title: Involvement of nitric oxide released from microglia-macrophages in pathological changes of cathepsin D-deficient mice.
abstract: Cathepsin D (CD) deficiency has been shown to induce ceroid-lipofuscin storage in lysosomes of mouse CNS neuron (Koike et al., 2000). To understand the behavior of microglial cells corresponding to these neuronal changes, CD-deficient (CD-/-) mice, which die at approximately postnatal day (P) 25 by intestinal necrosis, were examined using morphological as well as biochemical approaches. Light and electron microscopic observations revealed that microglia showing large round cell bodies with few processes appeared in the cerebral cortex and thalamus after P16. At P24, microglia often encircled neurons that were occupied with autolysosomes, indicating increased phagocytic activity. These morphologically transformed microglia markedly expressed inducible nitric oxide synthase (iNOS), which was also detected in the intestine of the mice. To assess the role of microglial nitric oxide (NO) in neuropathological changes in CD-/- mice, l-N(G)-nitro-arginine methylester (l-NAME), a competitive NOS inhibitor, or S-methylisothiourea hemisulfate (SMT), an iNOS inhibitor, was administered intraperitoneally for 13 consecutive days. The total number of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive cells counted in the thalamus was found to be significantly decreased by chronic treatment of l-NAME or SMT, whereas neither the neuronal accumulation of ceroid-lipofuscin nor the microglial phagocytic activity was affected by these treatments. Moreover, the chronic treatment of l-NAME or SMT completely suppressed hemorrhage-necrotic changes in the small intestine of CD-/- mice, resulting in normal growth of the body weight of the mice. These results suggest that NO production via iNOS activity in microglia and peripheral macrophages contributes to secondary tissue damages such as neuronal apoptosis and intestinal necrosis, respectively.
authors.affiliation: Laboratory of Oral Aging Science, Division of Oral Biological Sciences, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan. nakandeg@mbox.nc.kyushu-u.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Nakanishi
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Koike
authors.forename: T
authors.initials: T
authors.lastname: Nishioku
authors.forename: Y
authors.initials: Y
authors.lastname: Okamoto
authors.forename: E
authors.initials: E
authors.lastname: Kominami
authors.forename: K
authors.initials: K
authors.lastname: von Figura
authors.forename: C
authors.initials: C
authors.lastname: Peters
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: P
authors.initials: P
authors.lastname: Saftig
authors.forename: Y
authors.initials: Y
authors.lastname: Uchiyama
mesh_terms: D000818:Animals; D017209:Apoptosis; D001835:Body Weight / Q000187:drug effects; D002402:Cathepsin D / Q000172:deficiency* / Q000235:genetics; D002452:Cell Count; D018450:Disease Progression; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007421:Intestine, Small / Q000187:drug effects / Q000473:pathology; D007550:Isothiuronium / Q000031:analogs & derivatives / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010587:Phagocytosis; D013788:Thalamus / Q000187:drug effects / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; D007550:Isothiuronium; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D002402:Cathepsin D; C027744:S-methylisothiopseudouronium; D019331:NG-Nitroarginine Methyl Ester