Suicide transport blockade of motor neuron survival generates a focal graded injury and functional deficit  

作　　者：Allison S.Liang Joanna E.Pagano Christopher A.Chrzan Randall D.McKinnon 

机构地区：[1]Department of Neurosurgery,Rutgers-Robert Wood Johnson Medical School,Piscataway,NJ,USA [2]Member,The Cancer Institute of New Jersey,New Brunswick,NJ,USA

出　　处：《Neural Regeneration Research》2021年第7期1281-1287,共7页中国神经再生研究（英文版）

基　　金：Supported by grants to Dr McKinnon (PI) from the New Jersey Commission on Spinal Cord Research (05-3047;11-015)。

摘　　要：We describe a pre-clinical spinal cord motor neuron injury model that is minimal invasive, reproducible, focal and easily applied to small rodents.Retrograde axonal transport of a pro-apoptotic phosphatidylinosotol 3'-kinase inhibitor, wortmannin, via the sciatic nerve results in loss of ipsilateral lumbar motor neurons proportional to the level of drug administered.Motor neuron loss was detected by choline acetyltransferase(ChAT) immunostaining and with a transgenic thy1-eGFP marker.The short half-life of wortmannin generates minimal wound spread, and wortmannin does not affect axon transport, as determined by co-injection of a pseudorabies virus tracer.Using quantitative transcript analysis, we found that ChAT transcripts significantly decreased at 14 days post-delivery of 1 μg wortmannin, relative to sham controls, and remained low after 90 days.Smaller effects were observed with 200 ng and 100 ng wortmannin.Wortmannin also generated a transient and significant increase in astrocyte Gfap transcripts after 14 days with a return to control levels at 90 days.Treated mice had hind limb spasticity and a forced motor function defect that was quantified using a water exit test.Controls rapidly exit a shallow water tray, and wortmannin treated animals were up to 12-fold slower, a phenotype that persisted for at least 3 months.Thus the focal delivery of wortmannin to motor neurons generates a reproducible and scalable injury that can facilitate quantitative studies on neural regeneration and repair.The efficacy of sciatic nerve suicide transport can also explain neurotoxin-mediated selective loss of motor neurons in diseases such as amyotrophic lateral sclerosis.All procedures were performed at Rutgers under established Institutional Animal Care and Use protocols(eIACUC_TR201800022, approved on March 20, 2018).

关 键 词：amyotrophic lateral sclerosis INJURY motor function motor neuron PI3'kinase sciatic nerve suicide transport WORTMANNIN 

分 类 号：R453[医药卫生—治疗学] R364[医药卫生—临床医学]