In cerebral ischemic insults, activated inflammatory cells such as microglia and macrophages may be implicated in the pattern and degree of ischemic injury by producing various bioactive mediators. In the present study, we provide the evidence that activated microglia/macrophages accelerate cerebral ischemic injury by overexpression of inducible nitric oxide synthase (iNOS). To activate microglia/macrophages, a potent inflammation inducer lipopolysaccharide (LPS, 5 microg/5 microl) was microinjected into rat corpus callosum. Isolectin B4-positive microglia/macrophages were abundantly observed in ipsilateral hemisphere at 1 day after LPS injection. RT-PCR showed that LPS injection induced iNOS mRNA expression mostly in microglia/macrophages, peaking in intensity at 15 h after LPS injection. While ischemic injury was little evoked in control rats by 2-h middle cerebral artery occlusion (MCAO) followed by 3-h reperfusion, it was markedly increased in rats pre-injected with LPS 1 day before MCAO. However, no significant difference between control and LPS-pretreated groups was observed after 24-h reperfusion. The increased ischemic injury in LPS-treated rats was well correlated with iNOS level expressed over 3 orders of magnitude than in LPS-untreated rats. Immunohistochemical studies showed that iNOS- and nitrotyrosine (a peroxynitrite marker)-positive cells were prominent throughout the infarct area. NOS inhibitors aminoguanidine or N(G)-nitro-L-arginine, simultaneously injected with LPS, reduced the iNOS immunoreactivity and infarct volume, especially in penumbra regions. Total glutathione levels in ischemic regions were decreased more in LPS pre-injected rats than in control ones. Further defining the role of NO in cerebral ischemic insults would provide the rationale for new therapeutic strategies based on modulation of microglial and macrophageal NO production in the brain.

A topical application of 0.1% dexamethasone retarded the corneal epithelial healing. The cornea treated with 0.1% dexamethasone only for the 1st week maintained a well-preserved basement membrane for as long as 4 weeks after initial damage without enhancement of the inflammatory cell infiltration. However, further study is needed to prevent late disintegration of the basement membrane.

To explore the direct role of ␤-amyloid (A␤) and carboxyl-terminal fragments of amyloid precursor protein in the inflammatory processes possibly linked to neurodegeneration associated with Alzheimer's disease, the effects of the 105-amino acid carboxyl-terminal fragment (CT 105 ) of amyloid precursor protein on the production of tumor necrosis factor-␣ (TNF-␣) and matrix metalloproteinase-9 (MMP-9) were examined in a human monocytic THP-1 cell line and compared with that of A␤. CT 105 elicited a marked increase in TNF-␣ and MMP-9 production in the presence of interferon-␥ in a dose-and time-dependent manner. Similar patterns were obtained with A␤ despite its low magnitude of induction. Autocrine TNF-␣ is likely to be a main mediator of the induction of MMP-9 because the neutralizing antibody to TNF-␣ inhibits MMP-9 production. Genistein, a specific inhibitor of tyrosine kinase, dramatically diminished both TNF-␣ secretion and subsequent MMP-9 release in response to CT 105 or A␤. Furthermore, PD98059 and SB202190, specific inhibitors of ERK or p38 MAPK respectively, efficiently suppressed CT 105 -induced effects whereas only PD98059 was effective at reducing A␤-induced effects. Our results suggest that CT 105 in combination with interferon-␥ might serve as a more potent activator than A␤ in triggering inflammatory processes and that both tyrosine kinase and MAPK signaling pathways may represent potential therapeutic targets for the control of Alzheimer's disease progression.

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