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1.
ACS Med Chem Lett ; 7(5): 537-42, 2016 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-27190606

RESUMO

The orally bioavailable 1-deoxy-sphingosine analog, Enigmol, has demonstrated anticancer activity in numerous in vivo settings. However, as no Enigmol analog with enhanced potency in vitro has been identified, a new strategy to improve efficacy in vivo by increasing tumor uptake was adopted. Herein, synthesis and biological evaluation of two novel fluorinated Enigmol analogs, CF3-Enigmol and CF2-Enigmol, are reported. Each analog was equipotent to Enigmol in vitro, but achieved higher plasma and tissue levels than Enigmol in vivo. Although plasma and tissue exposures were anticipated to trend with fluorine content, CF2-Enigmol absorbed into tissue at strikingly higher concentrations than CF3-Enigmol. Using mouse xenograft models of prostate cancer, we also show that CF3-Enigmol underperformed Enigmol-mediated inhibition of tumor growth and elicited systemic toxicity. By contrast, CF2-Enigmol was not systemically toxic and demonstrated significantly enhanced antitumor activity as compared to Enigmol.

2.
Curr Cancer Drug Targets ; 14(4): 380-93, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24628271

RESUMO

The natural compound curcumin has been investigated as an anticancer agent in many cellular systems, in animal models and in the clinic. The overriding negative characteristics of curcumin are its low solubility, weak potency and poor bioavailability. We have examined the efficacy and mechanism of action of a synthetic curcumin analog, UBS109, in head and neck squamous cell carcinoma. By nephelometry, this analog exhibits considerably greater solubility than curcumin. Pharmacokinetic studies of a single oral dose of UBS109 in mice revealed that peak plasma concentrations were reached at 0.5 hours post-dose (Tmax) with average plasma concentrations (Cmax) of 131 and 248 ng/mL for oral doses of 50 and 150 mg/kg, respectively. The terminal elimination half-lives (T½) for these doses averaged 3.7 and 4.5 hours, respectively. In both in vitro and in vivo studies, we found that UBS109 decreased the levels of phosphorylated IKKß and phosphorylated p65 and, unexpectedly, increased the levels of phosphorylated IκBα by Western blot analysis. These observations may suggest that UBS109 suppresses tumor growth through, in part, inhibition of NF-κB p65 phosphorylation by PKAc and not through IκBα. Finally, we demonstrate that UBS109 is efficacious in retarding the growth of Tu212 (head and neck) squamous cell carcinoma (SCC) xenograft tumors in mice and may be useful for treating head and neck SCC tumors.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Curcumina/análogos & derivados , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Piperidonas/uso terapêutico , Piridinas/uso terapêutico , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Curcumina/metabolismo , Curcumina/farmacologia , Curcumina/uso terapêutico , Feminino , Meia-Vida , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Quinase I-kappa B/metabolismo , Camundongos Endogâmicos ICR , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Fosforilação/efeitos dos fármacos , Piperidonas/metabolismo , Piperidonas/farmacocinética , Piperidonas/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Piridinas/metabolismo , Piridinas/farmacocinética , Piridinas/farmacologia , Distribuição Aleatória , Organismos Livres de Patógenos Específicos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Fator de Transcrição RelA/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
ACS Med Chem Lett ; 4(11): 1025-30, 2013 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-24936240

RESUMO

A de novo hit-to-lead effort involving the redesign of benzimidazole-containing antagonists of the CXCR4 receptor resulted in the discovery of a novel series of 1,2,3,4-tetrahydroisoquinoline (TIQ) analogues. In general, this series of compounds show good potencies (3-650 nM) in assays involving CXCR4 function, including both inhibition of attachment of X4 HIV-1IIIB virus in MAGI-CCR5/CXCR4 cells and inhibition of calcium release in Chem-1 cells. Series profiling permitted the identification of TIQ-(R)-stereoisomer 15 as a potent and selective CXCR4 antagonist lead candidate with a promising in vitro profile. The drug-like properties of 15 were determined in ADME in vitro studies, revealing low metabolic liability potential. Further in vivo evaluations included pharmacokinetic experiments in rats and mice, where 15 was shown to have oral bioavailability (F = 63%) and resulted in the mobilization of white blood cells (WBCs) in a dose-dependent manner.

4.
J Med Chem ; 55(15): 6738-50, 2012 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-22746274

RESUMO

The hypoxia inducible factor (HIF) pathway is an attractive target for cancer, as it controls tumor adaptation to growth under hypoxia and mediates chemotherapy and radiation resistance. We previously discovered 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide as a novel, small-molecule HIF-1 pathway inhibitor in a high-throughput cell-based assay, but its in vivo delivery is hampered by poor aqueous solubility (0.009 µM in water; log P(7.4) = 3.7). Here we describe the synthesis of 12 N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, which were designed to possess optimal lipophilicities and aqueous solubilities by in silico calculations. Experimental log P(7.4) values of 8 of the 12 new analogs ranged from 1.2-3.1. Aqueous solubilities of three analogs were measured, among which the most soluble N-[(8-methoxy-2,2-dimethyl-2H-chromen-6-yl)methyl]-N-(propan-2-yl)pyridine-2-sulfonamide had an aqueous solubility of 80 µM, e.g., a solubility improvement of ∼9000-fold. The pharmacological optimization had limited impact on drug efficacy as the compounds retained IC(50) values at or below 5 µM in our HIF-dependent reporter assay.


Assuntos
Antineoplásicos/síntese química , Benzopiranos/síntese química , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Sulfonamidas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzopiranos/química , Benzopiranos/farmacologia , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos , Transdução de Sinais , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Transcrição Gênica/efeitos dos fármacos
5.
Integr Biol (Camb) ; 4(6): 633-40, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22532032

RESUMO

Objectives are to examine the efficacy, pharmacokinetics, and toxicology of a synthetic curcumin analog EF31 in head and neck squamous cell carcinoma. The synthesis of EF31 was described for the first time. Solubility of EF24 and EF31 was compared using nephelometric analysis. Human head and neck squamous cell carcinoma Tu212 xenograft tumors were established in athymic nude mice and treated with EF31 i.p. once daily five days a week for about 5-6 weeks. The long term effect of EF31 on the NF-κB signaling system in the tumors was examined by Western blot analysis. EF31 at 25 mg kg(-1), i.p. inhibited tumor growth almost completely. Solubilities of EF24 and EF31 are <10 and 13 µg mL(-1) or <32 and 47 µM, respectively. The serum chemistry profiles of treated mice were within the limits of normal, they revealed a linear increase of C(max). EF31 decreased the level of phosphorylation of NF-κB p65. In conclusion, the novel synthetic curcumin analog EF31 is efficacious in inhibiting the growth of Tu212 xenograft tumors and may be useful for treating head and neck squamous cell carcinoma. The long term EF31 treatment inhibited NF-κB p65 phosphorylation in xenografts, implicating downregulation of cancer promoting transcription factors such as angiogenesis and metastasis.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Curcumina/análogos & derivados , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Piperidonas/farmacologia , Animais , Western Blotting , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Sobrevivência Celular/efeitos dos fármacos , Curcumina/síntese química , Curcumina/química , Curcumina/farmacocinética , Curcumina/farmacologia , Feminino , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Nus , Fosforilação/efeitos dos fármacos , Piperidonas/síntese química , Piperidonas/química , Piperidonas/farmacocinética , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Solubilidade , Organismos Livres de Patógenos Específicos , Fator de Transcrição RelA/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
6.
ACS Med Chem Lett ; 3(1): 43-7, 2012 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-24900369

RESUMO

Plasmodium-infected erythrocytes have been shown to employ sphingolipids from both endogenous metabolism as well as existing host pools. Therapeutic agents that limit these supplies have thus emerged as intriguing, mechanistically distinct putative targets for the treatment of malaria infections. In an initial screen of our library of sphingolipid pathway modulators for efficacy against two strains of the predominant human malaria species Plasmodium falciparum and Plasmodium knowlesi, a series of orally available, 1-deoxysphingoid bases were found to possess promising in vitro antimalarial activity. To better understand the structural requirements that are necessary for this observed activity, a second series of modified analogues were prepared and evaluated. Initial pharmacokinetic assessments of key analogues were investigated to evaluate plasma and red blood cell concentrations in vivo.

7.
ACS Med Chem Lett ; 3(5): 362-6, 2012 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-24900479

RESUMO

After more than 30 years of research and 30 failed clinical trials with as many different treatments, progesterone is the first agent to demonstrate robust clinical efficacy as a treatment for traumatic brain injuries. It is currently being investigated in two, independent phase III clinical trials in hospital settings; however, it presents a formidable solubility challenge that has so far prevented the identification of a formulation that would be suitable for emergency field response use or battlefield situations. Accordingly, we have designed and tested a novel series of water-soluble analogues that address this critical need. We report here the synthesis of C-20 oxime conjugates of progesterone as therapeutic agents for traumatic brain injuries with comparable efficacy in animal models of traumatic brain injury and improved solubility and pharmacokinetic profiles. Pharmacodynamic analysis reveals that a nonprogesterone steroidal analogue may be primarily responsible for the observed activity.

8.
ACS Med Chem Lett ; 2(6): 438-43, 2011 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-24900327

RESUMO

Enigmol is a synthetic, orally active 1-deoxysphingoid base analogue that has demonstrated promising activity against prostate cancer. In these studies, the pharmacologic roles of stereochemistry and N-methylation in the structure of enigmols were examined. A novel enantioselective synthesis of all four possible 2S-diastereoisomers of enigmol (2-aminooctadecane-3,5-diols) from l-alanine is reported, which features a Liebeskind-Srogl cross-coupling reaction between l-alanine thiol ester and (E)-pentadec-1-enylboronic acid as the key step. In vitro biological evaluation of the four enigmol diastereoisomers and 2S,3S,5S-N-methylenigmol against two prostate cancer cell lines (PC-3 and LNCaP) indicates that all but one diastereomer demonstrate potent oncolytic activity. In nude mouse xenograft models of human prostate cancer, enigmol was equally effective as standard prostate cancer therapies (androgen deprivation or docetaxel), and two of the enigmol diastereomers, 2S,3S,5R-enigmol and 2S,3R,5S-enigmol, also caused statistically significant inhibition of tumor growth. A pharmacokinetic profile of enigmol and N-methylenigmol is also presented.

9.
J Immunol Methods ; 343(1): 28-41, 2009 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-19187782

RESUMO

Monoclonal antibodies (mAbs) have proven to be effective biological reagents in the form of therapeutic drugs and diagnostics for many pathologies, as well as valuable research tools. Existing methods for isolating mAb-producing hybridomas are tedious and time consuming. Herein we describe a novel system in which mAb-secreting hybridoma cells were induced to co-express significant amounts of the membrane form of the secreted immunoglobulin (Ig) on their surfaces and are efficiently recovered by fluorescent activated cell sorting (FACS). Fusion of a novel myeloma parent, SP2ab, expressing transgenic Igalpha and Igbeta of the B-cell receptor complex (BCR) with spleen cells resulted in hybridomas demonstrating order of magnitude increases in BCR surface expression. Surface Ig levels correlated with transgenic Igalpha expression, and these cells also secreted normal levels of mAb. Hundreds of hybridoma lines producing mAbs specific for a variety of antigens were rapidly isolated as single cell-derived clones after FACS. Significant improvements using the Direct Selection of Hybridomas (DiSH) by FACS include reduced time and labor, improved capability of isolating positive hybridomas, and the ease of manipulating cloned cell lines relative to previously existing approaches that require Limiting Dilution Subcloning (LDS).


Assuntos
Anticorpos Monoclonais/biossíntese , Hibridomas/metabolismo , Cadeias Pesadas de Imunoglobulinas/metabolismo , Proteínas de Membrana/metabolismo , Animais , Fusão Celular , Linhagem Celular Tumoral , Citometria de Fluxo , Hibridomas/imunologia , Camundongos , Receptores de Antígenos de Linfócitos B/metabolismo
10.
Neurobiol Dis ; 19(1-2): 293-300, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15837585

RESUMO

The "slow Wallerian degeneration" (Wld(S)) gene is neuroprotective in numerous models of axonal degeneration. Axonal degeneration is an early feature of disease progression in the SOD1G93A mouse, a widely used model of familial amyotrophic lateral sclerosis (fALS). We crossed the Wld(S) mouse with the SOD1G93A mouse to investigate whether the Wld(S) gene could prolong survival and modify neuropathology in these mice. SOD/Wld(S) mice showed levels of motor axon loss similar to that seen in SOD1G93A mice. The presence of the Wld(S) gene, however, modestly prolonged survival and delayed denervation at the neuromuscular junction. Prolonged survival was more prominent in female mice and did not depend on whether animals were heterozygous or homozygous for the Wld(S) gene. We also report that SOD1G93A mice show significant degeneration of sensory axons during the course of disease, supporting previous data from humans demonstrating that ALS is not purely a motor disorder.


Assuntos
Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/terapia , Proteínas do Tecido Nervoso/genética , Superóxido Dismutase/biossíntese , Superóxido Dismutase/genética , Esclerose Lateral Amiotrófica/mortalidade , Animais , Axônios/metabolismo , Axônios/patologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes Neurológicos , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/fisiologia , Junção Neuromuscular/genética , Junção Neuromuscular/metabolismo , Junção Neuromuscular/patologia , Teste de Desempenho do Rota-Rod/métodos , Taxa de Sobrevida
11.
Brain ; 127(Pt 3): 671-9, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14761904

RESUMO

Taxol is a highly effective anticancer agent that causes peripheral neuropathy as its major toxic side effect. The neuropathy is characterized by degeneration of sensory axons that may be severe enough to be dose limiting. Axonal degeneration involves the activation of the calcium-activated proteases calpains, and here we tested whether systemic inhibition of calpains with the peptide alpha-ketoamide calpain inhibitor AK295 can reduce the clinical and pathological effects of Taxol in a rodent model of Taxol neuropathy. In mice with Taxol neuropathy, AK295 reduced the degree of axonal degeneration in sensory nerve roots, and improved clinical measures of neuropathy, including behavioural and electrophysiological function. These findings were consistent for both 3- and 6-week models of neuropathy. In vitro, Taxol caused activation of both calpains and caspases in PC12 cells. AK295 inhibited the activation of calpains but did not interfere with the antimitotic effects of Taxol on microtubules, nor did it inhibit caspase-mediated cell death. These data implicate calpains in the pathogenesis of Taxol neuropathy, and demonstrate that AK295 can prevent axonal degeneration and clinical neuropathy in mice. In addition, AK295 did not interfere with the primary antineoplastic effects of Taxol on microtubules and cell death, suggesting that systemic calpain inhibition may be a good strategy for preventing neuropathy in patients being treated with Taxol.


Assuntos
Antineoplásicos/toxicidade , Axônios/efeitos dos fármacos , Dipeptídeos/farmacologia , Degeneração Neural/induzido quimicamente , Paclitaxel/toxicidade , Animais , Axônios/metabolismo , Calpaína/antagonistas & inibidores , Calpaína/metabolismo , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Eletrofisiologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Microtúbulos/efeitos dos fármacos , Microtúbulos/ultraestrutura , Degeneração Neural/prevenção & controle , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/metabolismo , Neurônios Aferentes/ultraestrutura , Ratos , Ratos Endogâmicos
12.
Exp Neurol ; 185(2): 232-40, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14736504

RESUMO

The SOD1 mutant mouse is the most widely used model of human amyotrophic lateral sclerosis (ALS). To determine where and when the pathological changes of motor neuron disease begins, we performed a comprehensive spatiotemporal analysis of disease progression in SOD1(G93A) mice. Quantitative pathological analysis was performed in the same mice at multiple ages at neuromuscular junctions (NMJ), ventral roots, and spinal cord. In addition, a patient with sporadic ALS who died unexpectedly was examined at autopsy. Mice became clinically weak at 80 days and died at 131 +/- 5 days. At 47 days, 40% of end-plates were denervated whereas there was no evidence of ventral root or cell body loss. At 80 days, 60% of ventral root axons were lost but there was no loss of motor neurons. Motor neuron loss was well underway by 100 days. Microglial and astrocytic activation around motor neurons was not identified until after the onset of distal axon degeneration. Autopsy of the ALS patient demonstrated denervation and reinnervation changes in muscle but normal appearing motor neurons. We conclude that in this widely studied animal model of human ALS, and in this single human case, motor neuron pathology begins at the distal axon and proceeds in a "dying back" pattern.


Assuntos
Esclerose Lateral Amiotrófica/patologia , Axônios/patologia , Esclerose Lateral Amiotrófica/enzimologia , Esclerose Lateral Amiotrófica/genética , Animais , Axônios/enzimologia , Humanos , Masculino , Camundongos , Camundongos Mutantes , Camundongos Transgênicos , Superóxido Dismutase/biossíntese , Superóxido Dismutase/genética , Superóxido Dismutase-1 , Fatores de Tempo
13.
Ann Neurol ; 52(4): 442-7, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12325073

RESUMO

The WldS mouse is a unique mutant strain that demonstrates the remarkable phenotype of prolonged survival of transected axons ("slow Wallerian degeneration"). In these studies, we tested whether this neuroprotective phenotype extends to axonal degeneration seen in a progressive peripheral neuropathy. WldS and wild-type mice were intoxicated with the cancer chemotherapeutic agent paclitaxel (Taxol). The severity of the resultant sensory neuropathy was compared with behavioral, physiological, and pathological measures. WldS mice were resistant to paclitaxel neuropathy by all measures, and the resistance was because of protection against axonal degeneration. These studies demonstrate for the first time that the WldS mouse is more than a slow Wallerian degeneration phenotype, emphasizing the mechanistic link between Wallerian degeneration and peripheral neuropathy. Understanding how this mutant gene confers protection against axonal degeneration will provide important clues toward prevention of axonal degeneration in several human neurological disorders.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Paclitaxel/farmacologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Células Cultivadas , Feminino , Gânglios Espinais/citologia , Predisposição Genética para Doença , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/patologia , Neurônios Aferentes/ultraestrutura , Doenças do Sistema Nervoso Periférico/patologia , Fenótipo , Degeneração Walleriana/genética
14.
J Neurol Sci ; 196(1-2): 9-20, 2002 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-11959150

RESUMO

Peripheral nerve injury results in a series of events culminating in degradation of the axonal cytoskeleton (Wallerian degeneration). In the time period between axotomy and cytoskeletal degradation (24-48 h in rodents), there is calcium entry and activation of calpains within the axon. The precise timing of these events during this period is unknown. In the present study, antibodies were generated to three distinct peptide epitopes of m-calpain, and a fusion protein antibody was generated to the intrinsic calpain inhibitor calpastatin. These antibodies were used to measure changes in these proteins in mouse sciatic nerves during Wallerian degeneration. In sciatic nerve homogenates and cultured dorsal root ganglion (DRG) neurites, m-calpain protein was significantly reduced in transected nerves very early after nerve injury, long before axonal degeneration occurred. Levels of m-calpain protein remained low as compared to control nerves for the remainder of the 72-h time course. No changes in calpastatin protein were evident. Systemic treatment of animals with the protease inhibitor leupeptin partially prevented the rapid loss of calpain protein. Removal of calcium in DRG cultures had the same effect. These data indicate that m-calpain protein is lost very early after axonal injury, and likely reflect activation and degradation of this protein long before the cytoskeleton is degraded. Calpain activation may be an early event in a proteolytic cascade that is initiated by axonal injury and culminates with axonal degeneration.


Assuntos
Axônios/metabolismo , Calpaína/metabolismo , Citoesqueleto/metabolismo , Nervos Periféricos/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismo , Degeneração Walleriana/metabolismo , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Proteínas de Ligação ao Cálcio/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/imunologia , Proteínas de Ligação ao Cálcio/metabolismo , Calpaína/efeitos dos fármacos , Calpaína/imunologia , Membrana Celular/metabolismo , Citoesqueleto/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Leupeptinas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peptídeo Hidrolases/efeitos dos fármacos , Peptídeo Hidrolases/metabolismo , Nervos Periféricos/patologia , Nervos Periféricos/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Inibidores de Proteases/farmacologia , Coelhos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fatores de Tempo , Tubulina (Proteína)/metabolismo , Degeneração Walleriana/fisiopatologia
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