Neuroprotective effect of the new thiadiazolidinone NP00111 against oxygen-glucose deprivation in rat hippocampal slices: implication of ERK1/2 and PPARgamma receptors.
Thiadiazolidinones (TDZDs) are small molecules that inhibit glycogen synthase kinase 3-beta (GSK3-beta) activity in a non competitive manner to ATP. NP00111, a new TDZD, besides causing inhibition of GSK-3beta, has also shown to be an agonist of PPARgamma . Since phosphorylation and consequent inhibition of GSK-3beta by PI-3K/Akt and agonism of PPARgamma have shown to afford neuroprotection in several in vitro and in vivo models, we have studied the potential neuroprotective effect of NP00111 in an "in vitro" model of ischemia-reperfusion. NP00111, at the concentration of 10 microM, significantly protected adult rat hippocampal slices subjected to oxygen and glucose deprivation (OGD) for 1 h followed by 3 h re-oxygenation, measured as lactic dehydrogenase (LDH) released to the extracellular media. The protective effects of NP00111 were more pronounced during the re-oxygenation period in comparison to the OGD period. Other GSK-3beta inhibitors like lithium or AR-A014418 did not afford protection in this model. However, the PPARgamma agonist rosiglitazone was protective at 3 microM. Protection afforded by NP00111 and rosiglitazone were prevented by the PPARgamma antagonist GW9662, suggesting that both NP00111 and rosiglitazone were preventing cell death caused by oxygen-glucose deprivation via activation of PPARgamma. NP00111 increased by two fold phosphorylation of ERK1/2 and its protective effects were lost when the hippocampal slices were co-incubated with the mitogen-activated protein kinase (MAPK) inhibitor PD98059. In conclusion, the novel TDZD NP00111 was protective against OGD in rat hippocampal slices by a mechanism related to phosphorylation of ERK1/2 via activation of PPARgamma.
Rosa
Angelo O
AO
Departamento de Farmacología y Terapéutica, Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Spain.
Egea
Javier
J
Martínez
Ana
A
García
Antonio G
AG
López
Manuela G
MG
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000077154:Rosiglitazone; D013830:Thiadiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000494:pharmacology
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D004791:Enzyme Inhibitors; C530042:NP00111; D018696:Neuroprotective Agents; D047495:PPAR gamma; D013830:Thiadiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D007770:L-Lactate Dehydrogenase; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D005947:Glucose