title: Neuroprotective effects of toll-like receptor 4 antagonism in spinal cord cultures and in a mouse model of motor neuron degeneration.
abstract: Sustained inflammatory reactions are common pathological events associated with neuron loss in neurodegenerative diseases. Reported evidence suggests that Toll-like receptor 4 (TLR4) is a key player of neuroinflammation in several neurodegenerative diseases. However, the mechanisms by which TLR4 mediates neurotoxic signals remain poorly understood. We investigated the role of TLR4 in in vitro and in vivo settings of motor neuron degeneration. Using primary cultures from mouse spinal cords, we characterized both the proinflammatory and neurotoxic effects of TLR4 activation with lipopolysaccharide (activation of microglial cells, release of proinflammatory cytokines and motor neuron death) and the protective effects of a cyanobacteria-derived TLR4 antagonist (VB3323). With the use of TLR4-deficient cells, a critical role of the microglial component with functionally active TLR4 emerged in this setting. The in vivo experiments were carried out in a mouse model of spontaneous motor neuron degeneration, the wobbler mouse, where we preliminarily confirmed a protective effect of TLR4 antagonism. Compared with vehicle- and riluzole-treated mice, those chronically treated with VB3323 showed a decrease in microglial activation and morphological alterations of spinal cord neurons and a better performance in the paw abnormality and grip-strength tests. Taken together, our data add new understanding of the role of TLR4 in mediating neurotoxicity in the spinal cord and suggest that TLR4 antagonists could be considered in future studies as candidate protective agents for motor neurons in degenerative diseases.
authors.affiliation: Department of Environmental Health Sciences, Mario Negri Institute for Pharmacological Research, Milan, Italy. massimiliano.depaola@marionegri.it
authors.forename: Massimiliano
authors.initials: M
authors.lastname: De Paola
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mariani
authors.forename: Paolo
authors.initials: P
authors.lastname: Bigini
authors.forename: Marco
authors.initials: M
authors.lastname: Peviani
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ferrara
authors.forename: Monica
authors.initials: M
authors.lastname: Molteni
authors.forename: Sabrina
authors.initials: S
authors.lastname: Gemma
authors.forename: Pietro
authors.initials: P
authors.lastname: Veglianese
authors.forename: Valeria
authors.initials: V
authors.lastname: Castellaneta
authors.forename: Valentina
authors.initials: V
authors.lastname: Boldrin
authors.forename: Carlo
authors.initials: C
authors.lastname: Rossetti
authors.forename: Chiara
authors.initials: C
authors.lastname: Chiabrando
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mennini
authors.forename: Roberto
authors.initials: R
authors.lastname: Fanelli
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D008024:Ligands; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009132:Muscles / Q000187:drug effects / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D018696:Neuroprotective Agents / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D008024:Ligands; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D009498:Neurotoxins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha