Haga Kristin K, Gregory Lloyd J, Hicks Caroline A, Ward Mark A, Beech John S, Bath Phillip W, Williams Steven C R, O'Neill Michael J
Department of Clinical Neuroscience, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
Brain Res. 2003 Dec 12;993(1-2):42-53. doi: 10.1016/j.brainres.2003.08.063.
Most neuroprotective compounds that appear promising in the pre-clinical phase of testing are subsequently dismissed as relatively ineffective when entered into large-scale clinical trials. Many pre-clinical studies of potential neuroprotective candidates evaluate efficacy in only one or possibly two different models of ischaemia. In this study we examined the effects of 1,2-trifluoromethylphenyl imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor, in three models of cerebral ischaemia (global gerbil, global rat and focal rat). In addition, to follow the progression of the pathology, we also compared traditional histology methods with more advanced magnetic resonance imaging (MRI) as endpoint measures for neurological damage and neuroprotection. TRIM (50 mg/kg i.p.) prevented ischaemia-induced hippocampal damage following global ischaemia in gerbils when administered before or immediately post-occlusion, but failed to protect when administration was delayed until 30 min post-occlusion. Further studies indicated that the compound (administered at 50 mg/kg, i.p., immediately after occlusion) also protected in a rat four-vessel occlusion (4-VO) model using both histological and diffusion-weighted (DW) imaging techniques. In a final study, TRIM (50 mg/kg i.p. 30 min after occlusion) provided a significant reduction in infarct volume at 4 and 24 h as measured using diffusion-weighted (DW) and proton density (PD)-weighted magnetic resonance imaging (MRI). This was confirmed using histological techniques. These studies confirm that nNOS inhibitors may have utility in stroke and provide evidence that combined magnetic resonance and histological methods can provide a powerful method of assessing neuronal damage in rodent models of cerebral ischaemia.
大多数在临床前测试阶段显示出有前景的神经保护化合物，在进入大规模临床试验时，随后都被认为相对无效而被摒弃。许多潜在神经保护候选物的临床前研究仅在一种或可能两种不同的缺血模型中评估疗效。在本研究中，我们研究了新型神经元型一氧化氮合酶（nNOS）抑制剂1,2-三氟甲基苯基咪唑（TRIM）在三种脑缺血模型（沙土鼠全脑缺血、大鼠全脑缺血和大鼠局灶性缺血）中的作用。此外，为了跟踪病理进展，我们还将传统组织学方法与更先进的磁共振成像（MRI）进行了比较，作为神经损伤和神经保护的终点测量方法。TRIM（50mg/kg腹腔注射）在沙土鼠全脑缺血前或闭塞后立即给药时，可预防缺血诱导的海马损伤，但在闭塞后30分钟延迟给药时则无法起到保护作用。进一步的研究表明，该化合物（闭塞后立即腹腔注射50mg/kg）在大鼠四血管闭塞（4-VO）模型中，使用组织学和扩散加权（DW）成像技术均具有保护作用。在最后一项研究中，TRIM（闭塞后30分钟腹腔注射50mg/kg）在4小时和24小时时，使用扩散加权（DW）和质子密度（PD）加权磁共振成像（MRI）测量显示梗死体积显著减小。这一点通过组织学技术得到了证实。这些研究证实nNOS抑制剂可能对中风有用，并提供了证据表明磁共振和组织学方法相结合可提供一种强大的方法来评估脑缺血啮齿动物模型中的神经元损伤。
