2-Aminotetraline derivative protects from ischemia/reperfusion brain injury with a broad therapeutic window.
The effect of ST1942, a 2-aminotetraline derivative with anti-inflammatory properties, was evaluated in ischemia/reperfusion injury in CD1 and C57BL/6 mice. ST1942 or saline were injected intraperitoneally 30 min and 6, 24, 36 h after ischemia. Forty-eight hours after ischemia, ST1942 (25 mg/kg) reduced the infarct volume by 50% in CD1 and 61% in C57BL/6 mice. All subsequent data were obtained from the latter strain. The ischemic lesion was significantly reduced by 30% when the first injection was administered 6 h after ischemia, revealing a broad effective window. Degenerating neurons in striatum, cortex and hippocampus of ischemic mice were markedly decreased by ST1942. Also examined was the effect of ST1942 on general and focal neurological deficits for 4 days after ischemia. Mice receiving the drug twice daily showed constantly reduced deficits. We then investigated the cortical mRNA expression of some inflammatory and apoptotic genes by real-time PCR. Forty-eight hours after ischemia ST1942 treatment significantly counteracted ischemia-induced activation of IL-1beta, TNFalpha, and Bax, and enhanced the expression of the antiapoptotic gene, Bcl-2, showing in vivo anti-inflammatory and antiapoptotic actions. The microglial activation/macrophage recruitment in the ischemic lesion was strongly prevented in mice receiving ST1942. In neuron-microglia cocultures, ST1942 significantly counteracted LPS-induced cytotoxicity. Binding data and experiments on microglial cell cultures indicate that the anti-inflammatory effect of ST1942 may be due to its action on 5-HT2B receptors, thus highlighting the possibility that this 5-HT receptor subtype may represent a novel target for neuroprotective drugs in ischemic injury.
Capone
Carmen
C
Department of Neuroscience, Laboratory of Inflammation and Nervous System Diseases, Mario Negri Institute, Milan, Italy.
Fabrizi
Cinzia
C
Piovesan
Paola
P
Principato
Maria Cristina
MC
Marzorati
Patrizia
P
Ghirardi
Orlando
O
Fumagalli
Lorenzo
L
Carminati
Paolo
P
De Simoni
Maria Grazia
MG
D000662:Amphetamines / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001927:Brain Diseases / Q000517:prevention & control*; D016466:CHO Cells; D002560:Cerebrovascular Circulation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005452:Fluoresceins; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000473:pathology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009930:Organic Chemicals; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D044403:Receptor, Serotonin, 5-HT2B / Q000187:drug effects; D015427:Reperfusion Injury / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D000662:Amphetamines; D018076:DNA, Complementary; D005452:Fluoresceins; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D009930:Organic Chemicals; D012333:RNA, Messenger; D044403:Receptor, Serotonin, 5-HT2B; C521408:ST-1942; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013764:Tetrahydronaphthalenes; C435731:fluoro jade; C006561:2-aminotetralin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine