Self-nanomicellizing solid dispersion of edaravone: part II: in vivo assessment of efficacy against behavior deficits and safety in Alzheimer's disease model.
机构：[1]School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia[2]Neuroscience Institute, Kunming Medical University, Kunming, Yunnan, China[3]Central Laboratory, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China[4]Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, Sichuan, China
Alzheimer's disease (AD) is a devastating neurodegenerative disorder that lacks any disease-modifying drug for the prevention and treatment. Edaravone (EDR), an approved free radical scavenger, has proven to have potential against AD by targeting multiple key pathologies including amyloid-beta (Aβ), tau phosphorylation, oxidative stress, and neuroinflammation. To enable its oral use, novel edaravone formulation (NEF) was previously developed. The aim of the present investigation was to evaluate safety and efficacy of NEF by using in vitro/in vivo disease model.
In vitro therapeutic potential of NEF over EDR was studied against the cytotoxicity induced by copper metal ion, H2O2 and Aβ42 oligomer, and cellular uptake on SH-SY5Y695 amyloid-β precursor protein (APP) human neuroblastoma cell line. For in vivo safety and efficacy assessment, totally seven groups of APP/PS1 (five treatment groups, one each as a basal and sham control) and one group of C57BL/6 mice as a positive control for behavior tests were used. Three groups were orally treated for 3 months with NEF at an equivalent dose of EDR 46, 138, and 414 µmol/kg, whereas one group was supplied with each Donepezil (5.27 µM/kg) and Soluplus (amount present in NEF of 414 µmol/kg dose of EDR). Behavior tests were conducted to assess motor function (open-field), anxiety-related behavior (open-field), and cognitive function (novel objective recognition test, Y-maze, and Morris water maze). For the safety assessment, general behavior, adverse effects, and mortality were recorded during the treatment period. Moreover, biochemical, hematological, and morphological parameters were determined.
Compared to EDR, NEF showed superior cellular uptake and neuroprotective effect in SH-SY5Y695 APP cell line. Furthermore, it showed nontoxicity of NEF up to 414 µM/kg dose of EDR and its potential to reverse AD-like behavior deficits of APP/PS1 mice in a dose-dependent manner.
Our results indicate that oral delivery of NEF holds a promise as a safe and effective therapeutic agent for AD.
基金：
The authors would specially like to acknowledge Fujian Kangshimei Co, China for the financial support for the present research, the University President’s Scholarships from University of South Australia for AP and ZS for their doctorate study; NHMRC fellowship for XFZ; and a scholarship under state scholarship fund from China Scholarship Council for JL. Fujian Kangshimei Co, China owns the intellectual property for Chinese patent 200610149832.9. The authors would like to acknowledge H Md Morshed Alam (BASF Australia Ltd) for providing samples of SOL; Rupal Pradhan and Andrew Beck from University of South Australia for hematological, coagulation parameters, and histology studies; Rebecca Summerton and Dr Ian Beckman from Veterinary Diagnostic Laboratory, the University of Adelaide, for serum biochemistry study; and Noralyn Manucat-Tan and Chun-Sheng Ruan for behavior tests. The staff members of Reid animal house facility including Alex Whittaker, Ruth Brogan, Jayne Skinner, Alysha Servin, Jess Parken, and Becky Nitschke from University of South Australia are acknowledged for their generous support in animal work.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2018]版：
大类|3 区医学
小类|3 区药物化学3 区药学
最新[2023]版：
大类|2 区医学
小类|2 区药物化学2 区药学
第一作者：
第一作者机构：[1]School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia
通讯作者：
通讯机构：[1]School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia[*1]School of Pharmacy and Medical Sciences, University of South Australia, GPO Box 2471, Adelaide, SA5001, Australia
推荐引用方式(GB/T 7714)：
Ankit Parikh,Krishna Kathawala,Jintao Li,et al.Self-nanomicellizing solid dispersion of edaravone: part II: in vivo assessment of efficacy against behavior deficits and safety in Alzheimer's disease model.[J].Drug design, development and therapy.2018,12:2111-2128.doi:10.2147/DDDT.S161944.
APA：
Ankit Parikh,Krishna Kathawala,Jintao Li,Chi Chen,Zhengnan Shan...&Xin-Fu Zhou.(2018).Self-nanomicellizing solid dispersion of edaravone: part II: in vivo assessment of efficacy against behavior deficits and safety in Alzheimer's disease model..Drug design, development and therapy,12,
MLA：
Ankit Parikh,et al."Self-nanomicellizing solid dispersion of edaravone: part II: in vivo assessment of efficacy against behavior deficits and safety in Alzheimer's disease model.".Drug design, development and therapy 12.(2018):2111-2128
