Differential Expression of Homer1a in the Hippocampus and Cortex Likely Plays a Role in Radiation-Induced Brain Injury

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 shamirradiated 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.

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

“…Homer1a is a protein under the control of the radiation-inducible ERK signaling pathway and binds to postsynaptic, G-protein coupled, metabotropic glutamate family 1 receptors (mGluR1), which modulate NMDA receptors and are linked to cognition. Two months later, the early changes correlated with decreases in hippocampal mGluR1 and increases in cortical mGluR1, suggesting that the ERK signaling pathway may function through Homer 1a to influence cognitive processes through glutamate receptors (Moore et al 2014).…”

Mechanisms of radiotherapy-associated cognitive disability in patients with brain tumours

“…1-5 Radiation is an indispensable treatment mainstay for the majority of these brain tumors. 6-9 Brain radiotherapy is subdivided into whole brain radiotherapy (WBRT) in which the entire brain and brainstem are irradiated, and partial brain radiotherapy (PBRT) which includes treatment of the tumor or tumor bed and surrounding margin, and some healthy brain tissue subject to incidental irradiation 4,10,11 Stereotactic radiosurgery (SRS) relies on precise 3D imaging and localization to deliver ablative doses of radiation to the tumor, and can significantly reduce exposure of healthy brain tissue. 12 These modes of brain radiotherapy fulfill any of a range of clinical objectives including; (1) long term tumor control or cure as mono or combined therapy, (2) salvage treatment for slowing tumor growth or palliation, and (3) prophylaxis to kill metastatic cells that would otherwise become established in the brain.…”

Cellular response of the rat brain to single doses of137Cs γ rays does not predict its response to prolonged ‘biologically equivalent’ fractionated doses

“…In general, ionizing radiation produces its biological effects either directly or indirectly by generating reactive oxygen species (ROS) that lead to molecular changes such as damage to DNA (Gobbel et al 1998, Otsuka et al 2006), lipids (Limoli et al 2004), and proteins (Stadtman and Berlett 1997, Manda et al 2007), as well as activation of early response genes (Hong et al 1995, Moore et al 2011, Moore et al 2013) and signal transduction pathways (Schmidt-Ullrich et al 2000, Dent et al 2003). Activation of these pathways leads to: (i) Induction of reparative and restorative processes (Mattson et al 1997, Moyer et al 1998, Kojima et al 1998, Heck et al 1999); (ii) changes in the cytokine milieu (Zhou et al 2001, Son et al 2006, Lee et al 2010), and (iii) activation/influx of inflammatory cells (Moravan et al 2011).…”