Radiation-Induced Growth Retardation and Microstructural and Metabolite Abnormalities in the Hippocampus

Abstract

Cranial radiotherapy (CRT) increases survival in pediatric brain-tumor patients but can cause deleterious effects. This study evaluates the acute and long-term impact of CRT delivered during childhood/adolescence on the brain and body using a rodent model. Rats received CRT, either 4 Gy fractions × 5 d (fractionated) or a cumulative dose of 20 Gy (single dose) at 28 d of age. Animals were euthanized 1 d, 5 d, or 3.5 mo after CRT. The 3.5 mo group was imaged prior to euthanasia. At 3.5 mo, we observed significant growth retardation in irradiated animals, versus controls, and the effects of single dose on brain and body weights were more severe than fractionated. Acutely single dose significantly reduced body weight but increased brain weight, whereas fractionation significantly reduced brain but not body weights, versus controls. CRT suppressed cell proliferation in the hippocampal subgranular zone acutely. Fractional anisotropy (FA) in the fimbria was significantly lower in the single dose versus controls. Hippocampal metabolite levels were significantly altered in the single dose animals, reflecting a heightened state of inflammation that was absent in the fractionated. Our findings indicate that despite the differences in severity between the doses they both demonstrated an effect on cell proliferation and growth retardation, important factors in pediatric CRT.

Olfactory Memory Impairment Differs by Sex in a Rodent Model of Pediatric Radiotherapy

“…Prior to examining long-term damage to the brain, we observed radiation-induced decreases in body lengths at 3 months post-CRT and weights over time. Our group has previously observed this in rats irradiated as juveniles ( Rodgers et al, 2016 ; Sahnoune et al, 2018 ), with a similar consistent lower body weight in irradiated animals in comparison to shams. Further, the present study demonstrated sex differences in body weight with no interaction with CRT: adult male mice consistently weighed more than females.…”

“…Previous work has demonstrated that SVZ to RMS neurogenesis is severely reduced by CRT ( Hellström et al, 2009 ; Lazarini et al, 2009 ; Balentova et al, 2014 ). Because we ( Rodgers et al, 2016 ) and others ( Raber et al, 2004 ; Rola et al, 2004 ) have found reduced hippocampal neurogenesis months after cranial irradiation, DCX was used in this study to demonstrate a similar late effect in a neurogenic region (SVZ to RMS) associated specifically with the NOdorR task ( Gil-Perotin et al, 2011 ). We reasoned that recognition memory of a social odor would be impaired 3 months post-CRT, thus providing a dependable means by which to detect CRT-induced cognitive impairment.…”

“…In the last two decades, pre-clinical or animal models of CRT have largely focused on measuring cognitive changes associated with impairment in hippocampal cell proliferation and neurogenesis ( Raber et al, 2004 ; Rola et al, 2004 ; Wong-Goodrich et al, 2010 ; Roughton et al, 2012 ), a cellular impairment that persists after CRT ( Rodgers et al, 2016 ). The majority of behavioral CRT research employs standard tasks, such as spatial learning in the Morris water maze and novel object recognition, robust tests of learning and memory.…”

Particle Radiation Induced Neurotoxicity in the Central Nervous System

“…Brain irradiation initiates an inflammatory response mediated by glial and endothelial cells, which compromises the blood-brain barrier, results in demyelination, reduces proliferation and initiates a chronic inflammatory milieu [45,46]. Cranial radiation induces an increase in tumor necrosis factor-a and nuclear factor-jB signaling and a decrease in brain-derived neurotropic factor levels in the brain after treatment with single and fractionated CRT [47][48][49][50]. Brain-derived neurotropic factor plays a key role in supporting neuronal development and function, so this phenomenon may be clinically relevant.…”

Radiation Effects on Brain Extracellular Matrix

“…RT aims to destroy the residual GBM cells at the resection border and prevent the disease relapse, but it has wide biological effects on different molecular and physiological parameters in the irradiated brain tissue as well ( 6 ). Negative side effects of X-ray radiation include: increased permeability of the blood-brain barrier ( 7 , 8 ); brain necrosis ( 9 ); morphological changes, microvascular injury, and activation of astrocytes after irradiation of mouse brain ( 10 ); metabolic and histopathological changes in the specific rat brain regions ( 11 ); suppressed cell proliferation in the hippocampal subgranular zone ( 12 ) and long-term neurocognitive impairment ( 13 , 14 ).…”