Gynther Mikko, Petsalo Aleksanteri, Hansen Steen H, Bunch Lennart, Pickering Darryl S
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
Neurochem Res. 2015 Mar;40(3):542-9. doi: 10.1007/s11064-014-1499-4. Epub 2014 Dec 9.
The glutamatergic neurotransmitter system is involved in important neurophysiological processes and thus constitutes a promising target for the treatment of neurological diseases. The two ionotropic glutamate receptor agonists kainic acid (KA) and dihydrokainic acid (DHK) have been used as research tools in various in vivo central nervous system disease models in rodents, as well as being templates in the design of novel ligands affecting the glutamatergic system. Both molecules are highly polar but yet capable of crossing the blood-brain barrier (BBB). We used an in situ rat brain perfusion technique to determine the brain uptake mechanism and permeability across the BBB. To determine KA and DHK concentrations in the rat brain, simple and rapid sample preparation and liquid chromatography mass spectrometer methods were developed. According to our results the BBB permeability of KA and DHK is low, 0.25 × 10(-6) and 0.28 × 10(-6) cm/s for KA and DHK, respectively. In addition, the brain uptake is mediated by passive diffusion, and not by active transport. Furthermore, the non-specific plasma and brain protein binding of KA and DHK was determined to be low, which means that the unbound drug volume of distribution in brain is also low. Therefore, even though the total KA and DHK concentrations in the brain are low after systemic dosing, the concentrations in the vicinity of the glutamate receptors are sufficient for their activation and thus the observed efficacy.
谷氨酸能神经递质系统参与重要的神经生理过程，因此成为治疗神经疾病的一个有前景的靶点。两种离子型谷氨酸受体激动剂 kainic acid（KA）和 dihydrokainic acid（DHK）已被用作啮齿动物各种体内中枢神经系统疾病模型的研究工具，也是设计影响谷氨酸能系统的新型配体的模板。这两种分子都具有高度极性，但仍能穿过血脑屏障（BBB）。我们使用原位大鼠脑灌注技术来确定脑摄取机制和跨血脑屏障的通透性。为了测定大鼠脑中 KA 和 DHK 的浓度，开发了简单快速的样品制备和液相色谱质谱仪方法。根据我们的结果，KA 和 DHK 的血脑屏障通透性较低，KA 和 DHK 分别为 0.25×10⁻⁶ 和 0.28×10⁻⁶ cm/s。此外，脑摄取是由被动扩散介导的，而不是主动转运。此外，测定 KA 和 DHK 与血浆和脑蛋白的非特异性结合较低，这意味着脑中未结合药物的分布容积也较低。因此，尽管全身给药后脑中 KA 和 DHK 的总浓度较低，但谷氨酸受体附近的浓度足以使其激活，从而产生观察到的疗效。
