Promoting Nigrostriatal Protection through the Intranasal Delivery of a GPER Agonist

• Autor(a) principal: Pinto, Hernâni dos Santos
• Data de Publicação: 2016
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.6/7189
• topic: Astrócito; Doença de Parkinson; G-1; Gper; Microglia; Neuroinflamação; Domínio/Área Científica::Ciências Médicas::Ciências Biomédicas

Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by progressive and preferential loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc). Estrogens have been recognized by their potential to protect dopaminergic neurons in PD. However, important side effects have been associated with estrogens therapy, mainly due to the activation of estrogen receptors alpha and beta, which discourages its use. The activation of cell survival pathways, together with the anti-inflammatory effects triggered by G protein– coupled estrogen receptor (GPER) activation makes this receptor a promising target for PD therapeutics avoiding most of the important side effects of estrogen therapy. We found that selective activation of GPER with G-1 protects neurons against the dopaminergic toxin MPP+/MPTP. GPER is expressed broadly and functions for GPER have been described in almost every physiological system, including reproductive, endocrine, urinary, immune, musculoskeletal and cardiovascular. Taking into consideration that the putative use of this agonists as protective strategy should be as specific as possible and that G-1 is a lipophilic molecule that rapidly diffuses through tissues we propose to test the effectiveness of the intranasal administration of this compound. We compared the effectiveness of delivering G-1 by subcutaneous injection and by intranasal administration in protecting the nigrostriatal pathway from a lesion induced by stereotaxic injection of lipopolysaccharide (LPS) bilaterally in the Substantia Nigra (SN). Besides evaluation of the lesion extent by tyrosine hydroxylase (TH) immunohistochemistry and the inflammatory effect through analysis of the microglial marker ionized calcium binding adaptor molecule 1 (iba-1) and astrocyte marker glial fibrillary acidic protein (GFAP), we also determined the capability of the two forms of G-1 administration to promote functional recovery of motor impairments induced by LPS by analyzing the motor behaviour of the animals with the Rota Rod and the Open Field test. Our results showed that both intranasal and subcutaneous delivery of G1 were efficient in controlling microglial reactivity and astrocyte activation in the LPS mice model. Concerning the dopaminergic protection, the results were less clear since in the experimental conditions used the extent of the dopaminergic lesion was very small, being insufficient to induce motor impairments.