Abstract
Amyloid <TEX>${\beta}$</TEX> (<TEX>$A{\beta}$</TEX>)의 신경독성은 알츠하이머병의 주된 원인이 되고 이러한 신경독성은 일련의 신경세포 사멸반응에 의해 일어난다고 알려져 있다. 본 연구에서는 알츠하이머병의 실험모델로 mouse primary neuronal cell에 <TEX>$A{\beta}_{25-35}$</TEX>를 처리하여 세포독성을 유도하는 세포실험모델과 C57BL/6J mouse 뇌실에 <TEX>$A{\beta}_{25-35}$</TEX>를 주입하여 인지장애를 일으키는 동물실험모델을 이용하여 phosphodiesterase III 억제제인 cilostazol의 신경보호 효과에 대해 조사하였다. <TEX>$A{\beta}_{25-35}$</TEX>를 신경세포에 처리하면 세포생존율이 감소되었고, 세포사멸이 일어난 세포의 수도 증가되었다. 이러한 <TEX>$A{\beta}_{25-35}$</TEX>에 의한 세포독성이 cilostazol처리에 의해 회복되었으며, peroxisome proliferator-activated receptor(PPAR)-<TEX>${\gamma}$</TEX> 항진제인 rosiglitazone 또한 동일한 회복효과를 나타내었다. Cilostazol과 rosiglitazone에 의한 이러한 회복효과가 PPAR-<TEX>${\gamma}$</TEX> 길항제인 GW9662에 의해 다시 억제되는 결과를 통해 cilostazol의 효과는 PPAR-<TEX>${\gamma}$</TEX>가 매개하는 신호전달이 관여함을 알 수 있었다. 직접 PPAR-<TEX>${\gamma}$</TEX> 활성화 정도를 측정한 결과, <TEX>$A{\beta}_{25-35}$</TEX> 처리에 의해 감소된 PPAR-<TEX>${\gamma}$</TEX> 활성화 정도가 cilostazol과 rosiglitazone에 의해 증가함을 관찰할 수 있었고, 이는 GW9662에 의해 다시 억제됨을 확인하였다. 게다가, cilostazol은 세포사멸이 일어난 세포의 수와 세포사멸 조절단백질인 Bax/Bcl-2의 비율도 감소시켰다. Cilostazol (20 mg/kg, 구강투여)을 C57BL/6J mice 뇌실에 <TEX>$A{\beta}_{25-35}$</TEX>를 주입하기 2주 동안 전처리하고, <TEX>$A{\beta}_{25-35}$</TEX> 주입 후 4주 동안 처리하면, 기억력과 학습능력을 증진시킨다는 결과를 water maze 실험을 통해 알 수 있었으며, rosiglitazone (10 mg/kg)을 먹인 동물에서도 동일한 결과를 얻을 수 있었다. 본 연구를 통해서 cilostazol이 PPAR-<TEX>${\gamma}$</TEX> 활성화를 통해 <TEX>$A{\beta}_{25-35}$</TEX>로 인한 신경세포 손상과 세포사멸을 약화시켜, 신경세포의 생존을 증진시키고, 알츠하이머에서 인지장애를 개선할 것으로 생각된다. 따라서, phosphodiesterase III 억제제인 cilostazol은 알츠하이머 질병 치료에 새로운 전략이 될 수 있을 것이다. The neurotoxicity of aggregated amyloid <TEX>${\beta}$</TEX> (<TEX>$A{\beta}$</TEX>) has been implicated as a critical cause in the pathogenesis of Alzheimer's disease (AD). It can cause neurotoxicity in AD by evoking a cascade of apoptosis to neuron. Here, we investigated the neuroprotective effects of cilostazol, which acts as a phosphodiesterase III inhibitor, on <TEX>$A{\beta}_{25-35}$</TEX>-induced cytotoxicity in mouse neuronal cells and cognitive decline in the C57BL/6J AD mouse model via peroxisome proliferator-activated receptor (PPAR)-<TEX>${\gamma}$</TEX> activation. <TEX>$A{\beta}_{25-35}$</TEX> significantly reduced cell viability and increased the number of apoptotic-like cells. Cilostazol treatment recovered cells from <TEX>$A{\beta}$</TEX>-induced cell death as well as rosiglitazone, a PPAR-<TEX>${\gamma}$</TEX> activator. These effects were suppressed by GW9662, an antagonist of PPAR-<TEX>${\gamma}$</TEX> activity, indicative of a PPAR-<TEX>${\gamma}$</TEX>-mediated signaling. In addition, cilostazol and rosiglitazone also restored PPAR-<TEX>${\gamma}$</TEX> activity levels that had been altered as a result of <TEX>$A{\beta}_{25-35}$</TEX> treatment, which were antagonized by GW9662. Furthermore, cilostazol also markedly decreased the number of apoptotic-like cells and decreased the Bax/Bcl-2 ratio. Intracerebroventricular injection of <TEX>$A{\beta}_{25-35}$</TEX> in C57BL/6J mice resulted in impaired cognitive function. Oral administration of cilostazol (20 mg/kg) for 2 weeks before <TEX>$A{\beta}_{25-35}$</TEX> injection and once a day for 4 weeks post-surgery almost completely prevented the <TEX>$A{\beta}_{25-35}$</TEX>-induced cognitive deficits, as did rosiglitazone. Taken together, our findings suggest that cilostazol could attenuate <TEX>$A{\beta}_{25-35}$</TEX>-induced neuronal cell injury and apoptosis as well as promote the survival of neuronal cells, subsequently improving cognitive decline in AD, partly because of PPAR-<TEX>${\gamma}$</TEX> activation. The phosphodiesterase III inhibitor cilostazol may be the basis of a novel strategy for the therapy of AD.
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