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1.
J Alzheimers Dis ; 88(4): 1585-1603, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35811522

RESUMO

BACKGROUND: Human diseases are multi-factorial biological phenomena resulting from perturbations of numerous functional networks. The complex nature of human diseases explains frequently observed marginal or transitory efficacy of mono-therapeutic interventions. For this reason, combination therapy is being increasingly evaluated as a biologically plausible strategy for reversing disease state, fostering the development of dedicated methodological and experimental approaches. In parallel, genome-wide association studies (GWAS) provide a prominent opportunity for disclosing human-specific therapeutic targets and rational drug repurposing. OBJECTIVE: In this context, our objective was to elaborate an integrated computational platform to accelerate discovery and experimental validation of synergistic combinations of repurposed drugs for treatment of common human diseases. METHODS: The proposed approach combines adapted statistical analysis of GWAS data, pathway-based functional annotation of genetic findings using gene set enrichment technique, computational reconstruction of signaling networks enriched in disease-associated genes, selection of candidate repurposed drugs and proof-of-concept combinational experimental screening. RESULTS: It enables robust identification of signaling pathways enriched in disease susceptibility loci. Therapeutic targeting of the disease-associated signaling networks provides a reliable way for rational drug repurposing and rapid development of synergistic drug combinations for common human diseases. CONCLUSION: Here we demonstrate the feasibility and efficacy of the proposed approach with an experiment application to Alzheimer's disease.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Reposicionamento de Medicamentos , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Humanos
2.
Sci Rep ; 5: 16084, 2015 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-26542636

RESUMO

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by the loss of dopaminergic nigrostriatal neurons but which involves the loss of additional neurotransmitter pathways. Mono- or polytherapeutic interventions in PD patients have declining efficacy long-term and no influence on disease progression. The systematic analysis of available genetic and functional data as well as the substantial overlap between Alzheimer's disease (AD) and PD features led us to repurpose and explore the effectiveness of a combination therapy (ABC) with two drugs - acamprosate and baclofen - that was already effective in AD animal models, for the treatment of PD. We showed in vitro that ABC strongly and synergistically protected neuronal cells from oxidative stress in the oxygen and glucose deprivation model, as well as dopaminergic neurons from cell death in the 6-hydroxydopamine (6-OHDA) rat model. Furthermore, we showed that ABC normalised altered motor symptoms in vivo in 6-OHDA-treated rats, acting by protecting dopaminergic cell bodies and their striatal terminals. Interestingly, ABC also restored a normal behaviour pattern in lesioned rats suggesting a symptomatic effect, and did not negatively interact with L-dopa. Our results demonstrate the potential value of combining repurposed drugs as a promising new strategy to treat this debilitating disease.


Assuntos
Baclofeno/farmacologia , Doença de Parkinson/tratamento farmacológico , Taurina/análogos & derivados , Acamprosato , Animais , Células Cultivadas , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Quimioterapia Combinada/métodos , Feminino , Masculino , Degeneração Neural/tratamento farmacológico , Degeneração Neural/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxidopamina/metabolismo , Doença de Parkinson/metabolismo , Ratos , Ratos Wistar , Taurina/farmacologia
3.
Sci Rep ; 5: 7608, 2015 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-25566747

RESUMO

Alzheimer disease (AD) represents a major medical problem where mono-therapeutic interventions demonstrated only a limited efficacy so far. We explored the possibility of developing a combinational therapy that might prevent the degradation of neuronal and endothelial structures in this disease. We argued that the distorted balance between excitatory (glutamate) and inhibitory (GABA/glycine) systems constitutes a therapeutic target for such intervention. We found that a combination of two approved drugs - acamprosate and baclofen - synergistically protected neurons and endothelial structures in vitro against amyloid-beta (Aß) oligomers. The neuroprotective effects of these drugs were mediated by modulation of targets in GABA/glycinergic and glutamatergic pathways. In vivo, the combination alleviated cognitive deficits in the acute Aß25-35 peptide injection model and in the mouse mutant APP transgenic model. Several patterns altered in AD were also synergistically normalised. Our results open up the possibility for a promising therapeutic approach for AD by combining repurposed drugs.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Baclofeno/uso terapêutico , Reposicionamento de Medicamentos , Taurina/análogos & derivados , Acamprosato , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Apoptose/efeitos dos fármacos , Baclofeno/farmacologia , Células Cultivadas , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/toxicidade , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Taurina/farmacologia , Taurina/uso terapêutico
4.
Orphanet J Rare Dis ; 9: 201, 2014 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-25491744

RESUMO

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited sensory and motor peripheral neuropathy. It is caused by PMP22 overexpression which leads to defects of peripheral myelination, loss of long axons, and progressive impairment then disability. There is no treatment available despite observations that monotherapeutic interventions slow progression in rodent models. We thus hypothesized that a polytherapeutic approach using several drugs, previously approved for other diseases, could be beneficial by simultaneously targeting PMP22 and pathways important for myelination and axonal integrity. A combination of drugs for CMT1A polytherapy was chosen from a group of authorised drugs for unrelated diseases using a systems biology approach, followed by pharmacological safety considerations. Testing and proof of synergism of these drugs were performed in a co-culture model of DRG neurons and Schwann cells derived from a Pmp22 transgenic rat model of CMT1A. Their ability to lower Pmp22 mRNA in Schwann cells relative to house-keeping genes or to a second myelin transcript (Mpz) was assessed in a clonal cell line expressing these genes. Finally in vivo efficacy of the combination was tested in two models: CMT1A transgenic rats, and mice that recover from a nerve crush injury, a model to assess neuroprotection and regeneration. Combination of (RS)-baclofen, naltrexone hydrochloride and D-sorbitol, termed PXT3003, improved myelination in the Pmp22 transgenic co-culture cellular model, and moderately down-regulated Pmp22 mRNA expression in Schwannoma cells. In both in vitro systems, the combination of drugs was revealed to possess synergistic effects, which provided the rationale for in vivo clinical testing of rodent models. In Pmp22 transgenic CMT1A rats, PXT3003 down-regulated the Pmp22 to Mpz mRNA ratio, improved myelination of small fibres, increased nerve conduction and ameliorated the clinical phenotype. PXT3003 also improved axonal regeneration and remyelination in the murine nerve crush model. Based on these observations in preclinical models, a clinical trial of PTX3003 in CMT1A, a neglected orphan disease, is warranted. If the efficacy of PTX3003 is confirmed, rational polytherapy based on novel combinations of existing non-toxic drugs with pleiotropic effects may represent a promising approach for rapid drug development.


Assuntos
Axônios/metabolismo , Doença de Charcot-Marie-Tooth/metabolismo , Modelos Animais de Doenças , Reposicionamento de Medicamentos/métodos , Proteínas da Mielina/biossíntese , Fibras Nervosas Mielinizadas/metabolismo , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Baclofeno/administração & dosagem , Doença de Charcot-Marie-Tooth/tratamento farmacológico , Doença de Charcot-Marie-Tooth/patologia , Técnicas de Cocultura , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Quimioterapia Combinada , Feminino , Regulação da Expressão Gênica , Masculino , Camundongos , Proteínas da Mielina/antagonistas & inibidores , Naltrexona/administração & dosagem , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Mielinizadas/patologia , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/metabolismo , Neuropatia Ciática/patologia , Sorbitol/administração & dosagem
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