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.

Effects of Age on the Disruption of Cognitive Performance by Exposure to Space Radiation

“…In turn, the cognitive deficits observed in aged organisms have been linked to the effects of oxidative stress and neuroinflammation on brain function [27]- [29]. Heavy particle radiation, like other toxic stimuli, produces oxidative stress [30]- [32] and neuroinflammation [32]- [34] resulting in changes in neuronal and cognitive function. In effect, exposure to HZE particles accelerates the aging process [4] [5] in terms of changes in both neuronal function and cognitive performance.…”

Dose- and ApoE Isoform-Dependent Cognitive Injury after Cranial56Fe Irradiation in Female Mice

“…Microglial activation and inflammatory cytokine production have been implicated in cognitive deficits (Jenrow et al 2013). Myeloid cell recruitment appears by 6 months following exposure.…”

Microglia provide unexplored avenues to attenuate cognitive decline following isoflurane exposure in susceptible young and elderly patients: A critical review of TREM2-DAP12 function and therapeutic potential

“…Microglia are implicated in the development of chronic neuroinflammatory phenotypes leading to learning impairments in neonatal rats 37 and adult mice 38 and the development of POCD in aged rats Many groups have used anti-inflammatory strategies following various CNS injury models and evaluated the efficacy in preserving cognition or attenuating cognitive decline. Jenrow et al administered MW01-2-151SRM, a selective inhibitor of pro-inflammatory cytokine production, to preserve functional dentate gyrus neurogenesis after radiation 40 . Minocycline 41,42 , memantine 43 and a TNF-a synthesis inhibitor 44 have all demonstrated anti-inflammatory based improvements in cognition, by major indicators of neuroinflammation 20,21 and proteins associated with Alzheimer's disease (AD) 22 .…”