Date of Award

1-1-2011

Document Type

Campus Access Dissertation

Department

Exercise Science

First Advisor

J. Mark Davis

Abstract

Fatigue is a symptom experienced by most people but can be a destructive symptom in those with a disease or a disorder, causing more severe problems. Our preliminary data suggested a possible role of monocyte chemotactic protein-1 (MCP-1) in the occurrence of fatigue, especially in fatigue associated with cancer and cancer chemotherapy treatments, known as cancer-related fatigue (CRF). Moreover, accumulating evidence shows that peripheral MCP-1 expression is increased with many diseases, disorders and treatments, including cancer chemotherapy, that are associated with the occurrence of central nervous system (CNS) fatigue, and that neural MCP-1 expression plays a role in modulating neural factors, including neurotransmitter systems and neuroinflammatory mediators, which may have a negative impact on CNS fatigue. Therefore, the primary objective of these studies is to examine the effects of peripheral MCP-1 on the occurrence of fatigue and CNS fatigue-related neural factors, including cytokine interleukine-1β (IL-1β), serotonin (5-HT) receptor subtypes, and dopamine D2 receptors in the brainstem and cerebellum, as well as to elucidate the role of peripheral MCP-1 in cancer chemotherapy 5-flouracil (5FU)-induced changes in these CNS fatigue-related neural factors. Methods: Male C57/BL6 mice were used in these studies, and gene expressions of IL-1β, MCP-1, dopamine D2 receptors, and 5-HT receptor subtypes (5-HT1A, 5-HT1B and/or 5-HT2A) were analyzed in the brainstem and cerebellum. In Specific Aim 1, mice were individually housed in a cage equipped with a running wheel for a period of seven acclimation days, three baseline days, and seven post days after 3-time intraperitoneal (i.p.) injections of either sterilized saline (sPBS) or MCP-1 (5ug/mouse/day). Their voluntary wheel running activities were monitored during the active period (19:00 - 07:00) for seven days after the last injection. Another set of mice were i.p. injected with either sPBS or MCP-1 for three continuous days and sacrificed 12 hours after the last injection. Serum MCP-1 levels were analyzed to confirm that the peripheral MCP-1 protein concentration was increased. Because we have previously shown that treatments of cancer chemotherapy 5FU induced fatigue as indicated by mice voluntary wheel-running activities but because no study has been performed to investigate whether 5FU-induced fatigue is associated with changes in CNS fatigue-related neural factors, the Specific Aims 2 and 3 were designed to investigate the effects of cancer chemotherapy 5FU on neural factors and the effects of inactivation of MCP-1 pathway induced by blocking its receptor CCR2 on 5FU-induced changes in neural factors that are currently known to be associated with the development of CNS fatigue. In Specific Aim 2, mice were i.p. injected with either sPBS or 5-fluorouracil (5FU; 60mg/kg body weight/day) for five continuous days and sacrificed 12 hours after the last injection. In Specific Aim 3, mice were i.p. injected with either sPBS or MCP-1 receptor CCR2 antagonists (2mg/kg body weight/day), immediately followed by i.p. injection of either sPBS or 5FU (60mg/kg body weight/day) for five continuous days. Twelve hours after the last i.p. injection, all mice were sacrificed. Results: Our data from the first experiment show that increased levels of peripheral MCP-1 induce declines in running distance, total running time, and average running speed during the active period. Thus, an increased level of peripheral MCP-1 protein induces the occurrence of fatigue. MCP-1 also resulted in an increased mRNA expression of IL-1β, and some 5-HT receptor subtypes in the brainstem and/or cerebellum. The second experiment shows that 5FU treatments for five continuous days induce increased mRNA expressions of IL-1β (p < 0.05) on post-9 (nine days after the last injection) in the brainstem and cerebellum, but mRNA expressions of MCP-1 were not affected by MCP-1 treatments in both brain regions at all. 5-HT2A receptors in the brainstem (24%, p = 0.09) on post-9 and cerebellum (39%, p < 0.05) on post-1. The mRNA expression of dopamine D2 receptor was continuously increased in both the brainstem (6% to 34%) and the cerebellum (16% to 22%) from post-1 to post-9 days after the cessation of 5FU treatments, but statistical significance was not detected at all. Interestingly, correlation results show robust positive correlations among mRNA expressions of 5-HT1A, 5-HT1B, 5-HT2A and dopamine D2 receptors in both the brainstem and the cerebellum (p < 0.05). Moreover, the MCP-1 mRNA expression is positively correlated with IL-1β (r = 0.49, p = 0.002), 5-HT1B (r = 0.46, p = 0.005), 5-HT2A (r = 0.40, p = 0.02), and dopamine D2 (r = 0.325, p = 0.06) in the brainstem, and also with 5-HT1A (r = 0.492, p = 0.05), 5-HT2A (r = 0.507, p = 0.04), and dopamine D2 (r = 0.502, p = 0.056) in the cerebellum. In Specific Aim 3, a significantly negative effect of 5FU on body weight was detected in 5FU and combination groups, but a significantly preventive effect of CCR2 antagonist treatments on the 5FU-induced body weight decline was detected during the last two days of CCR2 treatments. The combined treatments of CCR2 antagonists and 5FU significantly prevented a 5FU-induced increase in MCP-1 mRNA expression in the brainstem. Our data also reveal a significantly preventive effect of CCR2 antagonist treatments on 5FU-induced increases in 5-HT1B and 5-HT2A receptors in the brainstem, and 5-HT1A, 5-HT2A, and dopamine D2 receptors in the cerebellum. The correlation analysis also shows significantly positive correlations among all neurotransmitter receptor subtypes in both brain regions. Conclusions: The results from this dissertation are the first to show the effects of peripheral MCP-1 on the occurrence of fatigue and mRNA expressions of neural factors that are currently known to be associated with CNS fatigue, which are also induced by treatments of the cancer chemotherapy 5FU. Moreover, the results from this dissertation are the first to show that cancer chemotherapeutic 5FU-induced changes in these neural factors can be, at least partially, prevented if the MCP-1 cellular pathway is inactivated as induced by blocking its receptor CCR2. The results from this dissertation, therefore, suggest a potential role of peripheral MCP-1 in the cancer chemotherapeutic 5FU-induced CNS fatigue.

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© 2011, Seung Ho Jung

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