應用磁振造影新穎診斷法及Albendazole合併
薑黃素治療方法對感染廣東住血線蟲小鼠之評估

廣東住血線蟲引起的嗜酸性白血球腦膜炎之診斷異常困難，脊椎引流採集腦脊髓液並找出蟲體是目前臨床檢查採用的方式，但是半數的患者卻因找不到蟲體而無法獲得確診，而現有偵測特異性廣東住血線蟲（Angiostrongylus cantonensis）抗原方法出現偽陽性的可能性也極高。磁振造影在臨床影像學上，較傳統放射線及斷層掃描提供更多的好處：如多面向影像及較強的軟組織對比影像可以強化輔助診斷，且沒有放射線傷害之顧慮；因此，將磁振造影應用於臨床研究、診斷及治療監控上，值得大力開發。本研究以廣東住血線蟲第三期幼蟲感染小白鼠，應用高解析軸面T2WI（High-resolution Axial T2-weighted MR images）造影，結果軸向斷面影像可發現小白鼠側腦室擴大，大腦、小腦和橋腦外緣，明顯有高度訊號表現，大腦實質及嗅球出現大小不等的訊號表現；對照肉眼病變及組織病理切片發現廣東住血線蟲蟲體寄生於腦膜面、蜘蛛膜下腔及脈絡叢，造成嚴重發炎、充鬱血和出血情形，大腦實質組織存在蟲體並有液化現象。本研究首次以活體模式證實小白鼠感染廣東住血線蟲後，其腦部磁振造影影像（MR imaging）與組織病理檢查之結果相符合，提供直接證據證明磁振造影可有效提升廣東住血線蟲感染後對腦部傷害的確診比率。治療廣東住血線蟲感染，以驅蟲藥albendazole為主，然albendazole雖可殺死廣東住血線蟲的幼蟲，但這些被殺死的幼蟲卻常常引發嚴重的發炎反應導致腦部損傷。從過去的研究已知感染廣東住血線蟲的病理變化都與細胞外基質的破壞或蛋白質成份的分解有關（Aldape, 1994）。感染廣東住血線蟲的ICR小鼠腦部組織也被證實有基質金屬蛋白酶-9（MMP-9）之表現（Lai , 2004）。薑黃素（curcumin）是一種天然物，具有抗發炎、抗氧化、可以抑制MMP-9分泌之特性。本研究主要探討以驅蟲藥albendazole 配合薑黃素合併治療感染廣東住血線蟲之小鼠，是否能改善因感染廣東住血線蟲引發所造成的腦部傷害及神經病變。結果發現，雖然單獨薑黃素治療不能減少蟲體數目和抑制MMP-9的表現，但合併驅蟲藥albendazole和薑黃素可以顯著有效地減少感染廣東住血線蟲小白鼠腦部的蟲體數和腦脊髓液嗜酸性白血球計數以減緩感染廣東住血線蟲小白鼠的症狀。綜合上述，本研究首次建立小鼠活體模式，證實磁振造影有助早期確診廣東住血線蟲之感染，以利早期投藥治療，同時以薑黃素合併albendazole之治療方式則大幅降低廣東住血線蟲感染之腦部傷害及神經病變，達到最佳治療效果，提供及早輔助診斷和醫療研究之重要活體模式。

關鍵字

廣東住血線蟲；嗜酸性腦膜炎；磁振照影；薑黃素

並列摘要

The diagnosis of eosinophilic meningitis can be achieved through detection of elevated cranial pressure and increased volumes of eosinophils. The diagnosis of the cause of eosinophilic meningitis and the presence of Angiostrongylus cantonensis (A. cantonensis) is remarkably difficult. A spinal tap, or a sample of cerebrospinal fluid (CSF), must be taken to search for A. cantonensis worms or larvae. A. cantonensis is virtually undetectable in the CSF of half of the infected individuals. Current methods of detecting specific antigens associated with A. cantonensis are also unreliable, due to possible chance of false positive results. High-resolution Axial T2-weighted MR was used widely in image diagnosis in humans. We hypothesized whether High-resolution Axial T2-weighted MR can be used as a diagnostic tool in parasite infection or not. In this study, BALB/c mice were used and infected by one hundred 3rd larvae of A. cantonensis, and then observed the infected status by High-resolution Axial T2-weighted MR images. The image of axial-section revealed enlargement of lateral ventricles, obvious enhancement over the outer rims of cerebella, cerebrum, and pons, and various sizes of enlargement over the cerebral parenchymal and olfactory bulb. Besides histopathological findings, immature adult worms and liquefactive necrosis were found in cerebral parenchymal, causing severe inflammation, congestion and hemorrhage in meninges and dura. The histopathological findings were in accordance with the observation of MR imaging. Hence, the MR imaging may have the diagnostic value for grade and location in brain damage those who were infected by A. cantonensis. A nature product, curcumin, which has the effects of anti- inflammation, and anti-carcinogensis, can inhibit MMP-9 secretion to achieve anti-carcinogensis. By using an animal model of BALB/c mice infected with A. cantonensis, previous studies indicated that the anthelmintic drug, albendazole, could kill A. cantonensis larvae and prevent further infection. However, the dead larvae will induce severe immune responses targeting at brain tissues. To alleviate the detrimental effects caused by the dead larvae, we administered curcumin, a traditional anti-inflammatory agent, as a complementary treatment in addition to albendazole therapy, to determine whether curcumin could be beneficial for treatment. The results showed that although curcumin treatment alone did not reduce worm number, combined treatment by albendazole and curcumin helped to reduce eosinophil count in the cerebrospinal fluid, better than using albendazole alone. This alleviating effect did not affect albendazole treatment alone, since histological analysis showed similar worm eradication with or without addition of curcumin. Nevertheless, curcumin treatment alone and combined albendazole-curcumin treatment did not inhibit MMP-9 expression in the brain tissue. In conclusion, curcumin, when used as a complementary treatment to albendazole, could help to alleviate eosinophilic meningitis through suppression of eosinophil count in the cerebrospinal fluid

並列關鍵字

Angiostrongylus cantonensis ； eosinophlic meningitis ； MRI ； curcumin

參考文獻

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Hwang KP, Chen ER, and Chen TS. Eosinophilic meningitis and meningoencephalitis in children. Acta Paediatr Scand. 1994; 35: 124 -135.

Chao D, Lin CC, and Chen YA. Studies on growth and distribution of Angiostrongylus cantonensis larvae in Ampullarium canaliculatus. Southeast Asian J Trop Med and Public Health. 1987; 18: 248-252.

Hwang KP, Hwang AL, Hsieh HC, Liu KM, and Chen SC. Urtastructural findings of mice brain infected with Angiostrongylus cantonensis. Scientific Program and Abstracts of the 9 Annual Meeting of the Chinese Society of Parasitology. 1993; 4: 37.

Abe Y, Hashimoto S, and Horie T. Curcumin inhibition of inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages. Pharmacol Res. 1999; 39: 41-47.

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應用磁振造影新穎診斷法及Albendazole合併薑黃素治療方法對感染廣東住血線蟲小鼠之評估

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