Department of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, Szeged, Hungary.
Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.
Br J Pharmacol. 2019 May;176(9):1222-1234. doi: 10.1111/bph.14611. Epub 2019 Apr 1.
A new class of dihydropyridine derivatives, which act as co-inducers of heat shock protein but are devoid of calcium channel antagonist and vasodilator effects, has recently been developed with the purpose of selectively targeting neurodegeneration. Here, we evaluated the action of one of these novel compounds LA1011 on neurovascular coupling in the ischaemic rat cerebral cortex. As a reference, we applied nimodipine, a vasodilator dihydropyridine and well-known calcium channel antagonist.
Rats were treated with LA1011 or nimodipine, either by chronic, systemic (LA1011), or acute, local administration (LA1011 and nimodipine). In the latter treatment group, global forebrain ischaemia was induced in half of the animals by bilateral common carotid artery occlusion under isoflurane anaesthesia. Functional hyperaemia in the somatosensory cortex was created by mechanical stimulation of the contralateral whisker pad under α-chloralose anaesthesia. Spreading depolarization (SD) events were elicited subsequently by 1 M KCl. Local field potential and cerebral blood flow (CBF) in the parietal somatosensory cortex were monitored by electrophysiology and laser Doppler flowmetry.
LA1011 did not alter CBF, but intensified SD, presumably indicating the co-induction of heat shock proteins, and, perhaps an anti-inflammatory effect. Nimodipine attenuated evoked potentials and SD. In addition to the elevation of baseline CBF, nimodipine augmented hyperaemia in response to both somatosensory stimulation and SD, particularly under ischaemia.
In contrast to the CBF improvement achieved with nimodipine, LA1011 seems not to have discernible cerebrovascular effects but may up-regulate the stress response.
最近开发了一类新的二氢吡啶衍生物，它们作为热休克蛋白的共诱导剂，而没有钙通道拮抗剂和血管扩张剂的作用，目的是选择性靶向神经退行性变。在这里，我们评估了其中一种新型化合物 LA1011 对缺血性大鼠大脑皮层神经血管偶联的作用。作为参考，我们应用了尼莫地平，一种血管扩张剂二氢吡啶和众所周知的钙通道拮抗剂。
用 LA1011 或尼莫地平对大鼠进行治疗，通过慢性、全身（LA1011）或急性、局部给药（LA1011 和尼莫地平）。在后一种治疗组中，在异氟烷麻醉下通过双侧颈总动脉闭塞在一半动物中诱导全脑缺血。在氯醛糖麻醉下通过对侧须垫机械刺激在体感皮层中产生功能性充血。随后用 1 M KCl 引出扩散性去极化（SD）事件。通过电生理学和激光多普勒血流仪监测顶叶体感皮层的局部场电位和脑血流（CBF）。
LA1011 不改变 CBF，但增强了 SD，可能表明共诱导了热休克蛋白，并且可能具有抗炎作用。尼莫地平减弱了诱发的电位和 SD。除了基线 CBF 的升高外，尼莫地平还增强了对体感刺激和 SD 的充血反应，尤其是在缺血时。
与尼莫地平实现的 CBF 改善相反，LA1011 似乎没有明显的脑血管作用，但可能上调应激反应。
