RESUMO
Memory consolidation is an essential process of long-term memory formation. Neurotrophins have been suggested as key regulators of activity dependent changes in the synaptic efficacy and morphology, which are considered the downstream mechanisms of memory consolidation. The neurotrophin 3 (NT-3), a member of the neurotrophin family, and its high affinity receptor TrkC, are widely expressed in the insular cortex (IC), a region with a critical role in the consolidation of the conditioned taste aversion (CTA) paradigm, in which an animal associates a novel taste with nausea. Nevertheless, the role of this neurotrophin in the cognitive processes that the IC mediates remains unexamined. To answer whether NT-3 is involved in memory consolidation at the IC, adult male Wistar rats were administered with NT-3 or NT-3 in combination with the Trk receptors inhibitor K252a into the IC, immediately after CTA acquisition under two different conditions: a strong-CTA (0.2 M lithium chloride i.p.) or a weak-CTA (0.1 M lithium chloride i.p.). Our results show that NT-3 strengthens the memory trace of CTA, transforming a weak conditioning into a strong one, in a Trk-dependent manner. The present evidence suggests that NT-3 has a key role in the consolidation process of an aversive memory in a neocortical region.
Assuntos
Córtex Cerebral , Córtex Insular , Ratos , Animais , Masculino , Ratos Wistar , Paladar , Cloreto de Lítio/farmacologia , Neurotrofina 3 , Aprendizagem da EsquivaRESUMO
Glucocorticoids (GC) affect neuronal plasticity, development and function of the nervous system by inhibiting neurotrophin-induced Trk signaling. It has been established that pretreatment with dexamethasone (DEX) restricts Neurotrophin-induced neurite outgrowth by inhibiting Trk-dependent activation of Ras-Erk1/2 signaling pathways. However, the precise molecular mechanism through which DEX interferes with neurotrophin signaling and Trk-mediated neurite outgrowth has not been clearly defined yet. Here, we observed that in PC12 cells DEX treatment promotes the transcription of Sprouty4, a regulatory molecule that is part of a negative feedback module that specifically abrogates Ras to Erk1/2 signaling in response to NGF. In line with this, either knockdown of Sprouty4 or overexpression of a dominant negative form of Sprouty4 (Y53A), rescue the inhibition of NGF/TrkA-promoted neurite outgrowth and Erk1/2 phosphorylation induced by DEX. Likewise, treatment of hippocampal neurons with DEX induces the expression of Sprouty4 and its knockdown abrogates the inhibitory effect of DEX on primary neurite formation, dendrite branching and Erk1/2 activation induced by BDNF. Thus, these results suggest that the induction of Sprouty4 mRNA by DEX translates into a significant inhibition of Trk to Erk1/2 signaling pathway. Together, these findings bring new insights into the crosstalk between DEX and neurotrophin signaling and demonstrate that Sprouty4 mediates the inhibitory effects of DEX on neurotrophin function.
RESUMO
NTRK fusions drive oncogenesis in a variety of adult cancers. The approval of the first-generation TRK inhibitors, larotrectinib and entrectinib, for any cancer with an NTRK fusion represented a focal point in tumor-agnostic drug development. These agents achieve high response rates and durable disease control, and display intracranial activity. The use of these agents has resulted in a deeper understanding of the clinical consequences of TRK inhibition. These on-target side effects include dizziness, weight gain, and withdrawal pain. The study of TRK inhibitor resistance led to the development of next generation drugs, such as selitrectinib, repotrectinib, taletrectinib, and other agents that maintain disease control against selected acquired kinase domain mutations. This review discusses the clinical efficacy of TRK inhibitors, their safety profiles, and resistance mechanisms with a focus on data in adult cancers.
Assuntos
Neoplasias , Proteínas de Fusão Oncogênica , Adulto , Humanos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Introduction: Neurotrophin-3 (NT-3) is thought to play a role in the neurobiological processes implicated in mood and anxiety disorders. NT-3 is a potential pharmacological target for mood disorders because of its effects on monoamine neurotransmitters, regulation of synaptic plasticity and neurogenesis, brain-derived neurotrophic factor (BDNF) signaling boosting, and modulation of the hypothalamic-pituitary-adrenal (HPA) axis. The mechanisms underlying NT-3 anxiolytic properties are less clear and require further exploration and definition. Areas covered: The evidence that supports NT-3 as a pharmacological target for anxiety and mood disorders is presented and this is followed by a reflection on the quandaries, stumbling blocks, and future perspectives for this novel target. Expert opinion: There is evidence for miRNAs being key post-transcriptional regulators of neurotrophin-3 receptor gene (NTRK3) in anxiety disorders; however, the anxiolytic properties of NT-3 need further examination and delineation. Moreover, NT-3 expression by non-neuronal cells and its role in brain circuits that participate in anxiety and mood disorders require further scrutiny. Further work is vital before progression into clinical trials can be realized.
Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Neurotrofina 3/metabolismo , Animais , Transtornos de Ansiedade/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Humanos , MicroRNAs/genética , Terapia de Alvo Molecular , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/fisiopatologia , Receptor trkC/genéticaRESUMO
Due to the critical tumorigenic role of fused NTRK genes in multiple cancers, TRK kinases have attracted extensive attention as a drug discovery target. Starting from an indazole based scaffold, through the type II kinase inhibitor fragments hybrid design approach with a ring closure strategy, we discovered a novel potent type II TRK kinase inhibitor compound 34 (IHMT-TRK-284), which exhibited IC50 values of 10.5 nM, 0.7 nM and 2.6 nM to TRKA, B, and C respectively. In addition, it displayed great selectivity profile in the kinome when tested among 468 kinases and mutants (S score (1) = 0.02 at 1 µM). Importantly, 34 could overcome drug resistant mutants including V573M and F589L in the ATP binding pocket as well as G667C/S in the DFG region. In vivo, 34 exhibited good PK profiles in different species including mice, rats, and dogs. It also displayed good in vivo antitumor efficacies in the TRKA/B/C, TRKA mutants, and KM-12-LUC cells mediated mouse models. The potent activity against clinically important TRK mutants combined with the good in vivo PK and efficacy properties of 34 indicated that it might be a new potential therapeutic candidate for TRK kinase fusion or mutants driven cancers.
Assuntos
Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mutação , Receptor trkA/antagonistas & inibidores , Tiazóis/química , Tiazóis/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Disponibilidade Biológica , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cães , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Masculino , Camundongos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Ratos , Receptor trkA/genética , Tiazóis/administração & dosagem , Tiazóis/farmacocinética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
RATIONALE: Reduced levels of orexin-A (OXA) in the central nervous system (CNS) have been associated with the pathophysiology of depression and its exogenous administration promotes antidepressant-like effect. The mechanisms associated with these effects are, however, not yet known. Herein, we investigated the hypothesis that OXA effects could be associated with orexin 1 receptor (OX1R) and tyrosine receptor kinase B (TrkB) activation, in the ventromedial prefrontal cortex (vmPFC), a brain region that is central to depression neurobiology. OBJECTIVES: 1. To Investigate the effects induced by OXA administration into the vmPFC; 2. Evaluate the participation of OX1R and TrkB in behavioral responses induced by OXA. METHODS: Male Wistar rats received intra-vmPFC injections of OXA (10, 50 and 100 pmol/0.2 µL) and were exposed to the forced swimming test (FST) or the open field test (OFT). Independent groups received an intra-vmPFC injection of SB334867 (OX1R antagonist, 10 nmol/0.2 µL) or K252a (non-selective Trk antagonist, 10 pmol/0.2 µL), before local injection of OXA, and were exposed to the same tests. RESULTS: OXA injection (100 pmol/0.2 µL) into the vmPFC induced antidepressant-like effect, which was prevented by SB334867 and K252a pretreatments. CONCLUSION: OXA signaling in the vmPFC induces antidepressant-like effect in the FST which is dependent on OX1R and Trk receptors.
Assuntos
Depressão/tratamento farmacológico , Orexinas/farmacologia , Córtex Pré-Frontal/metabolismo , Animais , Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Receptores de Orexina/efeitos dos fármacos , Receptores de Orexina/metabolismo , Orexinas/administração & dosagem , Orexinas/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Wistar , Receptor trkB/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse PsicológicoRESUMO
OPINION STATEMENT: Care should be taken to ensure that the diagnostic strategy for a recently diagnosed advanced non-small cell lung cancer includes NTRK fusion testing. RNA sequencing is the gold standard method of detection of NTRK fusion; however, pan-TRK immunohistochemistry could be used as a screening method with good sensitivity. Larotrectinib and entrectinib are approved therapies for TRK fusion-positive lung cancers as first or subsequent lines of therapy. TRK inhibition has demonstrated clinically meaningful, deep, and durable systemic and central nervous system responses. Larotrectinib and entrectinib have a manageable safety profile, including some TRK-related adverse events, such as dizziness and weight gain. At disease progression on first-generation TRK inhibitors, enrollment on a clinical trial should be encouraged, as new-generation TRK inhibitors are being tested.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Antineoplásicos/farmacologia , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/etiologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/mortalidade , Técnicas de Diagnóstico Molecular , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/métodos , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Resultado do TratamentoRESUMO
BACKGROUND: Arsenic trioxide (As2O3), a drug that has been used in China for approximately two thousand years, induces cell death in a variety of cancer cell types, including neuroblastoma (NB). The tyrosine kinase receptor (Trk) family comprises three members, namely TrkA, TrkB and TrkC. Various studies have confirmed that TrkA and TrkC expression is associated with a good prognosis in NB, while TrkB overexpression can lead to tumor cell growth and invasive metastasis. Previous studies have shown that As2O3 can inhibit the growth and proliferation of a human NB cell line and can also affect the N-Myc mRNA expression. It remains unclear whether As2O3 regulates Trks for the purposes of treating NB. METHODS: The aim of the present study was to investigate the effect of As2O3 on Trk expression in NB cell lines and its potential therapeutic efficacy. SK-N-SH cells were grown with increasing doses of As2O3 at different time points. We cultured SK-N-SH cells, which were treated with increasing doses of As2O3 at different time points. Trk expression in the NB samples was quantified by immunohistochemistry, and the cell cycle was analyzed by flow cytometry. TrkA, TrkB and TrkC mRNA expression was evaluated by real-time PCR analysis. RESULTS: Immunohistochemical and real-time PCR analyses indicated that TrkA and TrkC were over-expressed in NB, and specifically during stages 1, 2 and 4S of the disease progression. TrkB expression was increased in stage 3 and 4 NB. As2O3 significantly arrested SK-N-SH cells in the G2/M phase. In addition, TrkA, TrkB and TrkC expression levels were significantly upregulated by higher concentrations of As2O3 treatment, notably in the 48-h treatment period. Our findings suggested that to achieve the maximum effect and appropriate regulation of Trk expression in NB stages 1, 2 and 4S, As2O3 treatment should be at relatively higher concentrations for longer delivery times;however, for NB stages 3 and 4, an appropriate concentration and infusion time for As2O3 must be carefully determined. CONCLUSION: The present findings suggested that As2O3 induced Trk expression in SK-N-SH cells to varying degrees and may be a promising adjuvant to current treatments for NB due to its apoptotic effects.
Assuntos
Arsenicais/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicoproteínas de Membrana/efeitos dos fármacos , Neuroblastoma/metabolismo , Óxidos/farmacologia , Receptor trkB/efeitos dos fármacos , Trióxido de Arsênio , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Humanos , Glicoproteínas de Membrana/metabolismo , Neuroblastoma/patologia , Receptor trkB/metabolismoRESUMO
PURPOSE: We have previously shown that stress prior to induction worsens clinical presentation and inflammatory parameters in a rat model of endometriosis. This study was designed to examine whether stress during the development of endometriosis can affect the growth of endometriotic implants through nerve growth and immune alterations. METHODS: Endometriosis was surgically induced in female Sprague-Dawley rats by suturing uterine horn implants onto the small intestine mesentery. Two weeks later, one group of rats (endo-stress) was subjected to a 10-day swim stress protocol. Controls had no stress (endo-no stress) or sutures only and stress (sham-stress). On day 60, all rats were killed and examined for the presence of endometriotic vesicles. The size of each vesicle was measured. The uterus and colon were removed and assessed for damage, cell infiltration, and expression of nerve growth factor (NGF), its receptors (p75 and Tropomyosin receptor kinase A (Trk-A)/pTrk-A), and calcitonin gene-related peptide, a sensory fiber marker. A differential analysis of peritoneal fluid white blood cell count was performed. RESULTS: Stress significantly increased endometriotic vesicle size but not colonic damage and increased infiltration of mast cells. Significantly increased expression of NGF and its receptors was found in the uterus of animals with endometriosis receiving stress. CONCLUSIONS: Stress stimulates the development of ectopic endometrial vesicles in an animal model of endometriosis and increases inflammatory cell recruitment to the peritoneum. In addition, stress promotes nerve fiber growth in the uterus.
Assuntos
Endometriose/metabolismo , Fator de Crescimento Neural/metabolismo , Neurogênese/fisiologia , Receptor trkA/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Estresse Fisiológico/fisiologia , Estresse Psicológico/metabolismo , Animais , Modelos Animais de Doenças , Progressão da Doença , Endometriose/patologia , Feminino , Proteínas do Tecido Nervoso , Fosforilação , Ratos , Ratos Sprague-Dawley , Receptores de Fatores de Crescimento , Estresse Psicológico/patologiaRESUMO
BACKGROUND: Arsenic trioxide (As2O3), a drug that has been used in China for approximately two thousand years, induces cell death in a variety of cancer cell types, including neuroblastoma (NB). The tyrosine kinase receptor (Trk) family comprises three members, namely TrkA, TrkB and TrkC. Various studies have confirmed that TrkA and TrkC expression is associated with a good prognosis in NB, while TrkB overexpression can lead to tumor cell growth and invasive metastasis. Previous studies have shown that As2O3 can inhibit the growth and proliferation of a human NB cell line and can also affect the N-Myc mRNA expression. It remains unclear whether As2O3 regulates Trks for the purposes of treating NB. METHODS: The aim of the present study was to investigate the effect of As2O3 on Trk expression in NB cell lines and its potential therapeutic efficacy. SK-N-SH cells were grown with increasing doses of As2O3 at different time points. We cultured SK-N-SH cells, which were treated with increasing doses of As2O3 at different time points. Trk expression in the NB samples was quantified by immunohistochemistry, and the cell cycle was analyzed by flow cytometry. TrkA, TrkB and TrkC mRNA expression was evaluated by real-time PCR analysis. RESULTS: Immunohistochemical and real-time PCR analyses indicated that TrkA and TrkC were over-expressed in NB, and specifically during stages 1, 2 and 4S of the disease progression. TrkB expression was increased in stage 3 and 4 NB. As2O3significantly arrested SK-N-SH cells in the G2/M phase. In addition, TrkA, TrkB and TrkC expression levels were significantly upregulated by higher concentrations of As2O3 treatment, notably in the 48-h treatment period. Our findings suggested that to achieve the maximum effect and appropriate regulation of Trk expression in NB stages 1, 2 and 4S, As2O3 treatment should be at relatively higher concentrations for longer delivery times;however, for NB stages 3 and 4, an appropriate concentration and infusion time for As2O3 must be carefully determined. CONCLUSION: The present findings suggested that As2O3 induced Trk expression in SK-N-SH cells to varying degrees and may be a promising adjuvant to current treatments for NB due to its apoptotic effects.
Assuntos
Humanos , Óxidos/farmacologia , Arsenicais/farmacologia , Glicoproteínas de Membrana/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Receptor trkB/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Neuroblastoma/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptor trkB/metabolismo , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Trióxido de Arsênio , Neuroblastoma/patologiaRESUMO
Beta-caryophyllene (BCP) is a phytocannabinoid whose neuroprotective activity has been mainly associated with selective activation of cannabinoid-type-2 (CB2) receptors, inhibition of microglial activation and decrease of inflammation. Here, we addressed the potential of BCP to induce neuritogenesis in PC12 cells, a model system for primary neuronal cells that express trkA receptors, respond to NGF and do not express CB2 receptors. We demonstrated that BCP increases the survival and activates the NGF-specific receptor trkA in NGF-deprived PC12 cells, without increasing the expression of NGF itself. The neuritogenic effect of BCP in PC12 cells was abolished by k252a, an inhibitor of the NGF-specific receptor trkA. Accordingly, BCP did not induce neuritogenesis in SH-SY5Y neuroblastoma cells, a neuronal model that does not express trkA receptors and do not respond to NGF. Additionally, we demonstrated that BCP increases the expression of axonal-plasticity-associated proteins (GAP-43, synapsin and synaptophysin) in PC12 cells. It is known that these proteins are up-regulated by NGF in neurons and neuron-like cells, such as PC12 cells. Altogether, these findings suggest that BCP activates trka receptors and induces neuritogenesis by a mechanism independent of NGF or cannabinoid receptors. This is the first study to show such effects of BCP and their beneficial role in neurodegenerative processes should be further investigated.
Assuntos
Canabinoides/farmacologia , Neuritos/metabolismo , Neurogênese/efeitos dos fármacos , Receptores de Canabinoides/metabolismo , Sesquiterpenos/farmacologia , Animais , Carbazóis/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Alcaloides Indólicos/farmacologia , Fator de Crescimento Neural/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Neuritos/efeitos dos fármacos , Células PC12 , Sesquiterpenos Policíclicos , Ratos , Receptor trkA/antagonistas & inibidores , Receptor trkA/metabolismoRESUMO
TRK transporters, a class of proteins which generally carry out the bulk of K(+) accumulation in plants, fungi, and bacteria, mediate ion currents driven by the large membrane voltages (-150 to -250 mV) common to non-animal cells. Bacterial TRK proteins resemble K(+) channels in their primary sequence, crystallize as membrane dimers having intramolecular K(+)-channel-like folding, and complex with a cytoplasmic collar formed of four RCK domains (Nature 471:336, 2011; Ibid 496:324, 2013). Fungal TRK proteins appear simpler in form than the bacterial members, but do possess two special features: a large built-in regulatory domain, and a highly conserved pair of transmembrane helices (TM7 and TM8, ahead of the C-terminus), which were postulated to facilitate intramembranal oligomerization (Biophys. J. 77:789, 1999; FEMS Yeast Res. 9:278, 2009). A surprising associated functional process in the fungal proteins which have been explored (Saccharomyces, Candida, and Neurospora) is facilitation of channel-like chloride efflux. That process is suppressed by osmoprotective agents, appears to involve hydrophobic gating, and strongly resembles conduction by Cys-loop ligand-gated anion channels. And it leads to a rather general hypothesis: that the thermodynamic tendency for hydrophobic or amphipathic transmembrane helices to self-organize into oligomers can create novel ionic pathways through biological membranes: fundamental hydrophobic nanopores, pathways of low selectivity governed by the chaotropic behavior of individual ionic species and under the strong influence of membrane voltage.
Assuntos
Cloretos/metabolismo , Canais de Potássio/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Sequência de Aminoácidos , Dados de Sequência Molecular , Potássio/metabolismo , Canais de Potássio/química , Estrutura Terciária de Proteína , Proteínas de Saccharomyces cerevisiae/química , Leveduras/genética , Leveduras/metabolismoRESUMO
The molecular structure modeling of the ß1 subunit of the skeletal muscle voltage-gated sodium channel (Nav1.4) was carried out in the twilight zone of very low homology. Structural significance can per se be confounded with random sequence similarities. Hence, we combined (i) not automated computational modeling of weakly homologous 3D templates, some with interfaces to analogous structures to the pore-bearing Nav1.4 α subunit with (ii) site-directed mutagenesis (SDM), as well as (iii) electrophysiological experiments to study the structure and function of the ß1 subunit. Despite the distant phylogenic relationships, we found a 3D-template to identify two adjacent amino acids leading to the long-awaited loss of function (inactivation) of Nav1.4 channels. This mutant type (T109A, N110A, herein called TANA) was expressed and tested on cells of hamster ovary (CHO). The present electrophysiological results showed that the double alanine substitution TANA disrupted channel inactivation as if the ß1 subunit would not be in complex with the α subunit. Exhaustive and unbiased sampling of "all ß proteins" (Ig-like, Ig) resulted in a plethora of 3D templates which were compared to the target secondary structure prediction. The location of TANA was made possible thanks to another "all ß protein" structure in complex with an irreversible bound protein as well as a reversible protein-protein interface (our "Rosetta Stone" effect). This finding coincides with our electrophysiological data (disrupted ß1-like voltage dependence) and it is safe to utter that the Nav1.4 α/ß1 interface is likely to be of reversible nature.
RESUMO
Synaptic transmission in the sympathetic nervous system is a plastic process modulated by different factors. We characterized the effects of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) on basal transmission and ganglionic long-term potentiation (LTP) in the rat superior cervical ganglion. LTP was elicited by supramaximal tetanic stimulation (40 Hz, 3 s) of the sympathetic trunk and was quantified by measuring LTP decay time and LTP extent. Neurotrophins did not affect basal transmission, however, they differentially affected LTP. BDNF (200 ng/ml) increased LTP decay time and LTP extent 2.0-fold (p < 0.01). In contrast, NGF showed a dual effect: 200 ng/ml NGF reduced LTP decay time and LTP extent to 53% and to 32% of control value (p < 0.0001 and p < 0.02; respectively), whereas >350 ng/ml NGF significantly increased LTP decay time and LTP extent (p < 0.02). Digital analysis of compound action potentials suggests that neurotrophins could change the synchronization of unitary action potentials. Pharmacological data obtained in intact ganglia show that C2-ceramide produced a 2-fold enhancement in LTP, whereas tyrphostin AG879, an inhibitor of tyrosine kinase activity, reversed the NGF blockade and produced by itself an enhancement in LTP. In sliced ganglia we observed that an anti-TrkA antibody reversed the NGF-induced LTP blockade. Immunohistochemistry studies revealed that 83% of ganglionic neurons express TrkA, whereas 52% express p75 receptor, and 18% express TrkB receptor. We propose that p75 neurotrophin receptors and probably TrkB signaling enhance LTP, whereas TrkA signaling reduces it.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Fator de Crescimento Neural/farmacologia , Neurônios/efeitos dos fármacos , Gânglio Cervical Superior/citologia , Potenciais de Ação/efeitos dos fármacos , Animais , Ceramidas/farmacologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Masculino , Fator de Crescimento Neural/metabolismo , Proteínas do Tecido Nervoso , Ratos , Ratos Wistar , Receptor trkA/metabolismo , Receptor trkB/metabolismo , Receptores de Fatores de Crescimento , Receptores de Fator de Crescimento Neural/metabolismo , Tirfostinas/farmacologiaRESUMO
El tipo histológico más común de cáncer de tiroides es el cáncer papilar, comprende aproximadamente el 90% de la incidencia de cancer de tiroides. Alteraciones genéticas que incluyen reestructuraciones cromosómicas y mutaciones puntuales están implicadas en su patogénesis. las reestructuraciones cromosómicas incluyen reordenaciones del gen RET y del gen TRK, además de mutaciones puntuales en el gen BRAF y el gen RAS. Estas alteraciones genéticas que raramente ocurren simultaneamente en el tumor, producen señalizaciones aberrantes en la vía MAPK (mitogen-activated protón kinase). El desarrollo de nuevas modalidades terapéuticas en el cáncer de tiroides es crucial en aquellos tumores que han probado ser resistentes a la terapia con yodo radioactivo y a la supresión de hormona estimulante del tiroides.