title: Different reactions to irradiation in the juvenile and adult hippocampus.
abstract: OBJECTIVE
  Cranial radiotherapy is an important tool in the cure of primary brain tumors. Unfortunately, it is associated with late-appearing toxicity to the normal brain tissue, including cognitive impairment, particularly in children. The underlying mechanisms are not fully understood but involve changes in hippocampal neurogenesis. Recent studies report essentially different responses in the juvenile and the adult brain after irradiation, but this has never been verified in a comparative study.
  
  
  METHODS
  We subjected juvenile (9-day-old) and adult (6-month-old) male rats to a single dose of 6 Gray (Gy) whole brain irradiation and euthanized them 6 hours, 7 days or 4 weeks later. Hippocampal lysates were analyzed for caspase-3 activity (apoptosis) and the expression of cytokines, chemokines and growth factors. Four weeks after irradiation, the number of microglia (expressing ionized calcium-binding adapter molecule 1, Iba-1), activated microglia (expressing cluster of differentiation 68 [CD68]), bromodeoxyuridine (BrdU) incorporation and granule cell layer (GCL) volume were assessed.
  
  
  RESULTS
  The major findings were (i) higher baseline BrdU incorporation (cell proliferation) in juvenile than in adult controls, which explains the increased susceptibility to irradiation and higher level of acute cell death (caspase activity) in juvenile rats, leading to impaired growth and subsequently a smaller dentate gyrus volume 4 weeks after irradiation, (ii) more activated (CD68-positive) microglia in adult compared to juvenile rats, regardless of irradiation, and (iii) differently expressed cytokines and chemokines after cranial irradiation in the juvenile compared to the adult rat hippocampus, indicating a more pro-inflammatory response in adult brains.
  
  
  CONCLUSIONS
  We found essentially diverse irradiation reactions in the juvenile compared to the adult hippocampus, indicating different mechanisms involved in degeneration and regeneration after injury. Strategies to ameliorate the cognitive deficits after cranial radiotherapy should therefore likely be adapted to the developmental level of the brain.
authors.affiliation: Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology , Gothenburg , Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Blomstrand
authors.forename: Marie
authors.initials: M
authors.lastname: Kalm
authors.forename: Rita
authors.initials: R
authors.lastname: Grandér
authors.forename: Thomas
authors.initials: T
authors.lastname: Björk-Eriksson
authors.forename: Klas
authors.initials: K
authors.lastname: Blomgren
mesh_terms: D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D001921:Brain / Q000528:radiation effects*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D003072:Cognition Disorders / Q000517:prevention & control; D016207:Cytokines / Q000378:metabolism; D018891:Dentate Gyrus / Q000528:radiation effects; D006624:Hippocampus / Q000254:growth & development / Q000528:radiation effects*; D007249:Inflammation; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000528:radiation effects; D055495:Neurogenesis / Q000528:radiation effects; D051381:Rats; D017208:Rats, Wistar; D012038:Regeneration
chemical_list: C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D016207:Cytokines; D008840:Microfilament Proteins; C505410:Casp3 protein, rat; D053148:Caspase 3
keywords: BrdU; Cranial radiation therapy; Iba-1; active caspase-3; chemokines; cytokines; growth factors; irradiation; microglia; neurogenesis