RESUMO
Nicotinic acetylcholine receptors (nAChRs) present as many different subtypes in the nervous and immune systems, muscles and on the cells of other organs. In the immune system, inflammation is regulated via the vagus nerve through the activation of the non-neuronal α7 nAChR subtype, affecting the production of cytokines. The analgesic properties of α7 nAChR-selective compounds are mostly based on the activation of the cholinergic anti-inflammatory pathway. The molecular mechanism of neuropathic pain relief mediated by the inhibition of α9-containing nAChRs is not fully understood yet, but the role of immune factors in this process is becoming evident. To obtain appropriate drugs, a search of selective agonists, antagonists and modulators of α7- and α9-containing nAChRs is underway. The naturally occurring three-finger snake α-neurotoxins and mammalian Ly6/uPAR proteins, as well as neurotoxic peptides α-conotoxins, are not only sophisticated tools in research on nAChRs but are also considered as potential medicines. In particular, the inhibition of the α9-containing nAChRs by α-conotoxins may be a pathway to alleviate neuropathic pain. nAChRs are involved in the inflammation processes during AIDS and other viral infections; thus they can also be means used in drug design. In this review, we discuss the role of α7- and α9-containing nAChRs in the immune processes and in pain.
Assuntos
Conotoxinas , Neuralgia , Receptores Nicotínicos , Animais , Humanos , Receptores Nicotínicos/metabolismo , Neuralgia/tratamento farmacológico , Conotoxinas/uso terapêutico , Conotoxinas/química , Sistema Imunitário/metabolismo , Inflamação , Mamíferos/metabolismoRESUMO
Several Conus-derived venom peptides are promising lead compounds for the management of neuropathic pain, with α-conotoxins being of particular interest. Modification of the interlocked disulfide framework of α-conotoxin Vc1.1 has been achieved using on-resin alkyne metathesis. Although introduction of a metabolically stable alkyne motif significantly disrupts backbone topography, the structural modification generates a potent and selective GABAB receptor agonist that inhibits Cav2.2 channels and exhibits dose-dependent reversal of mechanical allodynia in a behavioral rat model of neuropathic pain. The findings herein support the hypothesis that analgesia can be achieved via activation of GABABRs expressed in dorsal root ganglion (DRG) sensory neurons.
Assuntos
Alcinos/uso terapêutico , Analgésicos/uso terapêutico , Conotoxinas/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Alcinos/química , Analgésicos/química , Animais , Células Cultivadas , Conotoxinas/química , Caramujo Conus/química , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Hiperalgesia/fisiopatologia , Masculino , Modelos Moleculares , Neuralgia/fisiopatologia , Ratos Sprague-Dawley , XenopusRESUMO
Snails can provide a considerable variety of bioactive compounds for cosmetic and pharmaceutical industries, useful for the development of new formulations with less toxicity and post effects compared to regular compounds used for the purpose. Compounds from crude extract, mucus, slime consist of glycans, polypeptides, proteins, etc., and can be used for curing diseases like viral lesions, warts, and different dermal problems. Some particular uses of snails involve treating post-traumatic stress. Micro RNA of Lymnaea stagnalis, was known to be responsible for the development of long-term memory and treatment of Alzheimer's and Dementia like diseases. This review explores the application of various bioactive compounds from snails with its potential as new translational medicinal and cosmetic applications. Snail bioactive compounds like ω-MVIIA, µ-SIIIA, µO-MrVIB, Xen2174, δ-EVIA, α-Vc1.1, σ-GVIIA, Conantokin-G, and Contulakin-G, conopeptides can be used for the development of anti-cancer drugs. These compounds target the innate immunity and improve the defense system of humans and provide protection against these life-threatening health concerns.AbbreviationsFDA: Food and Drug Administration; UTI: urinal tract infection; nAChRs: nicotinic acetylcholine receptors; NMDA: N-methyl-D-aspartate; CNS: central nervous system; CAR T: chimeric antigen receptors therapy; Micro RNA: micro ribonucleic acid.
Assuntos
Produtos Biológicos/uso terapêutico , Conotoxinas/uso terapêutico , Animais , Humanos , CaramujosRESUMO
Abstract: α-Conotoxin TxIB is a specific antagonist of α6/α3ß2ß3(α6ß2*) nicotinic acetylcholine receptor (nAChR) with an IC50 of 28 nM. Previous studies have shown that α6ß2* nAChRs are abundantly expressed in midbrain dopaminergic neurons and play an important role in mediating the mechanism of nicotine and other drugs reward effect. It provided important targets for the development of anti-addiction drugs. The present study evaluated the pharmacological activity of TxIB in vivo with conditioned place preference (CPP) model, which were induced by subcutaneous injection (s.c.) of nicotine (NIC, 0.5 mg/kg). α-Conotoxin TxIB inhibited the expression and reinstatement of CPP in mice dose-dependently, but had no significant effect on locomotor activity. The concentrations of dopamine (DA), γ-aminobutyric acid (GABA) and noradrenaline (NE) in different brain regions were measured by enzyme-linked immunosorbent assay (ELISA). We found that TxIB could inhibit the concentrations of DA, GABA and NE in different brain regions (such as nucleus accumbens (NAc), hippocampus (HIP) and prefrontal cortex (PFC)) in NIC-induced mice. The concentrations of DA and NE were decreased in ventral tegmental area (VTA), while GABA had little change. The current work described the inhibition activity of TxIB in NIC-induced CPP, suggesting that α6ß2* nAChR-targeted compound may be a promising drug for nicotine addiction treatment.
Assuntos
Condicionamento Psicológico/efeitos dos fármacos , Conotoxinas/farmacologia , Antagonistas Nicotínicos/farmacologia , Receptores Nicotínicos/metabolismo , Tabagismo/tratamento farmacológico , Animais , Técnicas de Observação do Comportamento , Comportamento Animal/efeitos dos fármacos , Conotoxinas/uso terapêutico , Modelos Animais de Doenças , Dopamina/análise , Dopamina/metabolismo , Humanos , Injeções Subcutâneas , Ligantes , Masculino , Camundongos , Nicotina/administração & dosagem , Nicotina/efeitos adversos , Antagonistas Nicotínicos/uso terapêutico , Norepinefrina/análise , Norepinefrina/metabolismo , Recompensa , Área Tegmentar Ventral/química , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo , Ácido gama-Aminobutírico/análise , Ácido gama-Aminobutírico/metabolismoRESUMO
Nicotinic acetylcholine receptors (nAChRs) are associated with various cancers, but the relation between nAChRs and cervical cancer remains unclear. Therefore, this study investigated the differential expression of nAChR subunits in human cervical cancer cell lines (SiHa, HeLa, and CaSki) and in normal ectocervical cell lines (Ect1/E6E7) at mRNA and protein levels. Two specific nAChR subtype blockers, αO-conotoxin GeXIVA and α-conotoxin TxID, were then selected to treat different human cervical cancer cell lines with specific nAChR subtype overexpression. The results showed that α3, α9, α10, and ß4 nAChR subunits were overexpressed in SiHa cells compared with that in normal cells. α9 and α10 nAChR subunits were overexpressed in CaSki cells. α*-conotoxins that targeted either α9α10 or α3ß4 nAChR were able to significantly inhibit cervical cancer cell proliferation. These findings may provide a basis for new targets for cervical cancer targeted therapy.
Assuntos
Caramujo Conus , Antagonistas Nicotínicos/farmacologia , Receptores Nicotínicos/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Conotoxinas/farmacologia , Conotoxinas/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Antagonistas Nicotínicos/uso terapêutico , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologiaRESUMO
Recently, the muscle-type nicotinic acetylcholine receptors (nAChRs) have been pursued as a potential target of several diseases, including myogenic disorders, muscle dystrophies and myasthenia gravis, etc. α-conotoxin GI isolated from Conus geographus selectively and potently inhibited the muscle-type nAChRs which can be developed as a tool to study them. Herein, alanine scanning mutagenesis was used to reveal the structureâ»activity relationship (SAR) between GI and mouse α1ß1δε nAChRs. The Pro5, Gly8, Arg8, and Tyr11 were proved to be the critical residues for receptor inhibiting as the alanine (Ala) replacement led to a significant potency loss on mouse α1ß1δε nAChR. On the contrary, substituting Asn4, His10 and Ser12 with Ala respectively did not affect its activity. Interestingly, the [E1A] GI analogue exhibited a three-fold potency for mouse α1ß1δε nAChR, whereas it obviously decreased potency at rat α9α10 nAChR compared to wildtype GI. Molecular dynamic simulations also suggest that loop2 of GI significantly affects the interaction with α1ß1δε nAChR, and Tyr11 of GI is a critical residue binding with three hydrophobic amino acids of the δ subunit, including Leu93, Tyr95 and Leu103. Our research elucidates the interaction of GI and mouse α1ß1δε nAChR in detail that will help to develop the novel analogues of GI.
Assuntos
Alanina/genética , Conotoxinas/química , Caramujo Conus , Antagonistas Nicotínicos/química , Receptores Nicotínicos/metabolismo , Sequência de Aminoácidos/genética , Animais , Conotoxinas/farmacologia , Conotoxinas/uso terapêutico , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Músculo Esquelético/metabolismo , Mutagênese , Doenças Neuromusculares/tratamento farmacológico , Junção Neuromuscular/metabolismo , Antagonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/uso terapêutico , Oócitos , Técnicas de Patch-Clamp , Receptores Nicotínicos/química , Relação Estrutura-Atividade , Transmissão Sináptica/efeitos dos fármacos , Xenopus laevisRESUMO
This 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.
Assuntos
Antioxidantes/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Conotoxinas/farmacologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Animais , Conotoxinas/efeitos adversos , Conotoxinas/uso terapêutico , Relação Dose-Resposta a Droga , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/fisiopatologia , Fatores de TempoRESUMO
α-Conotoxins are disulfide-bonded peptides from cone snail venoms and are characterized by their affinity for nicotinic acetylcholine receptors (nAChR). Several α-conotoxins with distinct selectivity for nAChR subtypes have been identified as potent analgesics in animal models of chronic pain. However, a number of α-conotoxins have been shown to inhibit N-type calcium channel currents in rodent dissociated dorsal root ganglion (DRG) neurons via activation of G protein-coupled GABAB receptors (GABABR). Therefore, it is unclear whether activation of GABABR or inhibition of α9α10 nAChRs is the analgesic mechanism. To investigate the mechanisms by which α-conotoxins provide analgesia, we synthesized a suite of Vc1.1 analogues where all residues, except the conserved cysteines, in Vc1.1 were individually replaced by alanine (A), lysine (K), and aspartic acid (D). Our results show that the amino acids in the first loop play an important role in binding of the peptide to the receptor, whereas those in the second loop play an important role for the selectivity of the peptide for the GABABR over α9α10 nAChRs. We designed a cVc1.1 analogue that is >8000-fold selective for GABABR-mediated inhibition of high voltage-activated (HVA) calcium channels over α9α10 nAChRs and show that it is analgesic in a mouse model of chronic visceral hypersensitivity (CVH). cVc1.1[D11A,E14A] caused dose-dependent inhibition of colonic nociceptors with greater efficacy in ex vivo CVH colonic nociceptors relative to healthy colonic nociceptors. These findings suggest that selectively targeting GABABR-mediated HVA calcium channel inhibition by α-conotoxins could be effective for the treatment of chronic visceral pain.
Assuntos
Analgésicos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Conotoxinas/uso terapêutico , Dor/tratamento farmacológico , Analgésicos/síntese química , Analgésicos/química , Animais , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio Tipo N/metabolismo , Conotoxinas/síntese química , Conotoxinas/química , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Antagonistas Nicotínicos/síntese química , Antagonistas Nicotínicos/química , Antagonistas Nicotínicos/uso terapêutico , Ratos Wistar , Receptores de GABA-B/metabolismo , Receptores Nicotínicos/metabolismo , Relação Estrutura-Atividade , Xenopus laevisRESUMO
Oxaliplatin, a third-generation diaminocyclohexane platinum drug, is widely used alone or in combination with 5-fluorouracil and leucovorin to treat metastatic colorectal, ovarian, and pancreatic cancers. Oxaliplatin long-term treatment is associated with the development of a dose-limiting painful neuropathy that dramatically impairs the patient's quality of life and therapy possibility. To study novel strategies to treat oxaliplatin-induced neuropathy, we evaluated α-conotoxin RgIA, a peptide that potently blocks the α9α10 nicotinic acetylcholine receptor (nAChR) subtype in a rat model of oxaliplatin-dependent neurotoxicity (2.4mgkg(-1) oxaliplatin intraperitoneally daily for 21days). The administration of RgIA (2 and 10nmol injected intramuscularly once a day concomitantly with oxaliplatin treatment), reduced the oxaliplatin-dependent hypersensitivity to mechanical and thermal noxious and non-noxious stimuli. Moreover, morphological modifications of L4-L5 dorsal root ganglia were significantly prevented. In the spinal cord the numerical increase of astrocyte cell density present in oxaliplatin-treated rats is partially prevented by RgIA treatment. Nevertheless, the administration of the α-conotoxin is able per se to elicit a numerical increase and a morphological activation of microglia and astrocytes in specific brain areas.
Assuntos
Antineoplásicos/toxicidade , Conotoxinas/uso terapêutico , Neuralgia/induzido quimicamente , Neuralgia/prevenção & controle , Antagonistas Nicotínicos/uso terapêutico , Compostos Organoplatínicos/toxicidade , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Gânglios Espinais/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Hiperalgesia/tratamento farmacológico , Masculino , Proteínas dos Microfilamentos/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neuroglia/patologia , Oxaliplatina , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia , Fatores de TempoRESUMO
Cone snails, also known as marine gastropods, from Conus genus produce in their venom a diverse range of small pharmacologically active structured peptides called conotoxins. The cone snail venoms are widely unexplored arsenal of toxins with therapeutic and pharmacological potential, making them a treasure trove of ligands and peptidic drug leads. Conotoxins are small disulfide bonded peptides, which act as remarkable selective inhibitors and modulators of ion channels (calcium, sodium, potassium), nicotinic acetylcholine receptors, noradrenaline transporters, N-methyl-D-aspartate receptors, and neurotensin receptors. They are highly potent and specific against several neuronal targets making them valuable as research tools, drug leads and even therapeutics. In this review, we discuss their gene superfamily classification, nomenclature, post-translational modification, structural framework, pharmacology and medical applications of the active conopeptides. We aim to give an overview of their structure and therapeutic potential. Understanding these aspects of conopeptides will help in designing more specific peptidic analogues.
Assuntos
Conotoxinas , Neoplasias/tratamento farmacológico , Ciática/tratamento farmacológico , Conotoxinas/química , Conotoxinas/farmacologia , Conotoxinas/uso terapêutico , Humanos , Canais Iônicos/antagonistas & inibidores , Canais Iônicos/metabolismo , Ligantes , Neoplasias/metabolismo , Ciática/metabolismoRESUMO
αO-conotoxin GeXIVA (GeXIVA) is a potent antagonist of α9α10 nicotinic acetylcholine receptors (nAChRs), which has four Cys residues and three disulfide isomers. Among the 3 isomers, both GeXIVA[1,2] (bead isomer) and GeXIVA[1,4] (ribbon isomer) showed potent block on α9α10 nAChRs with close low nanomolar IC50s. Here we report that anti-hypersensitive effects of the bead and ribbon isomers in the chronic constriction injury (CCI) model of neuropathic pain and acute pain model of tail flick test. Treatment was started and continued for 7 or 14days after the development of hyperalgesia which was induced by CCI surgery. GeXIVA[1,2] and GeXIVA[1,4] significantly reduced mechanical allodynia in CCI rats without tolerance, in which GeXIVA[1,2] remained up to two weeks after intramuscular administration of the toxins was ceased. The pain reliever effect of GeXIVA[1,2] on neuropathic rats was slightly better than GeXIVA[1,4]. The two isomers did not suppress the acute thermal pain behaviors significantly when they were tested in the tail flick model by intramuscular bolus injection. Both GeXIVA[1,2] and GeXIVA[1,4] had no significant effect on performance of rats in the accelerating rotarod test after intramuscular injections. This suggests that αO-conotoxin GeXIVA[1,2] and GeXIVA[1,4] may offer new strategies to the treatment of neuropathic pain.
Assuntos
Analgésicos/uso terapêutico , Conotoxinas/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Animais , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Chronic pain creates a large socio-economic burden around the world. It is physically and mentally debilitating, and many suffers are unresponsive to current therapeutics. Many drugs that provide pain relief have adverse side effects and addiction liabilities. Therefore, a great need has risen for alternative treatment strategies. One rich source of potential analgesic compounds that has immerged over the past few decades are conotoxins. These toxins are extremely diverse and display selective activity at ion channels. Voltage gated sodium (NaV) channels are one such group of ion channels that play a significant role in multiple pain pathways. This review will explore the literature around conotoxins that bind NaV channels and determine their analgesic potential.
Assuntos
Analgésicos/farmacologia , Conotoxinas/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Analgesia , Analgésicos/uso terapêutico , Animais , Dor Crônica/tratamento farmacológico , Dor Crônica/fisiopatologia , Conotoxinas/uso terapêutico , Humanos , Subunidades Proteicas/química , Subunidades Proteicas/fisiologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Canais de Sódio Disparados por Voltagem/química , Canais de Sódio Disparados por Voltagem/fisiologiaRESUMO
The α9α10-nicotinic acetylcholine receptor (nAChR) has been implicated in pain and has been proposed to be a novel target for analgesics. However, the evidence to support the involvement of the α9α10-nAChR in pain is conflicted. This receptor was first implicated in pain with the characterisation of conotoxin Vc1.1, which is highly selective for α9α10-nAChRs and is an efficacious analgesic in chronic pain models with restorative capacities and no reported side effects. Numerous other analgesic conotoxin and non-conotoxin molecules have been subsequently characterised that also inhibit α9α10-nAChRs. However, there is evidence that α9α10-nAChR inhibition is neither necessary nor sufficient for analgesia. α9α10-nAChR-inhibiting analogues of Vc1.1 have no analgesic effects. Genetically-modified α9-nAChR knockout mice have a phenotype that is markedly different from the analgesic profile of Vc1.1 and similar conotoxins, suggesting that the conotoxin effects are largely independent of α9α10-nAChRs. Furthermore, an alternative mechanism of analgesia by Vc1.1 and other similar conotoxins involving non-canonical coupling of GABAB receptors to voltage-gated calcium channels is known. Additional incongruities regarding α9α10-nAChRs in analgesia are discussed. A more comprehensive characterisation of the role of α9α10-nAChRs in pain is crucial for understanding the analgesic action of conotoxins and for improved drug design.
Assuntos
Analgésicos/farmacologia , Conotoxinas/farmacologia , Antagonistas Nicotínicos/farmacologia , Dor/tratamento farmacológico , Dor/metabolismo , Receptores Nicotínicos/metabolismo , Analgésicos/efeitos adversos , Analgésicos/uso terapêutico , Animais , Conotoxinas/efeitos adversos , Conotoxinas/uso terapêutico , Modelos Animais de Doenças , Humanos , Camundongos Knockout , Antagonistas Nicotínicos/efeitos adversos , Antagonistas Nicotínicos/uso terapêutico , RatosRESUMO
The neuroprotective activity of conantokin-G (con-G), a naturally occurring antagonist of N-methyl-D-aspartate receptors (NMDAR), was neurologically and histologically compared in the core and peri-infarct regions after ischemia/reperfusion brain injury in male Sprague-Dawley rats. The contralateral regions served as robust internal controls. Intrathecal injection of con-G, post-middle carotid artery occlusion (MCAO), caused a dramatic decrease in brain infarct size and swelling at 4 hr, compared to 26 hr, and significant recovery of neurological deficits was observed at 26 hr. Administration of con-G facilitated neuronal recovery in the peri-infarct regions as observed by decreased neurodegeneration and diminished calcium microdeposits at 4 hr and 26 hr. Intact Microtubule Associated Protein (MAP2) staining and neuronal cytoarchitecture was observed in the peri-infarct regions of con-G treated rats at both timepoints. Con-G restored localization of GluN1 and GluN2B subunits in the neuronal soma, but not that of GluN2A, which was perinuclear in the peri-infarct regions at 4 hr and 26 hr. This suggests that molecular targeting of the GluN2B subunit has potential for reducing detrimental consequences of ischemia. Overall, the data demonstrated that stroke-induced NMDAR excitoxicity is ameliorated by con-G-mediated repair of neurological and neuroarchitectural deficits, as well as by reconstituting neuronal localization of GluN1 and GluN2B subunits in the peri-infarct region of the stroked brain.
Assuntos
Infarto Encefálico/metabolismo , Conotoxinas/farmacologia , Fármacos Neuroprotetores/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Infarto Encefálico/complicações , Infarto Encefálico/tratamento farmacológico , Infarto Encefálico/patologia , Conotoxinas/uso terapêutico , Modelos Animais de Doenças , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Subunidades Proteicas/metabolismo , Transporte Proteico/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/complicações , Fatores de Tempo , Resultado do TratamentoRESUMO
Peptide neurotoxins from cone snails called conotoxins are renowned for their therapeutic potential to treat pain and several neurodegenerative diseases. Inefficient assay-guided discovery methods have been replaced by high-throughput bioassays integrated with advanced MS and next-generation sequencing, ushering in the era of 'venomics'. In this review, we focus on the impact of venomics on the understanding of cone snail biology as well as the application of venomics to accelerate the discovery of new conotoxins. We also discuss the continued importance of medicinal chemistry approaches to optimize conotoxins for clinical use, with a descriptive case study of MrIA featured.
Assuntos
Venenos de Moluscos/química , Caramujos/metabolismo , Animais , Conotoxinas/química , Conotoxinas/metabolismo , Conotoxinas/uso terapêutico , Descoberta de Drogas , Ensaios de Triagem em Larga Escala , Venenos de Moluscos/metabolismo , Venenos de Moluscos/uso terapêutico , Doenças do Sistema Nervoso/tratamento farmacológico , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Biblioteca de Peptídeos , Peptídeos/química , Peptídeos/metabolismo , Peptídeos/uso terapêutico , Peptidomiméticos , Relação Estrutura-AtividadeRESUMO
µ-Conotoxins block voltage-gated sodium channels (VGSCs) and compete with tetrodotoxin for binding to the sodium conductance pore. Early efforts identified µ-conotoxins that preferentially blocked the skeletal muscle subtype (NaV1.4). However, the last decade witnessed a significant increase in the number of µ-conotoxins and the range of VGSC subtypes inhibited (NaV1.2, NaV1.3 or NaV1.7). Twenty µ-conotoxin sequences have been identified to date and structure-activity relationship studies of several of these identified key residues responsible for interactions with VGSC subtypes. Efforts to engineer-in subtype specificity are driven by in vivo analgesic and neuromuscular blocking activities. This review summarizes structural and pharmacological studies of µ-conotoxins, which show promise for development of selective blockers of NaV1.2, and perhaps also NaV1.1,1.3 or 1.7.
Assuntos
Analgésicos/química , Conotoxinas/química , Bloqueadores dos Canais de Sódio/química , Canais de Sódio Disparados por Voltagem/química , Analgésicos/metabolismo , Analgésicos/uso terapêutico , Animais , Conotoxinas/metabolismo , Conotoxinas/uso terapêutico , Caramujo Conus/metabolismo , Dor/tratamento farmacológico , Dor/patologia , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Bloqueadores dos Canais de Sódio/metabolismo , Bloqueadores dos Canais de Sódio/uso terapêutico , Relação Estrutura-Atividade , Canais de Sódio Disparados por Voltagem/metabolismoRESUMO
Neuropathic pain affects millions of people worldwide, causing substantial disability and greatly impairing quality of life. Commonly used analgesics or antihyperalgesic compounds are generally characterized by limited therapeutic outcomes. Thus, there is a compelling need for novel therapeutic strategies able to prevent nervous tissue alterations responsible for chronic pain. The α9α10 nicotinic acetylcholine receptor antagonist α-conotoxin RgIA (RgIA), a peptide isolated from the venom of a carnivorous cone snail, induces relief in both acute and chronic pain models. To evaluate potential disease-modifying effects of RgIA, the compound was given to rats following chronic constriction injury (CCI) of the sciatic nerve. Two or 10 nmol RgIA injected intramuscularly once a day for 14 days reduced the painful response to suprathreshold stimulation, increased pain threshold to nonnoxious stimuli, and normalized alterations in hind limb weight bearing. Histological analysis of the sciatic nerve revealed that RgIA prevented CCI-induced decreases of axonal compactness and diameter, loss of myelin sheath, and decreases in the fiber number. Moreover, RgIA significantly reduced edema and inflammatory infiltrate, including a decrease of CD86(+) macrophages. In L4-L5 dorsal root ganglia, RgIA prevented morphometric changes and reduced the inflammatory infiltrate consistent with a disease-modifying effect. In the dorsal horn of the spinal cord, RgIA prevented CCI-induced activation of microglia and astrocytes. These data suggest that RgIA-like compounds may represent a novel class of therapeutics for neuropathic pain that protects peripheral nervous tissues as well as prevents central maladaptive plasticity by inhibiting glial cell activation.
Assuntos
Analgésicos/uso terapêutico , Dor Crônica/prevenção & controle , Conotoxinas/uso terapêutico , Neuralgia/prevenção & controle , Neuroglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/complicações , Analgésicos/farmacologia , Animais , Dor Crônica/tratamento farmacológico , Dor Crônica/etiologia , Conotoxinas/farmacologia , Gânglios Espinais/efeitos dos fármacos , Masculino , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/lesõesRESUMO
Venom derived peptides from marine cone snails, conotoxins, have demonstrated unique pharmacological targeting properties that have been pivotal in advancing medical research. The awareness of their true toxic origins and potent pharmacological nature is emphasized by their 'select agent' classification by the US Centers for Disease Control and Prevention. We briefly introduce the biochemical and pharmacological aspects of conotoxins, highlighting current advancements into their biological engineering, and provide details to the present regulations that govern their use in research.
Assuntos
Pesquisa Biomédica/legislação & jurisprudência , Conotoxinas/uso terapêutico , Caramujo Conus/metabolismo , Animais , Centers for Disease Control and Prevention, U.S./legislação & jurisprudência , Conotoxinas/classificação , Conotoxinas/farmacologia , Humanos , Estados UnidosRESUMO
A review describes general trends in research of conotoxins that are peptide toxins isolated from sea gastropods of the Conus genus, since the toxins were discovered in 1970th. There are disclosed a conotoxin classification, their structure diversity and different ways of action to their molecular targets, mainly, ion channels. In the applied aspect of conotoxin research, drug discovery and development is discussed, the drugs being based on conotoxin structure. A first exemplary drug is a ziconotide, which is an analgesic of new generation.
Assuntos
Conotoxinas/química , Conotoxinas/uso terapêutico , Descoberta de Drogas , Gastrópodes , Animais , Humanos , Estrutura Secundária de Proteína , Relação Estrutura-AtividadeRESUMO
Voltage-gated sodium channels (VGSC) are the primary mediators of electrical signal amplification and propagation in excitable cells. VGSC subtypes are diverse, with different biophysical and pharmacological properties, and varied tissue distribution. Altered VGSC expression and/or increased VGSC activity in sensory neurons is characteristic of inflammatory and neuropathic pain states. Therefore, VGSC modulators could be used in prospective analgesic compounds. VGSCs have specific binding sites for four conotoxin families: µ-, µO-, δ- and ί-conotoxins. Various studies have identified that the binding site of these peptide toxins is restricted to well-defined areas or domains. To date, only the µ- and µO-family exhibit analgesic properties in animal pain models. This review will focus on conotoxins from the µ- and µO-families that act on neuronal VGSCs. Examples of how these conotoxins target various pharmacologically important neuronal ion channels, as well as potential problems with the development of drugs from conotoxins, will be discussed.