Alterations of myelin proteins in inflammatory demyelination of BALB/c mice caused by Angiostrongylus cantonensis.

Angiostrongylus cantonensis causes eosinophilic meningitis or meningoencephalitis, yet little is known about demyelination caused by this parasite. To define the course of demyelination caused by A. cantonensis, we analyzed the expression of myelin proteins including myelin-associated glycoprotein (MAG), myelin basic protein (MBP), myelin-associated oligodendrocytic basic protein (MOBP), and proteolipid protein (PLP) in brain and cerebrospinal fluid (CSF)-like fluid of infected and uninfected BALB/c mice. In A. cantonensis-infected mice, the expression of MAG, MBP, MOBP, and PLP mRNAs in brain tissue was decreased, while expression of the corresponding proteins was significantly increased in CSF-like fluid. Light microscopy revealed perivascular infiltrates in the brain during meningoencephalitis, suggesting that the cause of demyelination in angiostrongyliasis was immune system attack on the oligodendrocytic myelin sheath and subsequent release of myelin proteins into the CSF. Thus, intracerebral myelin breakdown in angiostrongyliasis may be a response to inflammatory mediators and the cause of increased myelin proteins in the CSF-like fluid.

Differences of proteolytic enzymes and pathological changes in permissive and nonpermissive animal hosts for Angiostrongylus cantonensis infection.

In this study, mice (nonpermissive hosts) infected with Angiostrongylus cantonensis showed significant worm degeneration and eosinophil degranulation, whereas infected rats (permissive hosts) showed lower worm degeneration and eosinophil degranulation. Pathophysiological changes developed to a lesser extent in rat than in the mouse strains. Neurological evaluation of A. cantonensis-infected mice showed mechanical damage caused by worms migrating to the brain. A significant correlation between the proteolytic enzymes, plasminogen activator (PA) and matrix metalloproteinase-9 (MMP-9), and pathological changes was found in hosts with eosinophilic meningitis or meningoencephalitis. Also, the ratio of cerebrospinal fluid (CSF) to serum albumin was consistently increased in hosts with angiostrongyliasis as compared with control. These data clearly indicate that PA and MMP-9 proteolytic enzymes as well as pathological changes are different in permissive and nonpermissive hosts.

Induced eosinophilia and proliferation in Angiostrongylus cantonensis-infected mouse brain are associated with the induction of JAK/STAT1, IAP/NF-kappaB and MEKK1/JNK signals.

Eosinophilic meningitis or meningoencephalitis caused by Angiostrongylus cantonensis is endemic to the Pacific area of Asia, especially Taiwan, Thailand, and Japan. Although eosinophilia is an important clinical manifestation of A. cantonensis infection, the role of eosinophils in the progress of the infection remains to be elucidated. In this experiment, we show that A. cantonensis-induced eosinophilia and inflammation might lead to the induction of IAP/NF-kappaB, JAK/STAT1 and MEKK1/JNK signals. The phosphorylation levels of JAK and JNK, STAT1, IAP, NF-kappaB and MEKK1 protein products were significantly increased after 12 days or 15 days of A. cantonensis infection. However, no significant differences in MAPKs such as Raf, MEK-1, ERK1/2 and p38 expression were found between control and infected mice. The activation potency of JAK/STAT1, IAP/NF-kappaB and MEKK1/JNK started increasing on day 3, with significant induction on day 12 or day 15 after A. cantonensis infection. Consistent results were noted in the pathological observations, including eosinophilia, leukocyte infiltration, granulomatous reactions, and time responses in the brain tissues of infected mice. These data suggest that the development of brain injury by eosinophilia of A. cantonensis infection is associated with activation of JAK/STAT1 signals by cytokines, and/or activation of MEKK1/JNK by oxidant stress, and/or activation of NF-kappaB by increasing IAP expression.

The efficacy of therapy with albendazole in mice with parasitic meningitis caused by Angiostrongylus cantonensis.

Matrix metalloproteinase 9 (MMP-9) is involved in the pathogenesis of parasitic meningitis caused by the nematode Angiostrongylus cantonensis. The present study evaluated the efficacy of albendazole therapy in BALB/c mice infected with the third stage larvae of this nematode. Albendazole showed a pronounced larvicidal activity. Eosinophil numbers significantly increased in infected mice but decreased upon administration of albendazole. Densitometric scanning indicated that albendazole reduced gelatinolytic activity detected by gelatin-substrate zymography. In the cerebrospinal fluid, albendazole reduced the lytic area intensity of the 94 kDa MMP-9 band by 46.5% within 7 days, and by 51.5% by day 14. Examination of brain tissue revealed a similar pattern of decrease (48.6% by day 7, and 53.9% by day 14). Albendazole may thus be an effective compound for the treatment of angiostrongyliasis through its larvicidal activity and facilitation of an improved inflammatory response via the reduction of MMP-9 activity.

Tumor promoting effect of N-nitroso-N-(2-hexanonyl)-3'-nitrotyramine (a nitrosated Maillard reaction product) in benzo(a)pyrene-initiated mouse skin carcinogenesis.

N-nitroso-N-(2-hexanonyl)-3'-nitrotyramine (NO-HNTA) is a product generated in a model browning system in the presence of sodium nitrite. The chemical structure of this compound has been confirmed by UV, mass, nuclear magnetic resonance and infrared spectroscopy in our study. Twenty weeks, twice weekly, topical application of NO-HNTA at the concentration of 10, 50 and 250 mumol to mice previously initiated with benzo(a)pyrene (B[a]P) increased their tumor formation by 3.2-, 4.6- and 5.8-fold respectively. Application of the same amount of NO-HNTA not only caused significant induction of hyperplasia but also the activity of epidermal ornithine decarboxylase (ODC). Treatment of mouse skin with various amounts of NO-HNTA (10, 50 and 250 mumol) caused production of hydrogen peroxide by 1.38-, 1.95- and 3.26-fold respectively, and induction myeloperoxidase (MPO) by 24-, 63- and 102-fold. These results indicate that the formation of NO-HNTA or its derivatives derived from the reaction of tyrosine and glucose in the presence of sodium nitrite has the potential as a tumor promoter.