2024-03-29T23:39:14Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/2222612021-06-21T12:27:19Zcom_10261_22com_10261_1col_10261_275
2020-11-04T12:03:27Z
urn:hdl:10261/222261
Melatonin-sulforaphane hybrid ITH12674 attenuates glial response in vivo by blocking LPS binding to MD2 and receptor oligomerization
Michalska, Patrycja
Buendía Abaitua, Izaskun
Duarte, Pablo
Fernández-Mendívil, Cristina
Negredo, Pilar
Cuadrado, Antonio
López, Manuela G.
León, Rafael
Instituto de Salud Carlos III
Fundación "la Caixa"
Comunidad de Madrid
Agencia Estatal de Investigación (España)
Ministerio de Ciencia, Innovación y Universidades (España)
Ministerio de Educación, Cultura y Deporte (España)
Instituto Fundación Teófilo Hernando
European Commission
Ministerio de Economía y Competitividad (España)
Neuroinflammation
Neurodegenerative diseases
MD2 antagonist
TLR4 inhibitor
Antiinflammatory properties
Multi-target
Neuroinflammation is increasingly associated to the onset and progression of neurodegenerative diseases. Furthermore, several lines of evidence have demonstrated the capacity of aberrant protein aggregates to activate the immune response, accelerating the advance of the disease. Compound ITH12674 is a melatonin-sulforaphane hybrid designed to exert a dual drug-prodrug mechanism of action that combines potent NRF2 induction and free radical scavenger activity. ITH12674 also showed neuroprotective properties in oxidative stress related models, that were dependant on its NRF2 inducing properties. Given the high impact of neuroinflammation in the pathogenesis of neurodegeneration, we foresaw to study the anti-inflammatory properties of ITH12674. ITH12674 reduced inflammatory markers in glial cell cultures and hippocampal tissue after LPS administration. The anti-inflammatory effect was related to inhibition of TLR4 receptors due to a direct interaction with the TLR4/MD2 complex at the hydrophobic cavity of MD2. ITH12674 is endowed with anti-inflammatory properties, that are complementary to the NRF2 inducing activity and neuroprotective properties. Thus, ITH12674 could be of potential interest for the treatment of diseases with chronic neuroinflammation.
2020-11-04T12:03:27Z
2020-11-04T12:03:27Z
2020
artículo
Pharmacological Research 152: 104597 (2020)
1043-6618
http://hdl.handle.net/10261/222261
10.1016/j.phrs.2019.104597
http://dx.doi.org/10.13039/501100000780
http://dx.doi.org/10.13039/501100004587
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/501100003176
http://dx.doi.org/10.13039/100012818
http://dx.doi.org/10.13039/501100011033
eng
https://doi.org/10.1016/j.phrs.2019.104597
Sí
B2017/BMD-3827/NRF24AD-CM
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-095793-B-I00
RTI2018-095793-B-I00/AEI/10.13039/501100011033
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/FJCI-2016/28282
closedAccess
Elsevier