title: Selective inhibition of microglia-mediated neuroinflammation mitigates radiation-induced cognitive impairment.
abstract: Cognitive impairment precipitated by irradiation of normal brain tissue is commonly associated with radiation therapy for treatment of brain cancer, and typically manifests more than 6 months after radiation exposure. The risks of cognitive impairment are of particular concern for an increasing number of long-term cancer survivors. There is presently no effective means of preventing or mitigating this debilitating condition. Neuroinflammation mediated by activated microglial cytokines has been implicated in the pathogenesis of radiation-induced cognitive impairment in animal models, including the disruption of neurogenesis and activity-induced gene expression in the hippocampus. These pathologies evolve rapidly and are associated with relatively subtle cognitive impairment at 2 months postirradiation. However, recent reports suggest that more profound cognitive impairment develops at later post-irradiation time points, perhaps reflecting a gradual loss of responsiveness within the hippocampus by the disruption of neurogenesis. We hypothesized that inhibiting neuroinflammation using MW01-2-151SRM (MW-151), a selective inhibitor of proinflammatory cytokine production, might mitigate these deleterious radiation effects by preserving/restoring hippocampal neurogenesis. MW-151 therapy was initiated 24 h after 10 Gy whole-brain irradiation (WBI) administered as a single fraction and maintained for 28 days thereafter. Proinflammatory activated microglia in the dentate gyrus were assayed at 2 and 9 months post-WBI. Cell proliferation and neurogenesis in the dentate gyrus were assayed at 2 months post-WBI, whereas novel object recognition and long-term potentiation were assayed at 6 and 9 months post-WBI, respectively. MW-151 mitigated radiation-induced neuroinflammation at both early and late time points post-WBI, selectively mitigated the deleterious effects of irradiation on hippocampal neurogenesis, and potently mitigated radiation-induced deficits of novel object recognition consolidation and of long-term potentiation induction and maintenance. Our results suggest that transient administration of MW-151 is sufficient to partially preserve/restore neurogenesis within the subgranular zone and to maintain the functional integrity of the dentate gyrus long after MW-151 therapy withdrawal.
authors.affiliation: Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan 48202, USA. kjenrow1@hfhs.org
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jenrow
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Brown
authors.forename: Karen
authors.initials: K
authors.lastname: Lapanowski
authors.forename: Hoda
authors.initials: H
authors.lastname: Naei
authors.forename: Andrew
authors.initials: A
authors.lastname: Kolozsvary
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D016207:Cytokines / Q000096:biosynthesis; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D055495:Neurogenesis / Q000187:drug effects / Q000528:radiation effects; D011724:Pyridazines / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D011833:Radiation Injuries, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051381:Rats; D011916:Rats, Inbred F344; D021641:Recognition, Psychology / Q000187:drug effects / Q000528:radiation effects; D014916:Whole-Body Irradiation / Q000009:adverse effects
chemical_list: C575875:2-(4-(4-methyl-6-phenylpyridazin-3-yl)piperazin-1-yl)pyrimidine; D016207:Cytokines; D011724:Pyridazines; D011743:Pyrimidines
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