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.

De Paola, M., Sestito, S., Mariani, A., Memo, C., Fanelli, R., Freschi, M., et al. (2016). Synthetic and natural small molecule TLR4 antagonists inhibit motoneuron death in cultures from ALS mouse model. PHARMACOLOGICAL RESEARCH, 103, 180-187 [10.1016/j.phrs.2015.11.020].

Synthetic and natural small molecule TLR4 antagonists inhibit motoneuron death in cultures from ALS mouse model

SESTITO, STEFANIA ENZA
Secondo
;
CALABRESE, VALENTINA
Penultimo
;
PERI, FRANCESCO
Ultimo
2016

Abstract

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.
Articolo in rivista - Articolo scientifico
Amyotrophic lateral sclerosis (ALS); Extra virgin olive oil; Inflammation; Microgliaa; Motoneuron; TLR4;
Amyotrophic lateral sclerosis (ALS); Extra virgin olive oil; Inflammation; Microgliaa; Motoneuron; TLR4; Amyotrophic Lateral Sclerosis; Animals; Cell Death; Coculture Techniques; Disease Models, Animal; HEK293 Cells; Humans; Lipopolysaccharides; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Motor Neurons; Nitric Oxide; Olive Oil; Phenols; Spinal Cord; Superoxide Dismutase; Toll-Like Receptor 4; Pharmacology
English
2016
103
180
187
partially_open
De Paola, M., Sestito, S., Mariani, A., Memo, C., Fanelli, R., Freschi, M., et al. (2016). Synthetic and natural small molecule TLR4 antagonists inhibit motoneuron death in cultures from ALS mouse model. PHARMACOLOGICAL RESEARCH, 103, 180-187 [10.1016/j.phrs.2015.11.020].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/152483
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