DEFAR - Artigos publicados em periódicos
URI permanente para esta coleçãohttp://www.hml.repositorio.ufop.br/handle/123456789/531
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Item Targeting N-type calcium channels in young-onset of some neurological diseases.(2022) Antunes, Flavia Tasmin Techera; Souza, Alessandra Hubner de; Silva, Juliana Figueira da; Binda, Nancy Scardua; Carvalho, Vanice Paula Ricardo; Vieira, Luciene Bruno; Gomez, Marcus ViniciusCalcium (Ca 2+) is an important second messenger in charge of many critical processes in the central nervous system (CNS), including membrane excitability, neurotransmission, learning, memory, cell proliferation, and apoptosis. In this way, the voltage-gated calcium channels (VGCCs) act as a key supply for Ca2+ entry into the cytoplasm and organelles. Importantly, the dysregulation of these channels has been reported in many neurological diseases of young-onset, with associated genetic factors, such as migraine, multiple sclerosis, and Huntington’s disease. Notably, the literature has pointed to the role of N-type Ca2+ channels (NTCCs) in controlling a variety of processes, including pain, inflammation, and excitotoxicity. Moreover, several Ca2+ channel blockers that are used for therapeutic purposes have been shown to act on the N-type channels. Therefore, this review provides an overview of the NTCCs in neurological disorders focusing mainly on Huntington’s disease, multiple sclerosis, and migraine. It will discuss possible strategies to generate novel therapeutic strategies.Item Calcium channels blockers toxins attenuate abdominal hyperalgesia and inflammatory response associated with the cerulein-induced acute pancreatitis in rats.(2021) Carvalho, Vanice Paula Ricardo; Silva, Juliana Figueira da; Buzelin, Marcelo Araújo; Silva Júnior, Cláudio Antônio da; Santos, Duana Carvalho dos; Diniz, Danuza Montijo; Binda, Nancy Scardua; Borges, Marcia Helena; Guimarães, André Luiz Senna; Pereira, Elizete Maria Rita; Gomez, Marcus ViniciusAgents that modulate the activity of high-voltage gated calcium channels (HVCCs) exhibit experimentally and clinically significant effect by relieving visceral pain. Among these agents, the toxins Phα1β and ω-conotoxin MVIIA effectively reduce chronic pain in rodent models. The molecular mechanisms underlying the chronic pain associated with acute pancreatitis (AP) are poorly understood. Hypercalcemia is a risk factor; the role of cytosolic calcium is considered to be a modulator of pancreatitis. Blockade of Ca2+ signals may be useful as a prophylactic treatment of pancreatitis. We explored the pathophysiological roles of three peptide toxins: Phα1β and its re- combinant form CTK 01512-2—blockers of TRPA1 receptor and HVCCs and ω-conotoxin MVIIA, a specific blocker of N-type calcium channels in cerulein-induced AP. Cerulein injection elicits AP in rats, evidenced by an increase in hyperalgesic pain, inflammatory infiltration, amylase and lipase secretion, and reactive oxygen species, TNF-α, and p65 NF-κB levels. These effects of cerulein-induced AP were abolished by Phα1β and its recombinant form CTK 01512-2, whereas ω-conotoxin MVIIA had no effect on the induced increase in pancreatic enzyme secretion. Our results demonstrate that Phα1β and CTK 01512-2 toxins—antagonists of HVCCs and TRPA1 receptor presented an effective response profile, in the control of nociception and inflammatory process in the AP model in rats, without causing changes in spontaneous locomotion of the rats.Item Analgesic effects of Phα1β toxin : a review of mechanisms of action involving pain pathways.(2021) Silva, Juliana Figueira da; Binda, Nancy Scardua; Pereira, Elizete Maria Rita; Lavor, Mário Sérgio Lima de; Vieira, Luciene Bruno; Souza, Alessandra Hubner de; Rigo, Flávia Karine; Ferrer, Hèlia Tenza; Castro Junior, Célio José de; Ferreira, Juliano; Gomez, Marcus ViniciusPhα1β is a neurotoxin purified from spider venom that acts as a high-voltage-activated (HVA) calcium channel blocker. This spider peptide has shown a high selectivity for N-type HVA calcium channels (NVACC) and an analgesic effect in several animal models of pain. Its activity was associated with a reduction in calcium transients, glutamate release, and reactive oxygen species production from the spinal cord tissue and dorsal ganglia root (DRG) in rats and mice. It has been reported that intrathecal (i.t.) administration of Phα1β to treat chronic pain reverted opioid tolerance with a safer profile than ω-conotoxin MVIIA, a highly selective NVACC blocker. Following a recent development of recombinant Phα1β (CTK 01512-2), a new molecular target, TRPA1, the structural arrangement of disulphide bridges, and an effect on glial plasticity have been identified. CTK 01512-2 reproduced the antinociceptive effects of the native toxin not only after the intrathecal but also after the intravenous administration. Herein, we review the Phα1β antinociceptive activity in the most relevant pain models and its mechanisms of action, highlighting the impact of CTK 01512-2 synthesis and its potential for multimodal analgesia.Item Análise da associação entre diuréticos tiazídicos e o desenvolvimento do diabetes mellitus do tipo 2.(2021) Andrade, Ana Eliza Almeida de; Binda, Nancy Scardua; Silva, Juliana Figueira daA hipertensão arterial e o diabetes mellitus tipo 2 (DM2) são enfermidades importantes do ponto de vista da saúde em escala mundial. As alterações na pressão arterial (PA) e glicemia podem contribuir para eventos cardiovasculares graves, além do quadro tornar- se mais preocupante quando o mesmo paciente apresenta ambas as doenças. Diuréticos tiazídicos (DT) são fármacos anti-hipertensivos utilizados para reduzir a PA, e prevenir eventos cardiovasculares. Entretanto, podem causar efeitos adversos,sendo a hipocalemia e a hiperglicemia os mais relevantes para esse estudo, cujo objetivo é analisar dados que associem o uso de DT com o possível desenvolvimento de DM2. Essa revisão integrativa de literatura internacional selecionou oito estudos, dentre os quais observou-se possível relação entre o uso de DT, principalmente em altas doses, e a elevação da glicemia, que pode ocorrer com poucas semanas de uso contínuo. A partir desse estudo foi possível identificar como fatores que influenciam o desenvolvimento da hiperglicemia: a dose administrada; a duração do tratamento; o desenvolvimento da hipocalemia, e a variabilidade genética populacional. O principal mecanismo relacionado ao aumento dos níveis de glicose sanguínea é a hipocalemia ocasionada pela classe farmacológica, devido a essencial participação do potássio na exocitose de insulina. A elevação da glicose gerada pelos DT é pouco discutida até o momento, e ainda não é um fator preponderante para a interrupção do tratamento. No entanto, a atuação do farmacêutico e equipe multiprofissional é necessária para acompanhamento da adequada indicação clínica de DT e observação das contraindicações, como a presença prévia de hiperglicemia.Item Analgesic and side effects of intravenous recombinant Phα1β.(2020) Rigo, Flavia Karine; Rossato, Mateus Fortes; Borges, Vanessa; Silva, Juliana Figueira da; Pereira, Elizete Maria Rita; Ávila, Ricardo Andrez Machado de; Trevisan, Gabriela; Astoni, Duana Carvalho dos Santos; Diniz, Danuza Montijo; Silva, Marco Aurélio Romano; Castro Junior, Célio José de; Cunha, Thiago Mattar; Ferreira, Juliano; Gomez, Marcus ViniciusBackground: Intrathecal injection of voltage-sensitive calcium channel blocker peptide toxins exerts analgesic effect in several animal models of pain. Upon intrathecal administration, recombinant Phα1β exerts the same analgesic effects as the those of the native toxin. However, from a clinical perspective, the intrathecal administration limits the use of anesthetic drugs in patients. Therefore, this study aimed to investigate the possible antinociceptive effect of intravenous recombinant Phα1β in rat models of neuropathic pain, as well as its side effects on motor, cardiac (heart rate and blood pressure), and biochemical parameters. Methods: Male Wistar rats and male Balb-C mice were used in this study. Giotto Biotech® synthesized the recombinant version of Phα1β using Escherichia coli expression. In rats, neuropathic pain was induced by chronic constriction of the sciatic nerve and paclitaxel-induced acute and chronic pain. Mechanical sensitivity was evaluated using von Frey filaments. A radiotelemeter transmitter (TA11PA-C10; Data Sciences, St. Paul, MN, USA) was placed on the left carotid of mice for investigation of cardiovascular side effects. Locomotor activity data were evaluated using the open-field paradigm, and serum CKMB, TGO, TGP, LDH, lactate, creatinine, and urea levels were examined. Results: Intravenous administration of recombinant Phα1β toxin induced analgesia for up to 4 h, with ED50 of 0.02 (0.01-0.03) mg/kg, and reached the maximal effect (Emax = 100% antinociception) at a dose of 0.2 mg/kg. No significant changes were observed in any of the evaluated motor, cardiac or biochemical parameters. Conclusion: Our data suggest that intravenous administration of recombinant Phα1β may be feasible for drug-induced analgesia, without causing any severe side effects.Item Phoneutria toxin PnTx3-5 inhibits TRPV1 channel with antinociceptive action in an orofacial pain model.(2020) Pereira, Elizete Maria Rita; Souza, Jéssica Mabelle; Carobin, Natália Virtude; Silva, Juliana Figueira da; Astoni, Duana Carvalho dos Santos; Silva Júnior, Cláudio Antônio da; Binda, Nancy Scardua; Borges, Marcia Helena; Nagem, Ronaldo Alves Pinto; Kushmerick, Christopher; Ferreira, Juliano; Castro Junior, Célio José de; Ribeiro, Fabiola Mara; Gomez, Marcus ViniciusCapsaicin, an agonist of TRPV1, evokes intracellular [Ca2+] transients and glutamate release from perfused trigeminal ganglion. The spider toxin PnTx3-5, native or recombinant is more potent than the selective TRPV1 blocker SB-366791 with IC50 of 47 ± 0.18 nM, 45 ± 1.18 nM and 390 ± 5.1 nM in the same experimental conditions. PnTx3-5 is thus more potent than the selective TRPV1 blocker SB-366791. PnTx3-5 (40 nM) and SB-366791 (3 μM) also inhibited the capsaicin-induced increase in intracellular Ca2+ in HEK293 cells transfected with TRPV1 by 75 ± 16% and 84 ± 3.2%, respectively. In HEK293 cells transfected with TRPA1, cinnamaldehyde (30 μM) generated an increase in intracellular Ca2+ that was blocked by the TRPA1 antagonist HC-030031 (10 μM, 89% inhibition), but not by PnTx3-5 (40 nM), indicating selectivity of the toxin for TRPV1. In whole-cell patch-clamp experiments on HEK293 cells transfected with TRPV1, capsaicin (10 μM) generated inward currents that were blocked by SB-366791 and by both native and recombinant PnTx3-5 by 47 ± 1.4%; 54 ± 7.8% and 56 ± 9.0%, respectively. Intradermal injection of capsaicin into the rat left vibrissa induced nociceptive behavior that was blocked by pre-injection with either SB-366791 (3 nmol/site i.d., 83.3 ± 7.2% inhibition) or PnTx3-5 (100 fmol/site, 89 ± 8.4% inhibition). We conclude that both native and recombinant PnTx3-5 are potent TRPV1 receptor antagonists with antinociceptive action on pain behavior evoked by capsaicin.Item The inhibitory efect of Phα1β toxin on diabetic neuropathic pain involves the CXCR4 chemokine receptor.(2020) Silva Júnior, Cláudio Antônio da; Castro Junior, Célio José de; Pereira, Elizete Maria Rita; Binda, Nancy Scardua; Silva, Juliana Figueira da; Cordeiro, Marta do Nascimento; Diniz, Danuza Montijo; Santa Cecília, Flávia Viana; Ferreira, Juliano; Gomez, Marcus ViniciusBackground: Diabetic neuropathy is a common cause of painful diabetic neuropathy (PDN). C-X-C chemokine receptor type 4 (CXCR4) expression is increased in peripheral nerve samples from diabetes patients, suggesting a role for CXCR4 in PDN. Therefore, we evaluated the effects of Phα1β, ω-conotoxin MVIIA, and AMD3100 in a model of streptozotocin (STZ)-induced PDN in rodents and naïve model of rats with the activation of the CXCR4/stromal cell-derived factor 1 (SDF-1) signal. Methods: Diabetic neuropathy was induced by intraperitoneal (ip) injection of STZ in Wistar rats. Naïve rats were intrathecally injected with SDF-1 to test the CXCR4/SDF-1 signal. The effects of Phα1β intrathecal (it), ω-conotoxin MVIIA intrathecal (it), and AMD3100 intraperitoneal (ip) on rat hypersensitivity, IL-6, and the intracellular calcium [Ca2+]i content of diabetic synaptosomes were studied. Results: The drugs reduced the hypersensitivity in diabetic rats. SDF-1 (1.0 µg/it) administration in naïve rats induced hypersensitivity. Phα1β (100 pmol/it) or AMD3100 (2.5 µg/ip) reduced this hypersensitivity after 2 h treatments, while ω-conotoxin MVIIA did not have an effect. IL-6 and [Ca2+]i content increased in the spinal cord synaptosomes in diabetic rats. The drug treatments reduced IL-6 and the calcium influx in diabetic synaptosomes. Conclusions: Phα1β, ω-conotoxin MVIIA, and AMD3100, after 2 h of treatment of STZ-induced PDN, reduced hypersensitivity in diabetic rats. In naïve rats with CXCR4/SDF-1 activation, the induced hypersensitivity decreased after 2 h treatments with Phα1β or AMD-3100, while ω-conotoxin MVIIA did not affect. The inhibitory effects of Phα1β on PDN may involve voltage-dependent calcium channels.Item Conotoxin MVIIA improves cell viability and antioxidant system after spinal cord injury in rats.(2018) Oliveira, Karen Maciel de; Binda, Nancy Scardua; Lavor, Mário Sérgio Lima de; Silva, Carla Maria Osório; Rosado, Isabel Rodrigues; Alves, Endrigo Gabellini Leonel; Silva, Juliana Figueira da; Oliveira, Camila M.; Melo, Marilia Martins; Gomez, Marcus Vinicius; Melo, Eliane Gonçalves deThis study evaluates whether intrathecal MVIIA injection after spinal cord injury (SCI) elicits neuroprotective effects. The test rats were randomly distributed into six groups— sham, placebo, MVIIA 2.5 μM, MVIIA 5 μM, MVIIA 10 μM, and MVIIA 20 μM—and were administered the treatment four hours after SCI. After the optimal MVIIA dose (MVIIA 10 μM) was defined, the best time for application, one or four hours, was analyzed. Locomotor hind limb function and side effects were assessed. Forty-eight hours after the injury and immediately after euthanasia, spinal cord segments were removed from the test rats. Cell viability, reactive oxygen species, lipid peroxidation, and glutamate release were investigated. To examine the MVIIA mechanism of action, the gene expressions of pro-apoptotic (Bax, nNOS, and caspase-3, -8, -9, -12) and anti-apoptotic (Bcl-xl) factors in the spinal cord tissue samples were determined by real-time PCR, and the activities of antioxidant enzymes were also investigated. Application of intrathecal MVIIA 10 μM four hours after SCI prompted a neuroprotective effect: neuronal death decreased (22.46%), oxidative stress diminished, pro-apoptotic factors (Bax, nNOS, and caspase-3, -8) were expressed to a lesser extent, and mitochondrial viability as well as anti-apoptotic factor (Bcl-xl) expression increased. These results suggested that MVIIA provided neuroprotection through antioxidant effects. Indeed, superoxide dismutase (188.41%), and glutathione peroxidase (199.96%), reductase (193.86%), and transferase (175.93%) expressions increased. Therefore, intrathecal MVIIA (MVIIA 10 μM, 4 h) application has neuroprotective potential, and the possible mechanisms are related to antioxidant agent modulation and to intrinsic and extrinsic apoptotic pathways.