title: Enhanced lithium-induced brain recovery following cranial irradiation is not impeded by inflammation.
abstract: Radiation-induced brain injury occurs in many patients receiving cranial radiation therapy, and these deleterious effects are most profound in younger patients. Impaired neurocognitive functions in both humans and rodents are associated with inflammation, demyelination, and neural stem cell dysfunction. Here we evaluated the utility of lithium and a synthetic retinoid receptor agonist in reducing damage in a model of brain-focused irradiation in juvenile mice. We found that lithium stimulated brain progenitor cell proliferation and differentiation following cranial irradiation while also preventing oligodendrocyte loss in the dentate gyrus of juvenile mice. In response to inflammation induced by radiation, which may have encumbered the optimal reparative action of lithium, we used the anti-inflammatory synthetic retinoid Am80 that is in clinical use in the treatment of acute promyelocytic leukemia. Although Am80 reduced the number of cyclooxygenase-2-positive microglial cells following radiation treatment, it did not enhance lithium-induced neurogenesis recovery, and this alone was not significantly different from the effect of lithium on this proinflammatory response. Similarly, lithium was superior to Am80 in supporting the restoration of new doublecortin-positive neurons following irradiation. These data suggest that lithium is superior in its restorative effects to blocking inflammation alone, at least in the case of Am80. Because lithium has been in routine clinical practice for 60 years, these preclinical studies indicate that this drug might be beneficial in reducing post-therapy late effects in patients receiving cranial radiotherapy and that blocking inflammation in this context may not be as advantageous as previously suggested.
authors.affiliation: Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Jordane
authors.initials: J
authors.lastname: Malaterre
authors.forename: Cameron S
authors.initials: CS
authors.lastname: McPherson
authors.forename: Delphine
authors.initials: D
authors.lastname: Denoyer
authors.forename: Emily
authors.initials: E
authors.lastname: Lai
authors.forename: Jim
authors.initials: J
authors.lastname: Hagekyriakou
authors.forename: Sally
authors.initials: S
authors.lastname: Lightowler
authors.forename: Koishi
authors.initials: K
authors.lastname: Shudo
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.forename: David M
authors.initials: DM
authors.lastname: Ashley
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Short
authors.forename: Greg
authors.initials: G
authors.lastname: Wheeler
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ramsay
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects*; D002454:Cell Differentiation; D049109:Cell Proliferation; D003072:Cognition Disorders / Q000473:pathology; D016371:Cranial Irradiation / Q000009:adverse effects*; D019938:Cyclin D1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D018891:Dentate Gyrus / Q000473:pathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology*; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009836:Oligodendroglia / Q000473:pathology; D011833:Radiation Injuries, Experimental / Q000188:drug therapy / Q000473:pathology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
chemical_list: D001565:Benzoates; C530105:Ccnd1 protein, mouse; D013764:Tetrahydronaphthalenes; C061133:tamibarotene; D019938:Cyclin D1; D008094:Lithium; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2