| Budget Amount *help |
¥2,710,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥210,000)
Fiscal Year 2007: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
It is well evidenced that the olfactory dysfunction is a general and stable one that likely occurs in the early stage of Parkinson's disease (PD). A quantitative study of postmortem tissues from patients with PD has confirmed neuronal loss in the olfactory bulb (OB) and the presence of Lewy bodies in the anterior olfactory nucleus.
Inflammation and innate immune reactions have been considered to trigger PD. The actions of pro-inflammatory cytokines and nitric oxide produced in the brain by glial cells during the propagation of an immune response have been clarified. Pro-inflammatory cytokines provide a crucial link between the peripheral immune system and the CNS in coordinated host defense responses during infection. Several studies have examined the origin of active pro-inflammatory cytokines that appear in the brain parenchyma after peripheral lipopolysaccharide (LPS) injection. This is because LPS is a cell-wall component of Gram-negative bacteria, and therefore a useful tool with w
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hich to evoke a systemic acute phase response. A few groups including ours have examined the effect of peripheral LPS injections on the OB.
Therefore, we examine the effect of the propagation of innate immune reaction triggered by peripheral LPS on the OB of mice, because LPS-induced tumor necrosis factor (TNF)-α is known to trigger the apoptotic cascade mediated by TNF/TNF receptor pathway. After the intraperitoneal injection of LPS, the rectal temperature significantly decreased and mRNA expression levels in OB of the genes encoding TNF-α was significantly enhanced in the LPS-injected mice. Double immunofluorescence microscopy confirmed that almost all TNF-α-immunopositive cells in OB of the LPS-injected mice were in the subependymal zone and that they overlapped with those immunostained with antibody against glial fibrillary acidic protein, but not with the one against F4/80, an antigenic marker of microglia. And the number of TUNEL-positive cells exclusively identified in granule cell layer was significantly increased in LPS-injected mice sacrificed at 24h after the injection.
Taken together, these findings on the OB and inflammatory cytokines led us to speculate that altered production of the proinflammatory cytokine, TNF-a, in the olfactory system may underlie the occurrence of PD. Therefore, this study was undertaken to address the tentative alteration of the balance in the OB between neurogenesis and apoptosis supposedly generated by the systemic administration of LPS. In addition, a single i.p. injection of LPS did not induce dopamine (DA) neurons to undergo apoptosis in the OB. Therefore, the experiments to examine the LPS-induced degeneration of DA neurons during long-term inflammatory insults to the CNS have to be planned. Less
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