Involvement of nitric oxide released from microglia-macrophages in pathological changes of cathepsin D-deficient mice

Hiroshi Nakanishi, Jian Zhang, Masato Koike, Tsuyoshi Nishioku, Yoshiko Okamoto, Eiki Kominami, Kurt Von Figura, Christoph Peters, Kenji Yamamoto, Paul Saftig, Yasuo Uchiyama

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106 Citations (Scopus)


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-NG-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.

Original languageEnglish
Pages (from-to)7526-7533
Number of pages8
JournalJournal of Neuroscience
Issue number19
Publication statusPublished - Oct 1 2001

All Science Journal Classification (ASJC) codes

  • General Neuroscience


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