Central Nervous System Injury – A Newly Observed Bystander Effect of Radiation

Abstract

The unintended side effects of cancer treatment are increasing recognized. Among these is a syndrome of long-term neurocognitive dysfunction called cancer/chemotherapy related cognitive impairment. To date, all studies examining the cognitive impact of cancer treatment have emphasized chemotherapy. Radiation-induced bystander effects have been described in cell culture and, to a limited extent, in rodent model systems. The purpose of this study was to examine, for the first time, the impact of non-brain directed radiation therapy on the brain in order to elucidate its potential relationship with cancer/chemotherapy related cognitive impairment. To address this objective, female BALB/c mice received either a single 16 gray fraction of ionizing radiation to the right hind limb or three doses of methotrexate, once per week for three consecutive weeks. Mice were sacrificed either 3 or 30 days post-treatment and brain injury was determined via quantification of activated astrocytes and microglia. To characterize the effects of non-brain directed radiation on brain glucose metabolism, mice were evaluated by fluorodeoxygluocose positron emission tomography. A single fraction of 16 gray radiation resulted in global decreases in brain glucose metabolism, a significant increase in the number of activated astrocytes and microglia, and increased TNF-α expression, all of which lasted up to 30 days post-treatment. This inflammatory response following radiation therapy was statistically indistinguishable from the neuroinflammation observed following methotrexate administration. In conclusion, non-brain directed radiation was sufficient to cause significant brain bystander injury as reflected by multifocal hypometabolism and persistent neuroinflammation. These findings suggest that radiation induces significant brain bystander effects distant from the irradiated cells and tissues. These effects may contribute to the development of cognitive dysfunction in treated human cancer patients and warrant further study.

Experimental Observation on the Retransmission of Radiation Side Effects

“…A similar phenomenon was observed in animal experiments [4]. Experimental and clinical observations of more normal tissue damage in non-irradiated areas [5][6][7][8][9][10] can be over long distances and extra long time. When formulating the physical plan of radiotherapy, the side effect damage did not receive enough attention, and there was not enough theoretical support for its mechanism and how to antagonize it.…”

Neuroimmunology of Behavioral Comorbidities Associated With Cancer and Cancer Treatments

“…Both in vitro and in vivo models demonstrate off-target consequences of radiation on epigenetics, DNA health, apoptosis, cell proliferation, tumorigenesis, and inflammation ( 133 ). Indeed, peripheral radiation treatment to the right hind limb in tumor-free mice increases microglial Iba1 + cell numbers and TNF-α gene expression in the brain, comparable to the neuroinflammation observed following chemotherapy treatment ( 21 ). Whole-body radiation-induced neuroinflammation is associated with pro-inflammatory gene expression and reduced locomotion ( 134 ), although the direct brain radiation may be responsible for these effects.…”

“…Together, these behavioral symptoms are debilitating and reduce quality-of-life by limiting functional independence, reducing adherence to cancer treatment, undermining social and professional life, and generating a high psychosocial stress burden ( 16 – 18 ). They can manifest acutely or chronically, persisting in 35–75% of cancer patients for months or even years after they are cancer-free ( 19 – 21 ). Such large discrepancies in prevalence are likely related to differences in cancer types and treatments or methodological assessments across studies.…”

Traditional Chinese Medicine in Neuroprotection after Brain Insults with Special Reference to Radioprotection

“…Irradiation induces the activation of inflammatory cells and the release of inflammatory cytokines [17]. Anti-inflammation therapy has been proved to be radioprotective.…”