"Newton001" The effects of tetrathiomolybdate, a donator of hydrogen sulphide, in animal models of brain ischemia

“Newton001”四硫代钼酸盐（硫化氢供体）对脑缺血动物模型的影响

• 批准号: MR/N007085/1
• 负责人: Mervyn Singer
• 金额: $ 4.62万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN007085%2F1
• 关键词: Newton001; effects; tetrathiomolybdate; donator; hydrogen

Ischaemia (low oxygen) occurs when blood flow to a vital organ (e.g., heart, brain) is insufficient to meet metabolic demand. This leads to death of tissue and loss of function (i.e., as in heart attack, stroke). Presently, there are limited strategies to deal with ischaemia. Although reopening blood vessels (reperfusion) is a necessary, often lifesaving treatment that improves long-term outcome, 'reperfusion injury' upon restoration of blood supply can cause further damage. Attempts to decrease reperfusion injury have recently focussed on decreasing metabolism. For example, after cardiac arrest and resuscitation, decreasing body temperature (therapeutic hypothermia) may have a protective effect, although this takes time to initiate. Giving a drug that can decrease metabolism more rapidly could provide added benefit in this scenario. Hydrogen sulphide given either in gas form or intravenously could induce a state of 'suspended animation' in mice with marked reductions in core temperature and metabolic rate (Blackstone, Science 2005). However, this was far less effective in modulating metabolism in larger species, including rats. We made the novel discovery that the copper-modulating drug, tetrathiomolybdate (TTM), was a slow-releaser or hydrogen sulphide, and could safely induce suspended animation in rats, whereas native hydrogen sulphide had no effect, or toxicity at high doses. We previously found that, when used just prior to resuscitation in a severe haemorrhage-reperfusion injury rat model, mortality was halved. We also found benefit in a heart ischaemia-reperfusion model with a 43% reduction in damaged heart tissue. We wish to extend our findings to explore outcomes in animal models of brain ischaemia. We will focus on mechanisms associated with brain protection after TTM treatment, such as brain inflammation and cognitive performance.

缺血（低氧）发生在血液流向重要器官（例如，心脏、大脑）不足以满足代谢需求。这导致组织死亡和功能丧失（即，如心脏病发作、中风）。目前，处理缺血的策略有限。虽然重新开放血管（再灌注）是一种必要的，通常可以挽救生命的治疗方法，可以改善长期结果，但恢复血液供应后的“再灌注损伤”可能会导致进一步的损伤。减少再灌注损伤的尝试最近集中在降低代谢上。例如，在心脏骤停和复苏后，降低体温（治疗性低温）可能具有保护作用，尽管这需要时间才能启动。在这种情况下，给予一种可以更快地降低代谢的药物可以提供额外的好处。以气体形式或静脉注射硫化氢可诱导小鼠处于“假死”状态，核心温度和代谢率显著降低（黑石，Science 2005）。然而，这在调节包括大鼠在内的较大物种的代谢方面效果要差得多。我们有了新的发现，铜调节药物，四硫代钼酸盐（TTM），是一种缓慢的氢化物或硫化氢，可以安全地诱导大鼠假死，而天然的硫化氢在高剂量下没有效果或毒性。我们以前发现，在严重出血再灌注损伤大鼠模型中，在复苏前使用时，死亡率减半。我们还在心脏缺血再灌注模型中发现了益处，受损心脏组织减少了43%。我们希望将我们的发现扩展到探索脑缺血动物模型的结果。我们将重点关注TTM治疗后与脑保护相关的机制，如脑炎症和认知表现。

项目成果

Effects of MGC-0109, a slow-release sulphide donor, on myocardial ischaemia/reperfusion injury

• DOI: 10.1186/2197-425x-3-s1-a957
• 发表时间: 2015-10-01
• 期刊: Intensive Care Medicine Experimental
• 影响因子: 3.5
• 作者: Dyson A;Lach A;Singer M
• 通讯作者: Singer M

Ammonium tetrathiomolybdate following ischemia/reperfusion injury: Chemistry, pharmacology, and impact of a new class of sulfide donor in preclinical injury models.

• DOI: 10.1371/journal.pmed.1002310
• 发表时间: 2017-07
• 期刊: PLoS medicine
• 影响因子: 15.8
• 作者: Dyson A;Dal-Pizzol F;Sabbatini G;Lach AB;Galfo F;Dos Santos Cardoso J;Pescador Mendonça B;Hargreaves I;Bollen Pinto B;Bromage DI;Martin JF;Moore KP;Feelisch M;Singer M
• 通讯作者: Singer M