Argersinger Davis P, Walbridge Stuart, Wetjen Nicholas M, Vortmeyer Alexander O, Wu Tianxia, Butman John A, Heiss John D
1Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
2Neurological & Spinal Surgery, The Iowa Clinic, Des Moines, Iowa.
J Neurosurg. 2019 Jul 19;133(2):588-595. doi: 10.3171/2019.4.JNS19744. Print 2020 Aug 1.
Botulinum toxin serotype A (BoNT/A) was reported to raise the seizure threshold when injected into the seizure focus of a kindled rodent model. Delivering BoNT/A to the nonhuman primate (NHP) central nervous system via convection-enhanced delivery (CED) has not been performed. The objective of this study was to determine the toxicity and distribution characteristics of CED of BoNT/A into the NHP hippocampus and cisterna magna.
Escalating BoNT/A doses were delivered by CED into the NHP hippocampus (n = 4) and cisterna magna (n = 5) for behavioral and histological assessment and to determine the highest nonlethal dose (LD0) and median lethal dose (LD50). Hippocampal BoNT/A was coinfused with Gd-albumin, a surrogate MRI tracer. Gd-albumin and radioiodinated BoNT/A (125I-BoNT/A) were coinfused into the hippocampus of 3 additional NHPs to determine BoNT/A distribution by in vivo MRI and postmortem quantitative autoradiography. Scintillation counting of CSF assessed the flow of 125I-BoNT/A from the hippocampus to CSF postinfusion.
LD0 and LD50 were 4.2 and 18 ng/kg, and 5 and > 5 ng/kg for the NHP hippocampus and cisterna magna, respectively. Gd-albumin and 125I-BoNT/A completely perfused the hippocampus (155-234 mm3) in 4 of 7 NHPs. Fifteen percent of BoNT/A entered CSF after hippocampal infusion. The MRI distribution volume of coinfused Gd-albumin (VdMRI) was similar to the quantitative autoradiography distribution of 125I-BoNT/A (VdQAR) (mean VdMRI = 139.5 mm3 [n = 7]; VdQAR = 134.8 mm3 [n = 3]; r = 1.00, p < 0.0001). No infusion-related toxicity was identified histologically except that directly attributable to needle placement.
Gd-albumin accurately tracked BoNT/A distribution on MRI. BoNT/A did not produce CNS toxicity. BoNT/A LD0 exceeded 10-fold the dose administered safely to humans for cosmesis and dystonia.
据报道，将A型肉毒杆菌毒素（BoNT/A）注入点燃的啮齿动物模型的癫痫病灶时可提高癫痫阈值。尚未通过对流增强递送（CED）将BoNT/A递送至非人类灵长类动物（NHP）的中枢神经系统。本研究的目的是确定将BoNT/A通过CED递送至NHP海马体和小脑延髓池的毒性和分布特征。
通过CED将递增剂量的BoNT/A递送至NHP海马体（n = 4）和小脑延髓池（n = 5），进行行为学和组织学评估，以确定最高非致死剂量（LD0）和半数致死剂量（LD50）。将海马体BoNT/A与钆白蛋白（一种替代MRI示踪剂）共同注入。将钆白蛋白和放射性碘化BoNT/A（125I-BoNT/A）共同注入另外3只NHP的海马体，以通过体内MRI和死后定量放射自显影确定BoNT/A的分布。脑脊液闪烁计数评估注入后125I-BoNT/A从海马体到脑脊液的流动情况。
NHP海马体和小脑延髓池的LD0分别为4.2和18 ng/kg，以及5和>5 ng/kg。在7只NHP中的4只中，钆白蛋白和125I-BoNT/A完全灌注了海马体（155 - 234 mm3）。海马体注入后，15%的BoNT/A进入脑脊液。共同注入的钆白蛋白的MRI分布容积（VdMRI）与125I-BoNT/A的定量放射自显影分布（VdQAR）相似（平均VdMRI = 139.5 mm3 [n = 7]；VdQAR = 134.8 mm3 [n = 3]；r = 1.00，p < 0.0001）。组织学上未发现除与针放置直接相关之外的与注入相关的毒性。
钆白蛋白在MRI上准确追踪了BoNT/A的分布。BoNT/A未产生中枢神经系统毒性。BoNT/A的LD0超过了用于美容和肌张力障碍而安全给予人类的剂量的10倍。
