Dendrimer-based postnatal therapy for neuroinflammation and cerebral palsy in a rabbit model.
Dendrimer-based postnatal therapy for neuroinflammation and cerebral palsy in a rabbit model.
复制标题
DOI：
10.1126/scitranslmed.3003162
复制
发表时间：
2012-04-18
影响因子：
17.1
通讯作者：
Kannan RM
中科院分区：
文献类型：
--
作者：
Kannan S;Dai H;Navath RS;Balakrishnan B;Jyoti A;Janisse J;Romero R;Kannan RM
脑性瘫痪（CP）是一种慢性儿童疾病，目前尚无有效的治疗方法。由活化的小胶质细胞和星形胶质细胞引起的神经炎症在CP和诸如阿尔茨海默病和多发性硬化症的疾病的发病机制中起关键作用。靶向神经炎症可能是一种有效的治疗策略。然而，将药物穿过血脑屏障递送到靶细胞以治疗弥漫性脑损伤是一个重大挑战。在这里，我们表明，全身给药的聚酰胺-胺树枝状聚合物定位于激活的小胶质细胞和星形胶质细胞在新生兔脑CP，但不是健康对照。我们进一步证明了基于树枝状聚合物的N-乙酰-L-半胱氨酸（NAC）治疗脑损伤抑制神经炎症，并导致CP试剂盒中运动功能的显着改善。当与基于树枝状聚合物的靶向组合时，NAC的众所周知的和安全的临床特征为在人类神经炎性病症的治疗中的临床转化提供了机会。在出生后时期施用用于产前损伤的树枝状聚合物-NAC治疗的有效性表明了在出生后治疗人类CP的机会窗口。
Cerebral palsy (CP) is a chronic childhood disorder with no effective cure. Neuroinflammation, caused by activated microglia and astrocytes, plays a key role in the pathogenesis of CP and disorders such as Alzheimer’s disease and multiple sclerosis. Targeting neuroinflammation can be a potent therapeutic strategy. However, delivering drugs across the blood-brain-barrier to the target cells for treating diffuse brain injury is a major challenge. Here, we show that systemically administered polyamidoamine dendrimers localize in activated microglia and astrocytes in the brain of newborn rabbits with CP, but not healthy controls. We further demonstrate that dendrimer-based N-acetyl-L-cysteine (NAC) therapy for brain injury suppresses neuroinflammation and leads to a dramatic improvement in motor function in the CP kits. The well known and safe clinical profile for NAC when combined with dendrimer-based targeting, provides opportunities for clinical translation in the treatment of neuroinflammatory disorders in humans. The effectiveness of the dendrimer-NAC treatment, administered in the postnatal period for a prenatal insult, suggests a window of opportunity for treatment of CP in humans after birth.
登录
查看更多内容
影响因子：
9.3
作者：
Chen, Xuesong;Gawryluk, Jeremy W;Wagener, John F;Ghribi, Othman;Geiger, Jonathan D
通讯作者：
Geiger, Jonathan D
影响因子：
9.3
作者：
Kannan, Sujatha;Saadani-Makkil, Fadoua;Chugani, Diane C.
通讯作者：
Chugani, Diane C.
影响因子：
6.1
作者：
Kaya, M;Gulturk, S;Sivas, A
通讯作者：
Sivas, A
影响因子：
14
作者：
Iezzi, Raymond;Guru, Bharath R.;Kannan, Rangaramanujam M.
通讯作者：
Kannan, Rangaramanujam M.
影响因子：
3.3
作者：
Dommergues, MA;Plaisant, F;Gressens, P
通讯作者：
Gressens, P