School of Animal and Veterinary Sciences, Charles Sturt University, Wagga Wagga, New South Wales, 2560, Australia; Graham Centre for Agricultural Innovation (NSW Department of Primary Industries and Charles Sturt University), Wagga Wagga, New South Wales, 2560, Australia.
School of Science and Technology, University of New England, Armidale, NSW, 2351, Australia.
Toxicon. 2019 Oct;168:58-66. doi: 10.1016/j.toxicon.2019.06.228. Epub 2019 Jun 27.
The indole diterpenoid toxin lolitrem B is a tremorgenic agent found in the common grass species, perennial ryegrass (Lolium perenne). The toxin is produced by a symbiotic fungus Epichloë festucae (var. lolii) and ingestion of infested grass with sufficient toxin levels causes a movement disorder in grazing herbivores known as 'ryegrass staggers'. Beside ataxia, lolitrem B intoxicated animals frequently show indicators of cognitive dysfunction or exhibition of erratic and unpredictable behaviours during handling. Evidence from field cases in livestock and controlled feeding studies in horses have indicated that intoxication with lolitrem B may affect higher cortical or subcortical functioning. In order to define the role of lolitrem B in voluntary motor control, spatial learning and memory under controlled conditions, mice were exposed to a known dose of purified lolitrem B toxin and tremor, coordination, voluntary motor activity and spatial learning and memory assessed. Motor activity, coordination and spatial memory were compared to tremor intensity using a novel quantitative piezo-electronic tremor analysis. Peak tremor was observed as frequencies between 15 and 25Hz compared to normal movement at approximately 1.4-10Hz. A single exposure to a known tremorgenic dose of lolitrem B (2 mg/kg IP) induced measureable tremor for up to 72 h in some animals. Initially, intoxication with lolitrem B significantly decreased voluntary movement. By 25 h post exposure a return to normal voluntary movement was observed in this group, despite continuing evidence of tremor. This effect was not observed in animals exposed to the short-acting tremorgenic toxin paxilline. Lolitrem B intoxicated mice demonstrated a random search pattern and delayed latency to escape a 3 h post intoxication, however by 27 h post exposure latency to escape matched controls and mice had returned to normal searching behavior indicating normal spatial learning and memory. Together these data indicate that the tremor exhibited by lolitrem B intoxicated mice does not directly impair spatial learning and memory but that exposure does reduce voluntary motor activity in intoxicated animals. Management of acutely affected livestock suffering toxicosis should be considered in the context of their ability to spatially orientate with severe toxicity.
吲哚二萜毒素洛替雷姆 B 是一种震颤原，存在于普通草种多年生黑麦草（Lolium perenne）中。这种毒素是由共生真菌禾谷镰刀菌（var. lolii）产生的，当动物摄入含有足够毒素水平的受感染的草时，会导致一种称为“黑麦草蹒跚病”的运动障碍。除了共济失调外，洛替雷姆 B 中毒的动物在处理过程中经常表现出认知功能障碍或表现出不稳定和不可预测的行为的迹象。来自家畜田间病例和马的受控喂养研究的证据表明，洛替雷姆 B 中毒可能会影响皮质或皮质下的高级功能。为了在受控条件下定义洛替雷姆 B 在自愿运动控制、空间学习和记忆中的作用，用已知剂量的纯化洛替雷姆 B 毒素暴露小鼠，并评估震颤、协调、自愿运动活动和空间学习和记忆。使用新型压电电子震颤分析将运动活动、协调和空间记忆与震颤强度进行比较。与正常运动（约 1.4-10Hz）相比，观察到的最大震颤频率在 15-25Hz 之间。单次暴露于已知致震颤剂量的洛替雷姆 B（2mg/kg IP）在一些动物中可引起长达 72 小时的可测量震颤。最初，洛替雷姆 B 中毒会显著降低自愿运动。暴露后 25 小时，该组观察到自愿运动恢复正常，尽管仍有震颤的证据。在暴露于短作用震颤原白屈菜碱的动物中未观察到这种效应。洛替雷姆 B 中毒的小鼠表现出随机搜索模式，并且在中毒后 3 小时逃避的潜伏期延迟，但是在暴露后 27 小时，逃避潜伏期与对照匹配，并且小鼠已恢复正常搜索行为，表明正常的空间学习和记忆。这些数据表明，洛替雷姆 B 中毒小鼠表现出的震颤不会直接损害空间学习和记忆，但是暴露确实会降低中毒动物的自愿运动活动。在严重中毒的情况下，应考虑急性受影响的牲畜的管理，以考虑它们的空间定向能力。
