Ke-Min Chen

Albendazole-banlangen Co-therapy against Angiostrongylus cantonensis-induced Eosinophilic Meningitis

The proteolytic enzyme system may play a role in the pathogenesis of angiostrongyliasis meningitis. Although the anthelmintic agent albendazole can kill the Angiostrongylus cantonensis larvae that infect the brain, their dead larvae are capable of evoking a severe, inflammatory response in the brain. Administration of non-steroid anti inflammatory drugs have been reported to possibly relieve the symptoms of meningitis. Thus, this study evaluates the use of the traditional Chinese medicine banlangen in combination with albendazole as co-therapy for eosinophilic meningitis in BALB/c mice. Assay indicators for the therapeutic effect were (1) histopathological changes, (2) Worm recovery, (3)eosinophil counts, and (4) matrix metalloproteinase-9 (MMp-9). We found that the albendazole-banlangen co-therapy significantly decreased these factors (P＜0.05). The combined use of albendazole and banlangen to treat parasitic meningitis may be an effective new means of treating this disease.

Efficacy of N-acetylcysteine or GM6001 Therapy against Angiostrongylus cantonensis-induced Eosinophilic Meningitis

Matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis of Angiostrongylus cantonensis-induced eosinophilic meningitis or eosinophilic meningoencephalitis. To study the effect of the anti-oxidant N-acetylcysteine (NAC) or MMP inhibitor GM6001 on this disease, we used A. cantonensis to induce eosinophilic meningitis in BALB/c mice and measured its larvicidal effect, counted leukocytes and measured MMP-9 activity in angiostrongyliasis. We found that GM6001 mildly reduced MMP-9 activity and eosinophils, while NAC did not. We also found no significant difference in the in larvicidal effect in mice treated with GM6001 or NAC (P＞0.05). These findings suggest the effect of therapy with either NAC or GM6001 alone was not significant. GM6001 may be used with an anthelminthic drug to treat parasitic meningitis. However, when using NAC to treat this disease, one must consider NACs ability to cross the blood-brain barrier and get to the target site.

Association of Matrix Metalloproteinases with blood-brain Barrier Damage of Angiostrongyliasis

Blood-brain barrier (BBB) breakdown, causing extravasation of leukocytes into subarachnoid space, is regarded as an important pathophysiological event in meningitis. Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of various inflammatory diseases of the central nervous system. Excessive proteolytic activity of MMP-9 can be detrimental, leading to the disruption of the BBB. The present study showed that the activities of MMP-9 in the cerebrospinal fluid (CSF) were significantly increased in mice with eosinophilic meningitis compared with uninfected mice. CSF eosinophilia was significantly correlated with MMP-9 intensity and CSF total protein. In contrast, MMP-2 was presented and remain unchanged in all CSF samples showing that this enzyme was not correlated with CSF eosinophilia and CSF total protein. In addition, MMP-9 enzymatic activity and CSF total protein were significantly increased upon the establishment of infection but subsided due to an inhibition by GM6001, a specific inhibitor for MMPs, These results suggested that MMP-9 proteolytic activity may be associated with BBB disruption in angiostrongyliasis.

Induction of MMP-9 in Mouse Cerebellum with Purkinje Cell Loss Caused by Angiostrongylus Cantonensis

Neurological disorders in angiostrongyliasis are caused by invasion of the central nervous system by developing Angiostrongylus cantonensis larvae. After A. cantonensis infection, the cerebellums of BALB/c strain mice were observed to have a loss of Purkinje cells. Histologically, the Purkinje cells in the infected mice cerebellum were shown to have degenerative atrophy or partial loss. The matrix metalloproteinase-9 (MMP-9) mRNA and activity was induced in the infected mice, and the enzyme was absent in uninfected mice. Western blotting showed that the anti-MMP-9 antibody recognized a single 94 kDa protein from A. cantonensis-infected mice. Immunohistochemistry also showed localization of MMP-9 within the degenerative Purkinje cells. These results suggest MMP-9 in mice infected with A. cantonensis may be related to the loss of Purkinje cells.