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1.
J Bioenerg Biomembr ; 55(3): 179-193, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37357235

RESUMO

Diabetes mellitus (DM) is a chronic syndrome involving neuropathic pain. Increased oxidative stress in DM is assumed to increase free reactive oxygen radicals (ROS) and causes diabetic damage. The sciatic nerve (ScN) and dorsal root ganglion (DRG) both contain high levels of the TRPV1 channel, which is triggered by capsaicin and ROSs and results in increased Ca2+ entry into the neurons. Alpha-lipoic acid (ALA) is considered an important part of the antioxidant system. To better characterize the protective effects of ALA on the DM-induced neuronal through TRPV1 modulation, we investigated the role of ALA on DM-induced neuropathic pain, oxidative ScN, and DRG damage in diabetic rats. Forty adult Wistar albino female rats were divided into four groups as control, ALA (50 mg/kg for 14 days), streptozotocin (STZ and 45 mg/kg and single dose), and STZ + ALA. Rats were used for the pain tests. After obtaining the DRGs and ScN, they were used for plate reader, patch-clamp, and laser confocal microscope analyses. We observed the modulator role of ALA on the thresholds of mechanical withdrawal pain (von Frey test) and hot sensitivity pain (hot plate test) in the STZ + ALA group. The treatment of ALA decreased STZ-induced increase of TRPV1 current densities, intracellular free Ca2+ concentrations (Fura-2 and Fluo - 3/AM), ROS, caspase 3, caspase 9, mitochondrial membrane potential, and apoptosis values in the ScN and DRG neurons, although its treatment induced the increase of cell viability and body weight gain. The treatment of ALA acted a neuroprotective role on the TRPV1 channel stimulation-mediated Ca2+ influx, neuropathic pain, and neuronal damage in diabetic rats. The neuroprotective role of ALA treatment can be explained by its modulating the TRPV1 channel activity, intracellular Ca2+ increase-induced oxidative stress, and apoptosis.


Assuntos
Diabetes Mellitus Experimental , Neuralgia , Ácido Tióctico , Ratos , Animais , Ratos Wistar , Ácido Tióctico/farmacologia , Ácido Tióctico/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Estresse Oxidativo , Apoptose , Neuralgia/tratamento farmacológico , Gânglios Espinais/metabolismo , Canais de Cátion TRPV/metabolismo , Canais de Cátion TRPV/farmacologia
2.
Mol Neurobiol ; 58(11): 5581-5601, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34370177

RESUMO

Excessive Ca2+ influx and mitochondrial oxidative stress (OS) of trigeminal ganglia (TG) have essential roles in the etiology of migraine headache and aura. The stimulation of TRPM2 channel via the generation of OS and ADP-ribose (ADPR) induces pain, inflammatory, and oxidative neurotoxicity, although its inhibition reduces the intensity of pain and neurotoxicity in several neurons. However, the cellular and molecular effects of TRPM2 in the TG of migraine model (glyceryl trinitrate, GTN) on the induction of pain, OS, apoptosis, and inflammation remain elusive. GTN-mediated increases of pain intensity, apoptosis, death, cytosolic reactive oxygen species (ROS), mitochondrial ROS, caspase -3, caspase -9, cytosolic Ca2+ levels, and cytokine generations (TNF-α, IL-1ß, and IL-6) in the TG of TRPM2 wild-type mouse were further increased by the TRPM2 activation, although they were modulated by the treatments of GSH, PARP-1 inhibitors (PJ34 and DPQ), and TRPM2 blockers (ACA and 2APB). However, the effects of GTN were not observed in the TG of TRPM2 knockout mice. The current data indicate that the maintaining activation of TRPM2 is not only important for the quenching OS, inflammation, and neurotoxicity in the TG neurons of mice with experimental migraine but also equally critical to the modulation of GTN-induced pain.


Assuntos
Transtornos de Enxaqueca/metabolismo , Canais de Cátion TRPM/fisiologia , Gânglio Trigeminal/metabolismo , Adenosina Difosfato Ribose/metabolismo , Animais , Apoptose , Compostos de Boro/farmacologia , Sinalização do Cálcio , Caspases/metabolismo , Cinamatos/farmacologia , Citocinas/biossíntese , Citocinas/genética , Ativação Enzimática , Glutationa/metabolismo , Hiperalgesia/etiologia , Hiperalgesia/fisiopatologia , Peroxidação de Lipídeos , Potencial da Membrana Mitocondrial/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/fisiopatologia , Doenças Neuroinflamatórias , Neurônios/patologia , Nitroglicerina/toxicidade , Estresse Oxidativo , Fenantrenos/farmacologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Canais de Cátion TRPM/antagonistas & inibidores , Canais de Cátion TRPM/deficiência , Gânglio Trigeminal/efeitos dos fármacos , ortoaminobenzoatos/farmacologia
3.
Sci Rep ; 9(1): 12403, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455864

RESUMO

In proteinuric nephropathies of chronic kidney disease, the epithelial cells of the nephron including the collecting duct are exposed to high concentrations of luminal albumin. Albumin is taken up from collecting duct cells by endocytosis causing excessive reactive oxygen species (ROS) production and a proinflammatory response. Curcumin used in the traditional medicine possesses anti-inflammatory and antioxidant effects. ROS and ADP-ribose (ADPR) activate the cation channel TRPM2. We hypothesize, that albumin-induced cell stress and proinflammatory response are mediated by Ca2+ and can be reduced by curcumin. The cortical collecting duct (CCD) cells mpkCCDc14 exhibit spontaneous and inducible Ca2+ oscillations, which can be blocked by pre-treatment with curcumin. Curcumin accumulates in plasma membrane and intracellular vesicles, where it interferes with TRPM2 and decreases the influx of Ca2+. Albumin reduces cell viability and increases apoptosis, NF-κB activation, and mitochondrial membrane depolarization via Ca2+-dependent signaling, which results in increased ROS production. Albumin-induced cell stress is diminished by the inhibition of TRPM2 after administration of curcumin and ADPR (PARP1) inhibitors. Curcumin did not reduce the Ca2+ elevation induced by thapsigargin in Ca2+-free medium, but it reduced the function of store-operated Ca2+ channels and ATP-evoked Ca2+ response. In conclusion, albumin-induced oxidative stress is mediated by Ca2+-dependent signaling via TRPM2 and leads to cell damage and a proinflammatory response, strengthening the role of CCD cells in the progression of chronic kidney disease.


Assuntos
Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Curcumina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Soroalbumina Bovina/farmacologia , Canais de Cátion TRPM/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Linhagem Celular , Citocinas/metabolismo , Células HEK293 , Humanos , Túbulos Renais Coletores/citologia , Túbulos Renais Coletores/efeitos dos fármacos , Túbulos Renais Coletores/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Canais de Cátion TRPM/genética , Tapsigargina/farmacologia
4.
Mol Neurobiol ; 54(10): 7620-7638, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27832523

RESUMO

Relative 17ß-estradiol (E2) deprivation and excessive production of mitochondrial oxygen free radicals (OFRs) with a high amount of Ca2+ influx TRPA1, TRPM2, and TRPV1 activity is one of the main causes of neurodegenerative disease in postmenopausal women. In addition to the roles of tamoxifen (TMX) and raloxifene (RLX) in cancer and bone loss treatments, regulator roles in Ca2+ influx and mitochondrial oxidative stress in neurons have not been reported. The aim of this study was to evaluate whether TMX and RLX interactions with TRPA1, TRPM2, and TRPV1 in primary hippocampal (HPC) and dorsal root ganglion (DRG) neuron cultures of ovariectomized (OVX) rats. Forty female rats were divided into five groups: a control group, an OVX group, an OVX+E2 group, an OVX+TMX group, and an OVX+RLX group. The OVX+E2, OVX+TMX, and OVX+RLX groups received E2, TMX, and RLX, respectively, for 14 days after the ovariectomy. E2, ovariectomy-induced TRPA1, TRPM2, and TRPV1 current densities, as well as accumulation of cytosolic free Ca2+ in the neurons, were returned to the control levels by E2, TMX, and RLX treatments. In addition, E2, TMX, and RLX via modulation of TRPM2 and TRPV1 activity reduced ovariectomy-induced mitochondrial membrane depolarization, apoptosis, and cytosolic OFR production. TRPM2, TRPV1, PARP, and caspase-3 and caspase-9 expressions were also decreased in the neurons by the E2, TMX, and RLX treatments. In conclusion, we first reported the molecular effects of E2, TMX, and RLX on TRPA1, TRPM2, and TRPV1 channel activation in the OVX rats. In addition, we observed neuroprotective effects of E2, RLX, and TMX on oxidative and apoptotic injuries of the hippocampus and peripheral pain sensory neurons (DRGs) in the OVX rats. Graphical Abstract Possible molecular pathways of involvement of DEX in cerebral ischemia-induced apoptosis, oxidative stress, and calcium accumulation through TRPA1, TRPM2 and TRPV1 in the hippocampus and DRG neurons of rats. The N domain of the TRPM2 contains ADP-ribose (ADPR) pyrophosphate enzyme, which is separately activated by ADPR and oxidative stress, although the channel is reversibly inhibited by N-(p-amylcinnamoyl) anthranilic acid (ACA). The TRPV1 is also activated by mitochondrial oxidative stress and capsaicin, and it is blocked by capsazepine (CPZ). TRPA1 is also activated by oxidative stress it is inhibited by AP18. Increased cytosolic Ca2+ concentration through TRPA1, TRPM2 and TRPV1 in ovariectomized (OVX) rats may lead to neuronal toxicity, reactive oxygen species (ROS) processes, and eventual cell death. 17ß-Estradiol (E2), tamoxifen (TMX), and raloxifene (RLX) reduced oxidative stress, apoptosis (including caspase-3 and caspase-9), mitochondrial membrane depolarization, and Ca2+ influx through the inhibition of TRPA1, TRPM2 and TRPV1 activation.


Assuntos
Estradiol/administração & dosagem , Antagonistas de Estrogênios/administração & dosagem , Ovariectomia , Estresse Oxidativo/fisiologia , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPM/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Cálcio/metabolismo , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ovariectomia/tendências , Estresse Oxidativo/efeitos dos fármacos , Cloridrato de Raloxifeno/administração & dosagem , Ratos , Ratos Wistar , Canal de Cátion TRPA1/antagonistas & inibidores , Canais de Cátion TRPM/antagonistas & inibidores , Canais de Cátion TRPV/antagonistas & inibidores , Tamoxifeno/administração & dosagem
5.
J Mol Neurosci ; 60(2): 214-22, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27372663

RESUMO

It is well known that 17ß-estradiol (E2) has an antioxidant role on neurological systems in the brain. Raloxifene (RLX) and tamoxifen (TMX) are selective estrogen receptor modulators. An E2 deficiency stimulates mitochondrial functions for promoting apoptosis and increasing reactive oxygen species (ROS) production. However, RLX and TMX may reduce the mitochondrial ROS production via their antioxidant properties in the brain and erythrocytes of ovariectomized (OVX) rats. We aimed to investigate the effects of E2, RLX, and TMX on oxidative stress, apoptosis, and cytokine production in the brain and erythrocytes of OVX rats.Forty female rats were divided into five groups. The first group was used as a control group. The second group was the OVX group. The third, fourth, and fifth groups were OVX + E2, OVX + TMX, and OVX + RLX groups, respectively. E2, TMX, and RLX were given subcutaneously to the OVX + E2 and OVX + TMX, OVX + RLX groups for 14 days after the ovariectomy respectively.While brain and erythrocyte lipid peroxidation levels were high in the OVX group, they were low in the OVX + E2, OVX + RLX, and OVX + TMX groups. OVX + E2, OVX + RLX, and OVX + TMX treatments increased the lowered glutathione peroxidase activity in erythrocytes and the brain and reduced glutathione and vitamin E concentrations in the brain. ß-carotene and vitamin A concentrations in the brain and TNF-α and interleukin (IL)-1ß levels in the plasma of the five groups were not significantly changed by the treatments. However, increased plasma IL-4 levels and Western blot results for brain poly (ADP-ribose) polymerase (PARP) in the OVX groups were decreased by E2, TMX, and RLX treatments, although proapoptotic procaspase 3 and 9 activities were increased by the treatments.In conclusion, we observed that E2, RLX, and TMX administrations were beneficial on oxidative stress, inflammation, and PARP levels in the serum and brain of OVX rats by modulating antioxidant systems, DNA damage, and cytokine production.


Assuntos
Encéfalo/metabolismo , Citocinas/metabolismo , Antagonistas de Estrogênios/farmacologia , Estresse Oxidativo , Poli(ADP-Ribose) Polimerases/metabolismo , Cloridrato de Raloxifeno/farmacologia , Tamoxifeno/farmacologia , Animais , Apoptose , Encéfalo/efeitos dos fármacos , Citocinas/sangue , Citocinas/genética , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Feminino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ovariectomia , Poli(ADP-Ribose) Polimerases/sangue , Poli(ADP-Ribose) Polimerases/genética , Ratos , Ratos Wistar
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