Melatoninergic neuroprotection of the murine periventricular white matter against neonatal excitotoxic challenge.
Periventricular leukomalacia is one of the main causes of cerebral palsy. Perinatal white matter lesions associated with cerebral palsy appears to involve glutamate excitotoxicity and excess free radical production. When injected intracerebrally into newborn mice, the glutamatergic analog ibotenate induces white matter cysts mimicking human periventricular leukomalacia. Melatonin acts on specific receptors. It also exhibits intrinsic free radical scavenging properties. The goal of the present study is to determine whether melatonin can protect against excitotoxic lesions induced by ibotenate in newborn mice. Mice that received intraperitoneal melatonin had an 82% reduction in size of ibotenate-induced white matter cysts when compared with controls. Although melatonin did not prevent the initial appearance of white matter lesions, it did promote secondary lesion repair. Axonal markers supported the hypothesis that melatonin induced axonal regrowth or sprouting. The protective effects of melatonin were suppressed by coadministration of luzindole, a melatonin receptor antagonist. Forskolin, an adenylate cyclase activator, prevented the protective effects of melatonin; inhibitors of protein kinase C and mitogen-associated protein kinase had no detectable effect. Melatonin and derivatives that block cAMP production through activation of melatonin receptors could represent new avenues for treating human periventricular leukomalacia.
Husson
Isabelle
I
Service de Neuropédiatrie and INSERM E-9935, Hôpital Robert-Debré, Paris, France.
Mesplès
Bettina
B
Bac
Pierre
P
Vamecq
Joseph
J
Evrard
Philippe
P
Gressens
Pierre
P
D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002547:Cerebral Palsy / Q000139:chemically induced / Q000188:drug therapy / Q000401:mortality; D003553:Cystine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003714:Denervation; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006801:Humans; D007036:Hypothermia, Induced; D007051:Ibotenic Acid; D007231:Infant, Newborn; D007969:Leukomalacia, Periventricular / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019579:Neocortex / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics; D044094:Receptors, Melatonin; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014363:Tryptamines / Q000494:pharmacology
C114459:4-phenyl-2-propionamidotetraline; D000975:Antioxidants; D018690:Excitatory Amino Acid Agonists; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D009498:Neurotoxins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D013764:Tetrahydronaphthalenes; D014363:Tryptamines; C057154:luzindole; D007051:Ibotenic Acid; D003553:Cystine; D008550:Melatonin; C030905:N-monoacetylcystine