia for all extremities was evaluated using a visual analog scale for pain, dysesthesia, and the Japanese version of the short-form McGill Pain Questionnaire 2 (SFMPQ2). RESULTS: rTMS for target extremity significantly decreased the visual analog scale of pain and dysesthesia. The intensity of pain measured by the SFMPQ2 was also decreased in the target extremity. Regarding non-target extremities, only dysesthesia significantly decreased as a result of rTMS. No adverse events were observed. CONCLUSION: This is an initial report demonstrating the potential of rTMS for the treatment of CIPN. We suggest rTMS could be potentially beneficial and effective as a treatment for pain and dysesthesia in patients with CIPN.


Assuntos
Neuralgia/induzido quimicamente , Neuralgia/radioterapia , Estimulação Magnética Transcraniana/métodos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Motor/efeitos da radiação , Manejo da Dor , Medição da Dor , Parestesia , Projetos Piloto , Escala Visual Analógica
12.
Eur J Pharmacol ; 872: 172972, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-32006559

RESUMO

Cisplatin is used as a first line therapy in treating cancers. However, its use is often accompanied with the development of peripheral neuropathy. 6-Methoxyflavanone (6-MeOF) is a positive allosteric modulator at GABAA receptors and is known for attenuating diabetes-induced neuropathic pain. Neuropathy was induced in male Sprague-Dawley rats (150-250 g), via intraperitoneal injection of cisplatin (3 mg/kg) once a week for four consecutive weeks. 6-MeOF (25, 50 and 75 mg/kg, i.p) and gabapentin (75 mg/kg, i.p) were administered 30 min before each cisplatin injection. Static and dynamic allodynia were assessed using von Frey filaments and cotton buds. The anti-inflammatory activity was analyzed with plethysmometer. Body weights were also measured each week. The binding affinity of 6-MeOF with chloride channel, Cyclooxygenase-1 (COX-1) and Cyclooxygenase-2 (COX-2) was studied using docking approach. The in vitro COX-1 and COX-2 inhibitory effect of 6-MeOF was conducted with COX colorimetric assay. Administration of cisplatin for four consecutive weeks induced static (decreased paw withdrawal threshold; PWT) and dynamic allodynia (decreased paw withdrawal latency; PWL). Co-administration of 6-MeOF for four weeks significantly attenuated the cisplatin-induced expression of nocifensive behaviors observed as significant increase in PWT and PWL. Moreover, it also prevented the body weight loss induced by cisplatin administration. In silico studies depicted a good interaction of 6-MeOF with chloride ion channels and COX-1 and COX-2 enzymes. The in vitro study confirmed the inhibitory activity of 6-MeOF for COX-1 and COX-2. 6-MeOF may be effective in attenuating cisplatin-induced allodynia, probably through interaction with GABAergic receptors and reducing inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Cisplatino/efeitos adversos , Flavanonas/farmacologia , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Receptores de GABA-A/metabolismo , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/imunologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Flavanonas/química , Flavanonas/uso terapêutico , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/diagnóstico , Hiperalgesia/imunologia , Ativação do Canal Iônico/efeitos dos fármacos , Ativação do Canal Iônico/imunologia , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neuralgia/induzido quimicamente , Neuralgia/diagnóstico , Neuralgia/imunologia , Ratos , Receptores de GABA-A/química , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
13.
Eur J Med Chem ; 191: 112144, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32087465

RESUMO

We designed and synthesized a novel series of piperidine propionamide derivatives as potent sigma-1 (σ1) receptor antagonists and mu (µ) opioid receptor agonists, and measured their affinity for σ1 and µ receptors in vitro through binding assays. The basic scaffold of the new compounds contained a 4-substituted piperidine ring and N-aryl propionamide. Compound 44, N-(2-(4-(4-fluorobenzyl) piperidin-1-yl) ethyl)-N-(4-methoxy-phenyl) propionamide, showed the highest affinity for σ1 receptor (Ki σ1 = 1.86 nM) and µ receptor (Ki µ = 2.1 nM). It exhibited potent analgesic activity in the formalin test (ED50 = 15.1 ± 1.67 mg/kg) and had equivalent analgesic effects to S1RA (σ1 antagonist) in a CCI model. Therefore, Compound 44, which has mixed σ1/µ receptor profiles, may be a potential candidate for treating neuropathic pain.


Assuntos
Amidas/farmacologia , Neuralgia/tratamento farmacológico , Piperidinas/farmacologia , Receptores Opioides mu/agonistas , Receptores sigma/antagonistas & inibidores , Amidas/administração & dosagem , Amidas/química , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Formaldeído , Cobaias , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Neuralgia/induzido quimicamente , Neuralgia/patologia , Piperidinas/administração & dosagem , Piperidinas/química , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Relação Estrutura-Atividade
14.
Psychopharmacology (Berl) ; 237(4): 1131-1145, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31912189

RESUMO

RATIONALE: Current data indicate that the noradrenergic system plays a critical role in neuropathic pain treatment. Notably, drugs that directly affect this system may have curative potential in neuropathy-associated pain. OBJECTIVES: The aim of this study was to evaluate the potential therapeutic efficacy of reboxetine, a potent and selective noradrenaline reuptake inhibitor, on hyperalgesia and allodynia responses in rats with experimental diabetes. Furthermore, mechanistic studies were performed to elucidate the possible mode of actions. METHODS: Experimental diabetes was induced by a single dose of streptozotocin. Mechanical hyperalgesia, mechanical allodynia, thermal hyperalgesia, and thermal allodynia responses in diabetic rats were evaluated by Randall-Selitto, dynamic plantar, Hargreaves, and warm plate tests, respectively. RESULTS: Reboxetine treatment (8 and 16 mg/kg for 2 weeks) demonstrated an effect comparable to that of the reference drug, pregabalin, improving the hyperalgesic and allodynic responses secondary to diabetes mellitus. Pretreatment with phentolamine, metoprolol, SR 59230A, and atropine did not alter the abovementioned effects of reboxetine; however, the administration of α-methyl-para-tyrosine methyl ester, propranolol, ICI-118,551, SCH-23390, sulpiride, and naltrindole significantly inhibited these effects. Moreover, reboxetine did not induce a significant difference in the rat plasma glucose levels. CONCLUSIONS: Our findings indicate that the antihyperalgesic and antiallodynic effects of reboxetine are mediated by the catecholaminergic system; ß2-adrenoceptors; D1-, D2/D3-dopaminergic receptors; and δ-opioid receptors. The results suggest that this analgesic effect of reboxetine, besides its neutral profile on glycemic control, may be advantageous in the pharmacotherapy of diabetic neuropathy-induced pain.


Assuntos
Inibidores da Captação Adrenérgica/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Reboxetina/uso terapêutico , Receptores Opioides delta/metabolismo , Inibidores da Captação Adrenérgica/farmacologia , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/sangue , Neuropatias Diabéticas/induzido quimicamente , Hiperalgesia/sangue , Hiperalgesia/induzido quimicamente , Masculino , Neuralgia/sangue , Neuralgia/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Reboxetina/farmacologia , Receptores Adrenérgicos beta 2/metabolismo , Receptores Dopaminérgicos/metabolismo , Estreptozocina/toxicidade
15.
Eur J Med Chem ; 188: 111920, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31901745

RESUMO

γ-Aminobutyric acid (GABA) uptake transporters are membrane transport proteins that are involved in the pathophysiology of a number of neurological disorders. Some types of chronic pain appear to result from the dysfunction of the GABAergic system. The deficiency of mouse GAT1 transporter (mGAT1) abolishes the nociceptive response, which means that mGAT1 inhibition is an appropriate medical approach to achieve analgesia. The mGAT4 transporter is the second most abundant GAT subtype in the brain; however, its physiological role has not yet been fully understood in the central nervous system. In this study, we examined whether the combination of mGAT1 and mGAT3/mGAT4 inhibition in a single molecule might lead to potentially synergistic effects improving analgesic activity to relieve neuropathic pain. To study this hypothesis, new GABA uptake inhibitors were designed, synthesized, and evaluated in terms of their activity and subtype selectivity for mGAT1-4. Among new functionalized amino acid derivatives of serine and GABA analogs, compounds with preferential mGAT3/4 inhibitory activity were discovered. Two selected hits (19b and 31c) were subjected to in vivo tests. We found a statistically significant antiallodynic activity in the von Frey test in diabetic and oxaliplatin-induced neuropathic pain model. The novel compounds (4-hydroxybutanoic, 4-hydroxypentanoic, and 4-aminobutanoic acid derivatives and serine analogs) provide new insights into the structure-activity relationship of mGAT3/mGAT4 inhibitors and indicate a new direction in the search for potential treatment of neuropathic pain of various origin.


Assuntos
Analgésicos/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Inibidores da Captação de GABA/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Limiar da Dor/efeitos dos fármacos , Analgésicos/síntese química , Analgésicos/metabolismo , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Proteínas da Membrana Plasmática de Transporte de GABA/química , Inibidores da Captação de GABA/síntese química , Inibidores da Captação de GABA/metabolismo , Hiperalgesia/induzido quimicamente , Hiperalgesia/etiologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Neuralgia/induzido quimicamente , Neuralgia/etiologia , Oxaliplatina , Ligação Proteica , Estreptozocina , Relação Estrutura-Atividade
16.
Neuropeptides ; 79: 102003, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31902597

RESUMO

The complications of diabetic polyneuropathy (DN) determines its level of severity. It may occur with distinctive clinical symptoms (painful DN) or appears undetected (painless DN). This study aimed to investigate microglia activation and signalling molecules brain-derived neurotrophic factor (BDNF) and downstream regulatory element antagonist modulator (DREAM) proteins in spinal cord of streptozotocin-induced diabetic neuropathy rats. Thirty male Sprague-Dawley rats (200-230 g) were randomly assigned into three groups: (1) control, (2) painful DN and (3) painless DN. The rats were induced with diabetes by single intraperitoneal injection of streptozotocin (60 mg/kg) whilst control rats received citrate buffer as a vehicle. Four weeks post-diabetic induction, the rats were induced with chronic inflammatory pain by intraplantar injection of 5% formalin and pain behaviour responses were recorded and assessed. Three days later, the rats were sacrificed and lumbar enlargement region of spinal cord was collected. The tissue was immunoreacted against OX-42 (microglia), BDNF and DREAM proteins, which was also quantified by western blotting. The results demonstrated that painful DN rats exhibited increased pain behaviour score peripherally and centrally with marked increase of spinal activated microglia, BDNF and DREAM proteins expressions compared to control group. In contrast, painless DN group demonstrated a significant reduction of pain behaviour score peripherally and centrally with significant reduction of spinal activated microglia, BDNF and DREAM proteins expressions. In conclusions, the spinal microglia activation, BDNF and DREAM proteins correlate with the pain behaviour responses between the variants of DN.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas Interatuantes com Canais de Kv/metabolismo , Microglia/metabolismo , Neuralgia/metabolismo , Animais , Diabetes Mellitus/metabolismo , Neuropatias Diabéticas/metabolismo , Formaldeído/farmacologia , Masculino , Microglia/efeitos dos fármacos , Neuralgia/induzido quimicamente , Ratos Sprague-Dawley , Medula Espinal/metabolismo
17.
Biol Pharm Bull ; 43(2): 348-355, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31776306

RESUMO

Oxaliplatin is a first-line clinical drug in cancer treatment and its side effects of peripheral neuropathic pain have also attracted much attention. Neuroinflammation induced by oxidative stress-mediated activation of nuclear factor-kappa B (NF-κB) plays an important role in the course. Current studies have shown that curcumin has various biological activities like antioxidant, anti-inflammatory, antitumor and so on, while few studies were conducted about its role in oxaliplatin-induced peripheral neuropathic pain. The aim of this study is to verify the mechanism of curcumin alleviating oxaliplatin-induced peripheral neuropathic pain. Intraperitoneal injection with oxaliplatin (4 mg/kg body weight) was given to the rats twice a week and last for four weeks to establish the model rats. Gavage administration of curcumin (12.5, 25, and 50 mg/kg body weight, respectively) was conducted for consecutive 28 d to explore the effects and potential mechanism. Our results showed that curcumin administration could increase mechanical withdrawal threshold and decrease the paw-withdrawal times of cold allodynia significantly; meanwhile, motor nerve conduction velocity (MNCV) and sense nerve conduction velocity (SNCV) were both increased and the injured neurons of the spinal cord were repaired. In addition, curcumin administration increased superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) and reduced malondialdehyde (MDA). Moreover, the curcumin operation inhibited the activated of NF-κB and level of inflammatory factors like tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6). In conclusion, these findings suggested that curcumin could alleviate oxaliplatin-induced peripheral neuropathic pain; the mechanism might be inhibiting oxidative stress-mediated activation of NF-κB and mitigating neuroinflammation.


Assuntos
Curcumina/farmacologia , Inflamação/tratamento farmacológico , NF-kappa B/metabolismo , Neuralgia/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Catalase/metabolismo , Glutationa Peroxidase/metabolismo , Hiperalgesia/tratamento farmacológico , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Malondialdeído/metabolismo , Condução Nervosa/efeitos dos fármacos , Neuralgia/induzido quimicamente , Oxaliplatina , Ratos , Ratos Sprague-Dawley , Medula Espinal/patologia , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
18.
Pharmacology ; 105(3-4): 173-180, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31578020

RESUMO

BACKGROUND: Chemotherapy-induced neuropathic pain (CINP) is a serious side effect of chemotherapy. Korean Red Ginseng (KRG) is a popular herbal medicine in Asian countries. We examined the therapeutic potential of intrathecally administered KRG for CINP and clarified the mechanisms of action with regard to 5-hydroxytryptamine (5-HT)7 receptor at the spinal level. METHODS: CINP was evoked by intraperitoneal injection of cisplatin in male Sprague-Dawley rats. After examining the effects of intrathecally administered KRG on CINP, 5-HT receptor antagonist (dihydroergocristine [DHE]) was pretreated to determine the involvement of 5-HT receptor. In addition, intrathecal 5-HT7 receptor antagonist (SB269970) was administered to define the role of 5-HT7 receptor on the effect of KRG. 5-HT7 receptor mRNA expression levels and 5-HT concentrations were examined in the spinal cord. RESULTS: Intrathecally administered KRG produced a limited, but a dose-dependent, antiallodynic effect. Intrathecally administered DHE antagonized the antiallodynia caused by KRG. Furthermore, intrathecal SB269970 also reversed the effect of KRG. No changes in 5-HT7 receptor mRNA expression were seen in the dorsal horn of the spinal cord after cisplatin injection. After injecting cisplatin, 5-HT levels were decreased in the spinal cord, whereas those of 5-HT were increased by intrathecal KRG. CONCLUSIONS: Intrathecally administered KRG decreased CINP. In addition, spinal 5-HT7 receptors contributed to the antiallodynic effect of KRG.


Assuntos
Cisplatino/toxicidade , Neuralgia/prevenção & controle , Panax/química , Extratos Vegetais/farmacologia , Animais , Antineoplásicos/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hiperalgesia/induzido quimicamente , Hiperalgesia/prevenção & controle , Injeções Espinhais , Masculino , Neuralgia/induzido quimicamente , Extratos Vegetais/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo
19.
PLoS One ; 14(11): e0225586, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31765435

RESUMO

Oxaliplatin is the first-line chemotherapy for metastatic colorectal cancer. Unlike other platinum anticancer agents, oxaliplatin does not result in significant renal impairment and ototoxicity. Oxaliplatin, however, has been associated with acute and chronic peripheral neuropathies. Despite the awareness of these side-effects, the underlying mechanisms are yet to be clearly established. Therefore, in this study, we aimed to understand the factors involved in the generation of chronic neuropathy elicited by oxaliplatin treatment. We established a rat model of oxaliplatin-induced neuropathic pain (4 mg kg-1 intraperitoneally). The paw withdrawal thresholds were assessed at different time-points after the treatment, and a significant decrease was observed 3 and 4 weeks after oxaliplatin treatment as compared to the vehicle treatment (4.4 ± 1.0 vs. 16.0 ± 4.1 g; P < 0.05 and 4.4 ± 0.7 vs. 14.8 ± 3.1 g; P < 0.05, respectively). We further evaluated the role of different mitogen-activated protein kinases (MAPKs) pathways in the pathophysiology of neuropathic pain. Although the levels of total extracellular signal-regulated kinase (ERK) 1/2 in the dorsal root ganglia (DRG) were not different between oxaliplatin and vehicle treatment groups, phosphorylated ERK (p-ERK) 1/2 was up-regulated up to 4.5-fold in the oxaliplatin group. Administration of ERK inhibitor PD98059 (6 µg day-1 intrathecally) inhibited oxaliplatin-induced ERK phosphorylation and neuropathic pain. Therefore, upregulation of p-ERK by oxaliplatin in rat DRG and inhibition of mechanical allodynia by an ERK inhibitor in the present study may provide a better understanding of intracellular molecular alterations associated with oxaliplatin-induced neuropathic pain and help in the development of potential therapeutics.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Gânglios Espinais/metabolismo , Neuralgia/patologia , Oxaliplatina/toxicidade , Regulação para Cima/efeitos dos fármacos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Hiperalgesia/prevenção & controle , Masculino , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
20.
Int J Mol Sci ; 20(23)2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31775332

RESUMO

Paclitaxel-induced peripheral neuropathy is a common adverse effect during paclitaxel treatment resulting in sensory abnormalities and neuropathic pain during chemotherapy and in cancer survivors. Conventional therapies are usually ineffective and possess adverse effects. Here, we examined the effects of electroacupuncture (EA) on a rat model of paclitaxel-induced neuropathic pain and related mechanisms. EA robustly and persistently alleviated paclitaxel-induced pain hypersensitivities. Mechanistically, TLR4 (Toll-Like Receptor 4) and downstream signaling MyD88 (Myeloid Differentiation Primary Response 88) and TRPV1 (Transient Receptor Potential Vallinoid 1) were upregulated in dorsal root ganglion (DRGs) of paclitaxel-treated rats, whereas EA reduced their overexpression. Ca2+ imaging further indicated that TRPV1 channel activity was enhanced in DRG neurons of paclitaxel-treated rats whereas EA suppressed the enhanced TRPV1 channel activity. Pharmacological blocking of TRPV1 mimics the analgesic effects of EA on the pain hypersensitivities, whereas capsaicin reversed EA's effect. Spinal astrocytes and microglia were activated in paclitaxel-treated rats, whereas EA reduced the activation. These results demonstrated that EA alleviates paclitaxel-induced peripheral neuropathic pain via mechanisms possibly involving suppressing TLR4 signaling and TRPV1 upregulation in DRG neurons, which further result in reduced spinal glia activation. Our work supports EA as a potential alternative therapy for paclitaxel-induced neuropathic pain.


Assuntos
Eletroacupuntura/métodos , Neuralgia/prevenção & controle , Paclitaxel/toxicidade , Doenças do Sistema Nervoso Periférico/prevenção & controle , Células Receptoras Sensoriais/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Antineoplásicos Fitogênicos/toxicidade , Regulação da Expressão Gênica , Masculino , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Neuralgia/patologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/efeitos dos fármacos , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
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