Efficacy of different nitric oxide-based strategies in preventing experimental cerebral malaria by Plasmodium berghei ANKA.
Efficacy of different nitric oxide-based strategies in preventing experimental cerebral malaria by Plasmodium berghei ANKA.
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DOI：
10.1371/journal.pone.0032048
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Carvalho LJ
中科院分区：
文献类型：
--
作者：
Martins YC;Zanini GM;Frangos JA;Carvalho LJ
低的一氧化氮（NO）生物利用度在人类以及由伯氏疟原虫ANKA（PbA）引起的实验性脑型疟疾（ECM）的发病机制中起作用。ECM通过施用高浓度（1 mg/小鼠）的NO-供体二亚丙基三胺NONOate（DPTA-NO）而被部分地预防，其还诱导主要的副作用，例如血压急剧下降。我们问是否替代策略，以提高NO的生物利用度与轻微的副作用，也将有效地防止ECM。用PbA感染小鼠，并从感染的第0天开始每天两次用单独或组合的L-精氨酸、Nω-羟基-去甲-精氨酸（nor-NOHA）、四氢生物蝶呤（BH 4）、亚硝酸钠、西地那非或西地那非加DPTA-NO的推注进行免疫治疗。L-精氨酸和BH 4补充，有或没有nor-NOHA抑制，增加血浆亚硝酸盐水平，但未能防止ECM的发展。因此，使用渗透泵连续递送L-精氨酸的预防性治疗也没有改善存活率。用亚硝酸钠西地那非（旨在抑制磷酸二酯酶-5）或用DPTA-NO观察到类似的结果。然而，西地那非（0.1mg/小鼠）与较低剂量（0.1mg/小鼠）的DPTA-NO组合降低了ECM发生率（盐水组中82±7.4%死亡率和治疗组中38±10.6%死亡率; p<0.05）。与DPTA-NO 1 mg/小鼠相比，联合预防性治疗不会加重贫血，对收缩压、舒张压和平均动脉压具有延迟效应，并诱导较低的脉压效应。这些数据表明，西地那非降低了预防ECM所需的NO供体的量，也导致了较小的副作用。预防性L-精氨酸在推注或连续输送和推注BH 4补充剂时，有或没有酶抑制剂，能够增加PbA感染小鼠的NO生物利用度，但未能降低ECM的发生率在剂量和协议使用。
Low nitric oxide (NO) bioavailability plays a role in the pathogenesis of human as well as of experimental cerebral malaria (ECM) caused by Plasmodium berghei ANKA (PbA). ECM is partially prevented by administration of the NO-donor dipropylenetriamine NONOate (DPTA-NO) at high concentration (1 mg/mouse), which also induces major side effects such as a sharp drop in blood pressure. We asked whether alternative strategies to improve NO bioavailability with minor side effects would also be effective in preventing ECM. Mice were infected with PbA and prophylactically treated twice a day with bolus injections of L-arginine, Nω-hydroxy-nor-Arginine (nor-NOHA), tetrahydrobiopterin (BH4), separately or combined, sodium nitrite, sildenafil or sildenafil plus DPTA-NO starting on day 0 of infection. L-arginine and BH4 supplementation, with or without arginase inhibition by nor-NOHA, increased plasma nitrite levels but failed to protect against ECM development. Accordingly, prophylactic treatment with continuous delivery of L-arginine using osmotic pumps also did not improve survival. Similar outcomes were observed with sodium nitrite sildenafil (aimed at inhibiting phosphodiesterase-5) or with DPTA-NO. However, sildenafil (0.1 mg/mouse) in combination with a lower dose (0.1 mg/mouse) of DPTA-NO decreased ECM incidence (82±7.4% mortality in the saline group and 38±10.6% in the treated group; p<0.05). The combined prophylactic therapy did not aggravate anemia, had delayed effects in systolic, diastolic and mean arterial blood pressure and induced lower effects in pulse pressure when compared to DPTA-NO 1 mg/mouse. These data show that sildenafil lowers the amount of NO-donor needed to prevent ECM, resulting also in lesser side effects. Prophylactic L-arginine when given in bolus or continuous delivery and bolus BH4 supplementation, with or without arginase inhibition, were able to increase NO bioavailability in PbA-infected mice but failed to decrease ECM incidence in the doses and protocol used.
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影响因子：
82.9
作者：
Gramaglia, Irene;Sobolewski, Peter;van der Heyde, Henri C.
通讯作者：
van der Heyde, Henri C.
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Schmutzhard, E
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