Closure realized on ongoing research initiatives in BNS include studies examining the influence of cytokine activation on brainstem catecholaminergic systems relevant to Parkinsons disease. In this study young and aged mice were challenged with a single peripheral injection of lipopolysaccharide (LPS). As expected, treatment induced a substantial proinflammatory cytokine response in brain. Alongside this robust response, however, the numbers of immunocytochemically labeled dopaminergic neurons, quantified stereologically, were similar in young and aged animals sacrificed 14 week after LPS injection. These findings count against the idea that early inflammatory events render the dopamine system vulnerable to late-life degeneration, comprising a risk for Parkinsons disease. Preliminary results from this project were presented at the 2009 Annual Society for Neuroscience convention, and a full-length report is currently 'in press'in Neurobiology of Aging. In other translational research efforts LEG investigators and IRP collaborators have pursued the development of an animal model for examining the cognitive effects of chemotherapy agents commonly used in the treatment of breast cancer. Although complaints of mild cognitive impairment are common among women who have received chemotherapy, a detailed account of the specific nature of dysfunction, and its potential cause, has remained elusive. Earlier studies in animal models have reported conflicting results, and in a recently completed investigation, we conducted an extensive analysis examining the effects of two doses of common chemotherapy agents using multiple tests of learning and memory. Specifically, rats were trained in contextual and cued fear conditioning and then received i.p. injections of either saline, a low dose of cyclophosphamide (CYP) and 5-fluorouracil (5FU;50 mg/kg CYP and 75 mg/kg 5FU) or a high dose (75 mg/kg CYP and 120 mg/kg 5FU) of the cocktail every 30 days for 2 months. After a 2-month recovery, the rats were assessed for the retention of the pretreatment conditioned fear response, and for acquisition in the water maze and 14-unit T- maze. Rats administered either a low or high dose cocktail of CYP/5FU were not impaired in long-term retrograde fear memory, despite marked toxicity evidenced by unrecoverable weight loss and 50% mortality at the higher dose. Furthermore, new task acquisition assessed in the water maze and Stone maze was unimpaired in rats treated with the CYP/5FU cocktail. Together these findings raise the possibility that cognitive impairment associated with chemotherapy may arise from the additive or interactive effects of cancer and treatment on brain function, rather than a neurotoxic effect of treatment alone. A full-length report of these results is currently in preparation.
| Long, Jeffrey M; Lee, Garrick D; Kelley-Bell, Bennett et al. (2011) Preserved learning and memory following 5-fluorouracil and cyclophosphamide treatment in rats. Pharmacol Biochem Behav 100:205-11 |
| Qiu, Guang; Wan, Ruiqian; Hu, Jingping et al. (2011) Adiponectin protects rat hippocampal neurons against excitotoxicity. Age (Dordr) 33:155-65 |
| Pistell, Paul J; Nelson, Chris M; Miller, Marshall G et al. (2009) Striatal lesions interfere with acquisition of a complex maze task in rats. Behav Brain Res 197:138-43 |
| Mouton, Peter R; Chachich, Mark E; Quigley, Christopher et al. (2009) Caloric restriction attenuates amyloid deposition in middle-aged dtg APP/PS1 mice. Neurosci Lett 464:184-7 |
| Ahmet, Ismayil; Spangler, Edward; Shukitt-Hale, Barbara et al. (2009) Blueberry-enriched diet protects rat heart from ischemic damage. PLoS One 4:e5954 |
| Stranahan, Alexis M; Lee, Kim; Pistell, Paul J et al. (2008) Accelerated cognitive aging in diabetic rats is prevented by lowering corticosterone levels. Neurobiol Learn Mem 90:479-83 |
| Shukitt-Hale, Barbara; Lau, Francis C; Carey, Amanda N et al. (2008) Blueberry polyphenols attenuate kainic acid-induced decrements in cognition and alter inflammatory gene expression in rat hippocampus. Nutr Neurosci 11:172-82 |
