Therapeutic irradiation of the brain is commonly used to treat brain tumors but can induce cognitive impairments that can severely affect quality of life. The underlying mechanisms responsible for radiation-induced cognitive deficits are unknown but likely involve alterations in neuronal activity. To gain some mechanistic insight into how irradiation may affect hippocampal neurons known to be associated with cognitive function, we quantitatively assessed the molecular distribution of the behaviorally induced immediate-early gene Arc (activity-regulated cytoskeleton-associated protein) at the level of mRNA and the protein. Young adult C57BL/6J mice received whole-brain irradiation with 0 or 10 Gy, and 1 week or 2 months later, exploration of a novel environment was used to induce Arc expression. The fractions of neurons expressing Arc mRNA and Arc protein were detected using fluorescence in situ hybridization and immunocytochemistry, respectively. Our results showed that there was a significant reduction in the percentage of neurons expressing Arc protein 1 week after irradiation, whereas 2 months after irradiation, there was a reduction in the percentage of neurons expressing both Arc mRNA and Arc protein. Importantly, radiation-induced changes in Arc expression were not a result of neuronal cell loss. The changes observed at 2 months were associated with a significant increase in the number of activated microglia, supporting the idea that inflammation may contribute to neuronal dysfunction. These findings are the first to show that local brain irradiation initiates changes in hippocampal neurons that disrupt the activity patterns (Arc expression) associated with neuroplasticity and memory. [Cancer Res 2008;68(23):9763–70]

Neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and multiple sclerosis affect millions of people around the world. In addition to age, which is a key factor contributing to the development of all neurodegenerative diseases, genetic and environmental components are also important risk factors. Current methods of treating neurodegenerative diseases are mostly symptomatic and do not eliminate the cause of the disease. Many studies focus on searching for natural substances with neuroprotective properties that could be used as an adjuvant therapy in the inhibition of the neurodegeneration process. These compounds include flavonoids, such as luteolin, showing significant anti-inflammatory, antioxidant, and neuroprotective activity. Increasing evidence suggests that luteolin may confer protection against neurodegeneration. In this review, we summarize the scientific reports from preclinical in vitro and in vivo studies regarding the beneficial effects of luteolin in neurodegenerative diseases. Luteolin was studied most extensively in various models of Alzheimer’s disease but there are also several reports showing its neuroprotective effects in models of Parkinson’s disease. Though very limited, studies on possible protective effects of luteolin against Huntington’s disease and multiple sclerosis are also discussed here. Overall, although preclinical studies show the potential benefits of luteolin in neurodegenerative disorders, clinical evidence on its therapeutic efficacy is still deficient. Graphical abstract