Document details

Unraveling the role of microRNA-92 in Painful Diabetic Neuropathy

Author(s): Campos, Anita Joana de Araújo

Date: 2015

Persistent ID: http://hdl.handle.net/10400.22/9785

Origin: Repositório Científico do Instituto Politécnico do Porto

Subject(s): microRNA-92; medula espinhal; neuropatia diabética dolorosa; nocicepção mecânica; Domínio/Área Científica::Ciências Médicas::Ciências da Saúde; Domínio/Área Científica::Ciências Médicas::Ciências da Saúde; Domínio/Área Científica::Ciências Médicas::Ciências da Saúde


Description

Diabetes Mellitus (diabetes) is a disease characterized by hyperglycemia resulting from defects in insulin secretion and/or its action, associated with several acute and chronic complications that affects the life quality of the patients. One of the most common complications of diabetes is Painful Diabetic Neuropathy (PDN), being the fifth main cause of chronic pain worldwide and causing a very debilitating condition. PDN is characterized by mechanical hyperalgesia and tactile allodynia and is accompanied by functional and neurochemical changes at peripheral and central nervous system. Currently, there are no efficient treatments for this disease since they are based on symptoms’ prevention and management, and may present side effects. During PDN there is a loss of γaminobutyric acid (GABA)-mediated pain inhibition which was shown to be due to a reversal in chloride neuronal flux induced by the downregulation in + − cotransporter 2 (KCC2). STZdiabetic rats have been shown to exhibit a significant decrease in KCC2 expression at the spinal cord leading to an increase in chloride intracellular concentration and a reversal shift of GABA’s properties. Recently, selective inhibition of miR-92, using a mir-92 sponge lentiviral vector approach was shown to prevent the decrease in KCC2 hippocampal expression. In this context, considering the role of miR-92 on the regulation of KCC2 expression and the impairments reported in this cotransporter in the spinal cord during diabetes, it is important to evaluate the possible pain-relieving therapeutic potential of silencing miR-92 in STZ-diabetic rats with PDN and to evaluate the role of KCC2 and GABA as possible mediators of the actions of silencing miR-92. In our study, it is shown that selective inhibition of miR-92 in STZ-diabetic rats with PDN, increases spinal cord KCC2 expression and reduces mechanical nociception, pointing for a key role of miR-92 and KCC2 in spinal pain abnormal nociceptive processing during PDN. Besides, it was possible to show, through a pharmacological study, that the results abovementioned depend on KCC2 and GABA, corroborating previous studies on their involvement in PDN. Preliminary in vitro studies were also undertaken to evaluate if inflammation may interfere with miR-92 and KCC2 neuronal expression. Although these preliminary results are not conclusive, they suggest a role for inflammation on KCC2 expression. In conclusion, this project has identified a potential therapeutic target for reversal of the excitatory changes in spinal nociceptive transmission occurring during PDN.

Document Type Master thesis
Language English
Advisor(s) Oliveira, Sandra Marisa; Fernandes, Rúben
Contributor(s) Campos, Anita Joana de Araújo
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