The AMPA receptor positive allosteric modulator, S18986, is neuroprotective against neonatal excitotoxic and inflammatory brain damage through BDNF synthesis.
Brain lesions induced in newborn mice by the glutamatergic agonists ibotenate (acting on NMDA and metabotropic receptors) or S-willardiine (acting on AMPA-kainate receptors) mimic some aspects of periventricular white matter lesions and neocortical grey matter damage observed in human neonates at risk for developing cerebral palsy. The neonatal mouse brain can be sensitized to excitotoxic damage by IL-1beta exposure similar to that observed in the human situation. Positive modulators of AMPA receptors have received increasing attention as potential neuroprotective agents in a number of neurodegenerative disorders of the adult. However whether they can also act as a neuroprotectant in neonatal brain damage has yet to be defined. Therefore the present study uses a well-defined rodent model of neonatal excitotoxic brain lesions to assess the neuroprotective effects of S18986, a positive allosteric modulator of AMPA receptors, as well as its mechanisms of action. In this model, S18986 provided a dose-dependent and long-lasting protection of developing white matter and cortical grey matter against an excitotoxic insult and also when this was combined with a sensitizing inflammatory insult. Neuroprotective effects of S18986 in cortical grey matter involved decreased necrotic and apoptotic cell death. S18986-induced neuroprotection against NMDA receptor-mediated brain lesions was blocked by inhibitors of ERK and PI3 kinase-Akt pathways. S18986 effects were abolished by a neutralizing anti-BDNF antibody and real time PCR confirmed the stimulation by S18986 of BDNF production in the neonatal brain. The present study provides strong experimental support for the role of S18986 as a candidate molecule for therapy in cases of excitotoxic perinatal brain lesions and identifies BDNF as a key mediator of this S18986-mediated neuroprotection.
Destot-Wong
Kim-Da
KD
Inserm U676, Hôpital Robert Debré, 75019 Paris, France.
Liang
Kun
K
Gupta
Shailesh Kumar
SK
Favrais
Géraldine
G
Schwendimann
Leslie
L
Pansiot
Julien
J
Baud
Olivier
O
Spedding
Michael
M
Lelièvre
Vincent
V
Mani
Shyamala
S
Gressens
Pierre
P
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001581:Benzothiadiazines / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000503:physiopathology; D001927:Brain Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D019208:Brain-Derived Neurotrophic Factor / Q000276:immunology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D016202:N-Methylaspartate; D009336:Necrosis / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013997:Time Factors
D001581:Benzothiadiazines; D019208:Brain-Derived Neurotrophic Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D016202:N-Methylaspartate; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; C414205:S18986-1