Baosheng Huang1, Panhong Chen1, Lei Huang2,3, Shuai Li4, Ronglan Zhu5, Tao Sheng6, Wan Yu7, Zheng Chen1, Tianlu Wang1. 1. Department of Neurosurgery, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China. 2. Department of laboratory Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing, China. 3. National Key Clinical Department of Laboratory Medicine, Nanjing, China. 4. Department of Neurosurgery, Nanjing Jiangning Hospital, Nanjing Medical University, Nanjing, China. 5. Department of Neurosurgery, Jiangxi Provincial People's Hospital, Nanchang, China. 6. Institute of Virology, Wenzhou University, Chashan University Town, Wenzhou, China. 7. Department of Neurosurgery, Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing, China.
Abstract
BACKGROUND/AIMS: Calcium-permeable ionotropic NMDAR-mediated hyperactivity is regarded as the critical factor in modulating the development of ischaemic stroke. Recently, there has been increasing interest in preventing post-stroke neuronal death by focusing on intervening in the function of subpopulations of NMDARs and their downstream signalling. Geniposide, an iridoid glycoside, has been found to have cytoprotective functions in various conditions. However, it is still unclear whether and how geniposide affects neuronal insult under experimental stroke. METHODS: We demonstrate that dose-dependent geniposide significantly decreased the infarct volume in tMCAO models. RESULTS: A medium level of geniposide improved anti-apoptotic functions and inhibited BBB leakage/haemorrhage via elevating GluN2A-containing NMDAR expression in tMCAO rats. Importantly, these effects could be eliminated by co-treatment of geniposide with the GluN2A antagonist NVP but not the GluN2B inhibitor ifenprodil. Moreover, geniposide's protection was due to the enhancement of GluN2A-dependent survival signals, including pAKT, pERK and PSD-95. CONCLUSION: The results suggest that geniposide protects neurons against post-ischaemic neurovascular injury through the activation of GluN2A/AKT/ERK pathways. As a very promising natural agent, geniposide may be a future therapeutic for stroke patients.
BACKGROUND/AIMS: Calcium-permeable ionotropic NMDAR-mediated hyperactivity is regarded as the critical factor in modulating the development of ischaemic stroke. Recently, there has been increasing interest in preventing post-stroke neuronal death by focusing on intervening in the function of subpopulations of NMDARs and their downstream signalling. Geniposide, an iridoid glycoside, has been found to have cytoprotective functions in various conditions. However, it is still unclear whether and how geniposide affects neuronal insult under experimental stroke. METHODS: We demonstrate that dose-dependent geniposide significantly decreased the infarct volume in tMCAO models. RESULTS: A medium level of geniposide improved anti-apoptotic functions and inhibited BBB leakage/haemorrhage via elevating GluN2A-containing NMDAR expression in tMCAOrats. Importantly, these effects could be eliminated by co-treatment of geniposide with the GluN2A antagonist NVP but not the GluN2B inhibitor ifenprodil. Moreover, geniposide's protection was due to the enhancement of GluN2A-dependent survival signals, including pAKT, pERK and PSD-95. CONCLUSION: The results suggest that geniposide protects neurons against post-ischaemic neurovascular injury through the activation of GluN2A/AKT/ERK pathways. As a very promising natural agent, geniposide may be a future therapeutic for strokepatients.
Authors: Magda Gioia; Chiara Ciaccio; Paolo Calligari; Giovanna De Simone; Diego Sbardella; Grazia Tundo; Giovanni Francesco Fasciglione; Alessandra Di Masi; Donato Di Pierro; Alessio Bocedi; Paolo Ascenzi; Massimo Coletta Journal: Biochem Pharmacol Date: 2020-09-19 Impact factor: 5.858