Molecular Pathways: Radiation-Induced Cognitive Impairment

ArticleinClinical Cancer Research 19(9) · February 2013with17 Reads
DOI: 10.1158/1078-0432.CCR-11-2903 · Source: PubMed
Approximately 200,000/year in the US will receive partial or whole brain irradiation for the treatment of primary or metastatic brain cancer. Early and delayed radiation effects are transient and reversible with modern therapeutic standards; yet late radiation effects (≥6 months postirradiation) remain a significant risk, resulting in progressive cognitive impairment. These include functional deficits in memory, attention, and executive function that severely affect the patient's quality of life (QOL). The mechanisms underlying radiation-induced cognitive impairment remain ill defined. Classically, radiation-induced alterations in vascular and glial cell clonogenic populations were hypothesized to be responsible for radiation-induced brain injury. Recently, preclinical studies have focused on the hippocampus, one of two sites of adult neurogenesis within the brain, which plays an important role in learning and memory. Radiation ablates hippocampal neurogenesis, alters neuronal function, and induces neuroinflammation. Neuronal stem cells implanted into the hippocampus prevent the decrease in neurogenesis and improve cognition following irradiation. Clinically prescribed drugs, including PPAR α and γ agonists, as well as RAS blockers, prevent radiation-induced neuroinflammation and cognitive impairment independent of improved neurogenesis. Translating these exciting findings to the clinic offers the promise of improving the QOL of brain tumor patients who receive radiotherapy.
    • "These changes occur along with reductions in dendritic complexity and synaptic density of more mature neurons (Parihar and Limoli, 2013; Parihar et al., 2014b). Consequently, cranial radiotherapy causes substantial decrements in short-and long-term learning and memory function that persist well after exposure (Schloesser and Robbins, 2012; Greene-Schloesser et al., 2013). We have previously shown in rodent models that exposure to radiation leads to long lasting reductions in neural stem cell (NSC) proliferation, prolonged oxidative stress, inhibition of neurogenesis, elevated CNS inflammation and cognitive dysfunction (Acharya et al., 2009Acharya et al., , 2010Acharya et al., , 2011Acharya et al., , 2014a Lan et al., 2012; Parihar et al., 2014a). "
    [Show abstract] [Hide abstract] ABSTRACT: Clinical radiation therapy for the treatment of CNS cancers leads to unintended and debilitating impairments in cognition. Radiation-induced cognitive dysfunction is long lasting; however, the underlying molecular and cellular mechanisms are still not well established. Since ionizing radiation causes microglial and astroglial activation, we hypothesized that maladaptive changes in astrocyte function might be implicated in radiation-induced cognitive dysfunction. Among other gliotransmitters, astrocytes control the availability of adenosine, an endogenous neuroprotectant and modulator of cognition, via metabolic clearance through adenosine kinase (ADK). Adult rats exposed to cranial irradiation (10 Gy) showed significant declines in performance of hippocampal-dependent cognitive function tasks [novel place recognition, novel object recognition (NOR), and contextual fear conditioning (FC)] 1 month after exposure to ionizing radiation using a clinically relevant regimen. Irradiated rats spent less time exploring a novel place or object. Cranial irradiation also led to reduction in freezing behavior compared to controls in the FC task. Importantly, immunohistochemical analyses of irradiated brains showed significant elevation of ADK immunoreactivity in the hippocampus that was related to astrogliosis and increased expression of glial fibrillary acidic protein (GFAP). Conversely, rats treated with the ADK inhibitor 5-iodotubercidin (5-ITU, 3.1 mg/kg, i.p., for 6 days) prior to cranial irradiation showed significantly improved behavioral performance in all cognitive tasks 1 month post exposure. Treatment with 5-ITU attenuated radiation-induced astrogliosis and elevated ADK immunoreactivity in the hippocampus. These results confirm an astrocyte-mediated mechanism where preservation of extracellular adenosine can exert neuroprotection against radiation-induced pathology. These innovative findings link radiation-induced changes in cognition and CNS functionality to altered purine metabolism and astrogliosis, thereby linking the importance of adenosine homeostasis in the brain to radiation injury.
    Full-text · Article · Jul 2016
    • "Therefore, a mouse model of radiation-induced fatigue would be instrumental to understanding the pathobiology underlying this debilitating condition. Existing in vivo mouse models examining fatigue-like behavior related to cancer or cancer therapy involve the use of one or more of the following: tumorigenic mice [17], chemotherapeutics [10,18], antigenic challenge such as lipopolysaccharide or cytokine administration [19,20], or brain or total body irradiation [21,22]. These models often show symptoms associated with CRF, including cognitive deficiencies, assessed by learning or memory tests [23], and depressive behaviors, such as anhedonia [20]. "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose: Fatigue is the most ubiquitous side effect of cancer treatment, but its etiology remains elusive. Further investigations into cancer-related fatigue pathobiology necessitate the expanded use of animal models. This study describes the development of a murine model of radiation-induced fatigue. Methods: Voluntary wheel running activity measured fatigue in 5-8 week-old, male C57BL/6 mice before and after γ irradiation totaling 2400 cGy (3 consecutive days x 800 cGy daily fractionated doses) to the lower abdominal areas. Three trials confirmed fatigue behavior at this dose. Anhedonia, body weight, and hemoglobin were also measured. Gastrointestinal, skeletal muscle, and bone marrow tissue samples were evaluated for signs of damage. Results: In two validation trials, irradiated mice (trial 1, n=8; trial 2, n=8) covered less cumulative distance in kilometers post-irradiation (trial 1, mean=115.3±12.3; trial 2, mean=113.6±21.8) than sham controls (trial 1, n=5, mean=126.3±5.7, p=0.05; trial 2, n=8, mean=140.9±25.4, p=0.02). Decreased mean daily running distance and speed were observed during the last four hours of the dark cycle in irradiated mice compared to controls for two weeks post-irradiation. There were no differences in saccharin preference or hemoglobin levels between groups, no effect of changes in body weight or hemoglobin on wheel running distance, additionally, histology showed no damage to muscle, bone marrow, or gastrointestinal integrity, with the latter confirmed by ELISA. Conclusion: We characterized a novel mouse model of fatigue caused by peripheral radiation and not associated with anemia, weight changes, or anhedonia. This model provides opportunities for detailed study of the mechanisms of radiation-induced fatigue.
    Full-text · Article · Mar 2016
    • "Consequently, one of the uses of antibiotics before and after irradiation is to prevent systemic inflammation , and possibly a septic shock, caused by enteric bacteria entering the bloodstream due to gastrointestinal tissue damages. In human, brain irradiation often induces cognitive dysfunctions, thus representing a major concern for patients receiving partial-or whole-brain irradiation for the treatment of primary or metastatic brain cancer [63,64]. These cognitive impairments could be induced by defective neurogenesis, damage to oligodendrocytes, changes in the expression of proteins implicated in long-term potentiation, neuroinflammation and alteration of the BBB65666768. "
    [Show abstract] [Hide abstract] ABSTRACT: The central nervous system (CNS) is a very unique system with multiple features that differentiate it from systemic tissues. One of the most captivating aspects of its distinctive nature is the presence of the blood brain barrier (BBB), which seals it from the periphery. Therefore, to preserve tissue homeostasis, the CNS has to rely heavily on resident cells such as microglia. These pivotal cells of the mononuclear lineage have important and dichotomous roles according to various neurological disorders. However, certain insults can overwhelm microglia as well as compromising the integrity of the BBB, thus allowing the infiltration of bone marrow-derived macrophages (BMDMs). The use of myeloablation and bone marrow transplantation allowed the generation of chimeric mice to study resident microglia and infiltrated BMDM separately. This breakthrough completely revolutionized the way we captured these 2 types of mononuclear phagocytic cells. We now realize that microglia and BMDM exhibit distinct features and appear to perform different tasks. Since these cells are central in several pathologies, it is crucial to use chimeric mice to analyze their functions and mechanisms to possibly harness them for therapeutic purpose. This review will shed light on the advent of this methodology and how it allowed deciphering the ontology of microglia and its maintenance during adulthood. We will also compare the different strategies used to perform myeloablation. Finally, we will discuss the landmark studies that used chimeric mice to characterize the roles of microglia and BMDM in several neurological disorders.
    Full-text · Article · Oct 2015
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