TY - JOUR
T1 - Synthetic and natural small molecule TLR4 antagonists inhibit motoneuron death in cultures from ALS mouse model
AU - De Paola, Massimiliano
AU - Sestito, Stefania E.
AU - Mariani, Alessandro
AU - Memo, Christian
AU - Fanelli, Roberto
AU - Freschi, Mattia
AU - Bendotti, Caterina
AU - Calabrese, Valentina
AU - Peri, Francesco
PY - 2016/1/1
Y1 - 2016/1/1
N2 - Increasing evidence indicates that inflammatory responses could play a critical role in the pathogenesis of motor neuron injury in amyotrophic lateral sclerosis (ALS). Recent findings have underlined the role of Toll-like receptors (TLRs) and the involvement of both the innate and adaptive immune responses in ALS pathogenesis. In particular, abnormal TLR4 signaling in pro-inflammatory microglia cells has been related to motoneuron degeneration leading to ALS. In this study the effect of small molecule TLR4 antagonists on in vitro ALS models has been investigated. Two different types of synthetic glycolipids and the phenol fraction extracted from commercial extra-virgin olive oil (EVOO) were selected since they efficiently inhibit TLR4 stimulus in HEK cells by interacting with the TLR4·MD-2 complex and CD14 co-receptor. Here, TLR4 antagonists efficiently protected motoneurons from LPS-induced lethality in spinal cord cultures, and inhibited the interleukine-1β production by LPS-stimulated microglia. In motoneurons/glia cocultures obtained from wild type or SOD1 G93A mice, motoneuron death induced by SOD1mut glia was counteracted by TLR4 antagonists. The release of nitric oxide by LPS treatment or SOD1mut glia was also inhibited by EVOO, suggesting that the action of this natural extract could be mainly related to the modulation of this inflammatory mediator.
AB - Increasing evidence indicates that inflammatory responses could play a critical role in the pathogenesis of motor neuron injury in amyotrophic lateral sclerosis (ALS). Recent findings have underlined the role of Toll-like receptors (TLRs) and the involvement of both the innate and adaptive immune responses in ALS pathogenesis. In particular, abnormal TLR4 signaling in pro-inflammatory microglia cells has been related to motoneuron degeneration leading to ALS. In this study the effect of small molecule TLR4 antagonists on in vitro ALS models has been investigated. Two different types of synthetic glycolipids and the phenol fraction extracted from commercial extra-virgin olive oil (EVOO) were selected since they efficiently inhibit TLR4 stimulus in HEK cells by interacting with the TLR4·MD-2 complex and CD14 co-receptor. Here, TLR4 antagonists efficiently protected motoneurons from LPS-induced lethality in spinal cord cultures, and inhibited the interleukine-1β production by LPS-stimulated microglia. In motoneurons/glia cocultures obtained from wild type or SOD1 G93A mice, motoneuron death induced by SOD1mut glia was counteracted by TLR4 antagonists. The release of nitric oxide by LPS treatment or SOD1mut glia was also inhibited by EVOO, suggesting that the action of this natural extract could be mainly related to the modulation of this inflammatory mediator.
KW - Amyotrophic lateral sclerosis (ALS)
KW - Extra virgin olive oil
KW - Inflammation
KW - Microgliaa
KW - Motoneuron
KW - TLR4
UR - http://www.scopus.com/inward/record.url?scp=84949595598&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84949595598&partnerID=8YFLogxK
U2 - 10.1016/j.phrs.2015.11.020
DO - 10.1016/j.phrs.2015.11.020
M3 - Article
AN - SCOPUS:84949595598
VL - 103
SP - 180
EP - 187
JO - Pharmacological Research
JF - Pharmacological Research
SN - 1043-6618
ER -