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Attenuation of kindled seizures by intranasal delivery of neuropeptide-loaded nanoparticles.
Neurotherapeutics ( IF 5.6 ) Pub Date : 2009 , DOI: 10.1016/j.nurt.2009.02.001
Michael J Kubek 1 , Abraham J Domb , Michael C Veronesi
Affiliation  

Thyrotropin-releasing hormone (TRH; Protirelin), an endogenous neuropeptide, is known to have anticonvulsant effects in animal seizure models and certain intractable epileptic patients. Its duration of action, however, is limited by rapid tissue metabolism and the blood—brain barrier. Direct nose-to-brain delivery of neuropeptides in sustained-release biodegradable nanoparticles (NPs) is a promising mode of therapy for enhancing CNS neuropeptide bioavailability. To provide proof of principle for this delivery approach, we used the kindling model of temporal lobe epilepsy to show that 1) TRH-loaded copolymer microdisks implanted in a seizure focus can attenuate kindling development in terms of behavioral stage, after-discharge duration (ADD), and clonus duration; 2) intranasal administration of an unprotected TRH analog can acutely suppress fully kindled seizures in a concentration-dependent manner in terms of ADD and seizure stage; and 3) intranasal administration of polylactide nanoparticles (PLA-NPs) containing TRH (TRH-NPs) can impede kindling development in terms of behavioral stage, ADD, and clonus duration. Additionally, we used intranasal delivery of fluorescent dye-loaded PLA-NPs in rats and application of dye-loaded or dye-attached NPs to cortical neurons in culture to demonstrate NP uptake and distribution over time in vivo and in vitro respectively. Also, a nanoparticle immunostaining method was developed as a procedure for directly visualizing the tissue level and distribution of neuropeptide-loaded nanoparticles. Collectively, the data provide proof of concept for intranasal delivery of TRH-NPs as a viable means to 1) suppress seizures and perhaps epileptogenesis and 2) become the lead compound for intranasal anticonvulsant nanoparticle therapeutics.

中文翻译:


通过鼻内递送负载神经肽的纳米颗粒来减弱引发的癫痫发作。



促甲状腺素释放激素(TRH;Protirelin)是一种内源性神经肽,已知对动物癫痫模型和某些顽固性癫痫患者具有抗惊厥作用。然而,其作用持续时间受到快速组织代谢和血脑屏障的限制。通过持续释放的可生物降解纳米粒子(NP)将神经肽直接从鼻到脑输送是一种有前途的增强中枢神经系统神经肽生物利用度的治疗模式。为了为这种递送方法提供原理证明,我们使用颞叶癫痫的点燃模型来表明:1)植入癫痫病灶中的 TRH 负载共聚物微盘可以在行为阶段、放电后持续时间(ADD)方面减弱点燃发展。 ) 和阵挛持续时间; 2)鼻内给予未受保护的TRH类似物可以在ADD和癫痫发作阶段方面以浓度依赖的方式急性抑制完全点燃的癫痫发作; 3)鼻内给予含有TRH (TRH-NPs)的聚丙交酯纳米粒子(PLA-NPs)可以阻碍行为阶段、ADD和阵挛持续时间的点燃发育。此外,我们在大鼠中鼻内递送负载荧光染料的 PLA-NP,并将负载染料或附着染料的 NP 应用于培养的皮质神经元,以分别在体内体外证明 NP 随时间的吸收和分布。此外,还开发了纳米颗粒免疫染色方法作为直接可视化负载神经肽的纳米颗粒的组织水平和分布的程序。 总的来说,这些数据为鼻内递送 TRH-NP 作为一种可行的方法提供了概念证明,以 1) 抑制癫痫发作,或许还可以抑制癫痫发生;2) 成为鼻内抗惊厥纳米颗粒治疗的先导化合物。
更新日期:2020-09-23
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