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. 2014 Jan;181(1):21-32.
doi: 10.1667/RR13475.1. Epub 2013 Dec 30.

Differential expression of Homer1a in the hippocampus and cortex likely plays a role in radiation-induced brain injury

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Differential expression of Homer1a in the hippocampus and cortex likely plays a role in radiation-induced brain injury

Elizabeth D Moore et al. Radiat Res. 2014 Jan.

Abstract

Fractionated partial or whole-brain irradiation is the primary treatment for metastatic brain tumors. Despite reducing tumor burden and increasing lifespan, progressive, irreversible cognitive impairment occurs in >50% of the patients who survive >6 months after fractionated whole-brain irradiation. The exact mechanism(s) responsible for this radiation-induced brain injury are unknown; however, preclinical studies suggest that radiation modulates the extracellular receptor kinase signaling pathway, which is associated with cognitive impairment in many neurological diseases. In the study reported here, we demonstrated that the extracellular receptor kinase transcriptionally-regulated early response gene, Homer1a, was up-regulated transiently in the hippocampus and down-regulated in the cortex of young adult male Fischer 344 X Brown Norway rats at 48 h after 40 Gy of fractionated whole-brain irradiation. Two months after fractionated whole-brain irradiation, these changes in Homer1a expression correlated with a down-regulation of the hippocampal glutamate receptor 1 and protein kinase Cγ, and an up-regulation of cortical glutamate receptor 1 and protein kinase Cγ. Two drugs that prevent radiation-induced cognitive impairment in rats, the angiotensin type-1 receptor blocker, L-158,809, and the angiotensin converting enzyme inhibitor, ramipril, reversed the fractionated whole-brain irradiation-induced Homer1a expression at 48 h in the hippocampus and cortex and restored glutamate receptor 1 and protein kinase Cγ to the levels in sham-irradiated controls at 2 months after fractionated whole-brain irradiation. These data indicate that Homer1a is, (1) a brain region specific regulator of radiation-induced brain injury, including cognitive impairment and (2) potentially a druggable target for preventing it.

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Figures

FIG. 1
FIG. 1
fWBI alters Homer1a expression in the hippocampus and cortex of young adult male rats. Hippocampal and cortical Homer1a mRNA levels were determined by TaqMan real time PCR on mRNAs isolated 48 h (panel A) or 2 months (panel B) after fWBI and the data normalized to 18S mRNA levels. Hippocampal and cortical p-ERK proteins were analyzed by Western blot hybridization of lysates isolated 48 h (panel C) and 2 months (panel D) after fWBI; β-actin was the loading control. Data are expressed as the mean ± SEM from 4 rats. (*P < 0.05, ***P < 0.001)
FIG. 2
FIG. 2
mGluR1 and its downstream effector, PKCγ, are decreased in the hippocampus at 2 months after fWBI. Total mGluR1 (panel A), p-GluR1 (panel B), total GluR2/3 (panel C), p-GluR2 (panel D) and total PKCγ (panel E) protein levels were analyzed by Western blot hybridization at 2 months after fWBI; β-actin was the loading control. Data are expressed as the mean ± SEM from 4 rats. (***P < 0.001)
FIG. 3
FIG. 3
mGluR1 and its downstream effector, PKCγ, are increased in the cortex at 2 months after fWBI. Total mGluR1 (panel A), p-GluR1 (panel B), total GluR2/3 (panel C), p-GluR2 (panel D) and total PKCγ (panel E) protein levels were analyzed by Western blot hybridization at 2 months after fWBI; β-actin was the loading control. Data are expressed as the mean ± SEM from 4 rats. (***P < 0.001)
FIG. 4
FIG. 4
L-158,809 and ramipril prevent the changes in hippocampal Homer1a expression and its downstream signaling after fWBI. Homer1a mRNA levels were determined by TaqMan real time PCR on mRNAs isolated 48 h after fWBI, and the data normalized to 18S mRNA levels (panel A). Total mGluR1 at 2 months after fWBI (panel B), p-ERK at 48 h after fWBI (panel C) and total PKCγ at 2 months after fWBI (panel D) protein levels were analyzed by Western blot hybridization; β-actin was the loading control. Data are expressed as the mean ± SEM from 4 rats. (*P < 0.05, **P < 0.01)
FIG. 5
FIG. 5
L-158,809 and ramipril prevent the changes in cortical Homer1a expression and its downstream signaling after fWBI. Homer1a mRNA levels were determined by TaqMan real time PCR on mRNAs isolated 48 h after fWBI, and the data normalized to 18S mRNA levels (panel A). Total mGluR1 at 2 months after fWBI (panel B), p-ERK at 48 h after fWBI (panel C) and total PKCγ at 2 months after fWBI (panel D) protein levels were analyzed by Western blot hybridization; β-actin was the loading control. Data are expressed as the mean ± SEM from 4 rats. (*P < 0.05, ***P < 0.001)

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