Engelstein R, Ovadia H, Gabizon R
Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital, Jerusalem, Israel.
Eur J Neurol. 2007 Aug;14(8):877-84. doi: 10.1111/j.1468-1331.2007.01803.x.
The hallmark of prion disease-induced neurodegeneration is the accumulation of PrP(Sc), a misfolded form of PrP(C). In addition, several lines of evidence indicate a role for the immune system and, in particular, inflammation in prion disease pathogenesis. In this work, we tested whether Copaxone, an immunomodulatory agent currently used for the treatment of multiple sclerosis, can affect prion disease manifestation in scrapie-infected hamsters. We show here that Copaxone exerted no effect on prion disease incubation time when treatment commenced 2 weeks after i.p. prion infection. However, when Copaxone was mixed with the initial prion inoculum or administered to hamsters weekly starting on the day of infection, prion disease incubation time was prolonged by 30 days. This suggests that Copaxone may affect the initial infection process. In vitro experiments indicate that Copaxone significantly reduced PrP(Sc) binding to both Chinese hamster ovary (CHO) cells and heparin beads and also binds to heparin by itself. Interestingly, Copaxone also abolished PrP(Sc) accumulation in scrapie-infected cells. We propose that Copaxone delays prion infection by competing with the PrP(Sc)-glycosaminoglycans interaction. Whether the immunomodulating activity of Copaxone is related to its heparin binding and anti-prion properties remains to be established.
朊病毒疾病诱导的神经退行性变的标志是PrP(Sc)的积累，PrP(Sc)是PrP(C)的一种错误折叠形式。此外，多条证据表明免疫系统，特别是炎症在朊病毒疾病发病机制中发挥作用。在这项研究中，我们测试了目前用于治疗多发性硬化症的免疫调节剂考帕松是否会影响感染羊瘙痒病的仓鼠的朊病毒疾病表现。我们在此表明，在腹腔注射朊病毒感染2周后开始治疗时，考帕松对朊病毒疾病的潜伏期没有影响。然而，当考帕松与初始朊病毒接种物混合或从感染当天开始每周给仓鼠给药时，朊病毒疾病的潜伏期延长了30天。这表明考帕松可能会影响初始感染过程。体外实验表明，考帕松显著降低了PrP(Sc)与中国仓鼠卵巢（CHO）细胞和肝素珠的结合，并且其自身也能与肝素结合。有趣的是，考帕松还消除了感染羊瘙痒病的细胞中PrP(Sc)的积累。我们提出，考帕松通过与PrP(Sc)-糖胺聚糖相互作用竞争来延迟朊病毒感染。考帕松的免疫调节活性是否与其肝素结合和抗朊病毒特性有关仍有待确定。
