Agonistas dos receptores GLP-1 e GIP no tratamento da doença de Parkinson: revisão sistemática translacional e meta-análise de estudos clínicos e pré-clínicos
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2022-02-28
Autores
Vaccari, Carolina
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Universidade Estadual Paulista (Unesp)
Resumo
A Doença de Parkinson (DP) é uma condição neurodegenerativa progressiva e heterogênea na qual são observados, em intensidades variáveis, sinais motores e não motores. Apesar de por muito tempo ter sido essencialmente associada à morte de neurônios dopaminérgicos da substantia nigra pars compacta e diminuição dos níveis de dopamina estriatais, a DP têm se mostrado um distúrbio mais disseminado, com o envolvimento de outros neurotransmissores e interação entre o acúmulo de uma proteína anômala, a α-sinucleína, e o sistema imunológico. Independente do seu subtipo, ainda não há cura para a DP. Levodopa e medicamentos dopaminérgicos são utilizados como tratamento sintomático e não como agentes modificadores da doença. Recentemente, o Diabetes Mellitus tipo II (DMT2) tem sido associado a sintomas mais graves e progressão acelerada da DP, sugerindo possível ligação entre essas duas condições. Medicamentos utilizados ou mapeados como tratamento para a DMT2 têm sido sugeridos como possíveis tratamentos da DP, a exemplo dos agonistas dos receptores GLP-1 e GIP. Além de importantes para o controle glicêmico, a ativação desses receptores no sistema nervoso central pode estar envolvida em processos como autofagia, apoptose, função mitocondrial e neuroinflamação, bem como no aprendizado, memória e modulação da plasticidade sináptica. Este trabalho objetivou avaliar a força e o peso das evidências sobre a eficácia e segurança dos agonistas desses receptores no tratamento da DP por meio de revisão sistemática e metanálise de estudos clínicos e pré-clínicos. O risco de viés dos estudos clínicos foi avaliado pela ferramenta Cochrane (RoB 2) e dos estudos pré-clínicos por uma versão adaptada das ferramentas SYRCLE e CAMARADES. O sistema GRADE foi usado para classificar o nível de confiança dos estudos clínicos. Possíveis efeitos anti-parkinsonianos (avaliados pela melhora na atividade locomotora espontânea, coordenação, equilíbrio e força muscular) foram detectados em roedores por diferentes modelos de DP e diferentes esquemas de tratamento com os agonistas dos receptores GLP-1 e GIP. Já em ensaios clínicos (considerados baixo nível de evidência pelo GRADE), houve melhora significativa na atividade locomotora de pacientes com DP após tratamento com a exenatida, um dos agonistas do receptor GLP-1, após a retirada do medicamento por algumas semanas (washout). Tanto os estudos pré-clínicos como os clínicos aqui analisados apresentam limitações e vieses importantes, impedindo definir se os efeitos dos agonistas estudados são neuroprotetores ou sintomáticos. Estudos experimentais mais bem delineados e ensaios clínicos com maior período de washout são necessários para avançarmos no esclarecimento da ação desses potenciais fármacos para a DP.
Parkinson's Disease (PD) is a progressive and heterogeneous neurodegenerative condition in which motor and non-motor signs are observed at varying intensities. Although for a long time it has been primarily associated with the death of substantia nigra pars compacta dopaminergic neurons and decreased striatal dopamine levels, PD has been shown to be a more widespread disorder with the involvement of other neurotransmitters and an interaction between the accumulation of an anomalous protein, α-synuclein, and the immune system. Regardless of the subtype, there is still no cure for PD. Levodopa and dopaminergic drugs are used as symptomatic treatment rather than disease modifying agents. More recently, type II Diabetes Mellitus (DMT2) has been associated with more severe symptoms and accelerated progression of PD, revealing a possible link between these two. Medications used or mapped as a treatment for T2DM have been suggested as possible treatments for PD, such as GLP-1 and GIP receptor agonists. In addition to being important for glycemic control, the activation of these receptors in the central nervous system may be involved in processes such as autophagy, apoptosis, mitochondrial function and neuroinflammation, as well as in learning, memory and modulation of synaptic plasticity. This study aimed to evaluate the efficacy and safety of these receptor agonists in the treatment of PD through a systematic review and meta-analysis of clinical and preclinical studies. The risk of bias of clinical studies was assessed by the Cochrane tool (RoB 2) and the preclinical studies by an adapted version of the SYRCLE and CAMARADES tools; GRADE was used for the certainty of the evidence of clinical studies. Possible anti-parkinsonian effects (improvement in spontaneous locomotor activity, coordination, balance, and muscle strength) were detected in rodents by different PD lesion models and different treatment regimens with GLP-1 and GIP receptor agonists. In clinical trials (ranked as low levels of certainty evidence by GRADE), there was significant improvement in locomotor activity in PD patients treated with exenatide, one of the GLP-1 receptor agonists, after drug withdrawal for a few weeks (washout). Both the preclinical and clinical studies analyzed here have important limitations and/or biases, preventing us from defining whether the effects of the agonists are neuroprotective or symptomatic. Better-designed experimental studies and clinical trials with a longer washout period are necessary to advance in the clarification on the action of these potential drugs for PD.
Parkinson's Disease (PD) is a progressive and heterogeneous neurodegenerative condition in which motor and non-motor signs are observed at varying intensities. Although for a long time it has been primarily associated with the death of substantia nigra pars compacta dopaminergic neurons and decreased striatal dopamine levels, PD has been shown to be a more widespread disorder with the involvement of other neurotransmitters and an interaction between the accumulation of an anomalous protein, α-synuclein, and the immune system. Regardless of the subtype, there is still no cure for PD. Levodopa and dopaminergic drugs are used as symptomatic treatment rather than disease modifying agents. More recently, type II Diabetes Mellitus (DMT2) has been associated with more severe symptoms and accelerated progression of PD, revealing a possible link between these two. Medications used or mapped as a treatment for T2DM have been suggested as possible treatments for PD, such as GLP-1 and GIP receptor agonists. In addition to being important for glycemic control, the activation of these receptors in the central nervous system may be involved in processes such as autophagy, apoptosis, mitochondrial function and neuroinflammation, as well as in learning, memory and modulation of synaptic plasticity. This study aimed to evaluate the efficacy and safety of these receptor agonists in the treatment of PD through a systematic review and meta-analysis of clinical and preclinical studies. The risk of bias of clinical studies was assessed by the Cochrane tool (RoB 2) and the preclinical studies by an adapted version of the SYRCLE and CAMARADES tools; GRADE was used for the certainty of the evidence of clinical studies. Possible anti-parkinsonian effects (improvement in spontaneous locomotor activity, coordination, balance, and muscle strength) were detected in rodents by different PD lesion models and different treatment regimens with GLP-1 and GIP receptor agonists. In clinical trials (ranked as low levels of certainty evidence by GRADE), there was significant improvement in locomotor activity in PD patients treated with exenatide, one of the GLP-1 receptor agonists, after drug withdrawal for a few weeks (washout). Both the preclinical and clinical studies analyzed here have important limitations and/or biases, preventing us from defining whether the effects of the agonists are neuroprotective or symptomatic. Better-designed experimental studies and clinical trials with a longer washout period are necessary to advance in the clarification on the action of these potential drugs for PD.
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Revisão sistemática, Metanálise, GLP-1, GIP, Doença de Parkinson, Estudo clínico