Kretschmer B D, Kratzer U, Schmidt W J
Department of Neuropharmacology, University of Tübingen, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1998 Aug;358(2):181-90. doi: 10.1007/pl00005241.
Riluzole (2-amino-6-trigluoromethoxy benzothiazole) has neuroprotective, anticonvulsant, anxiolytic and anesthetic qualities. These effects are mediated by blockade of glutamate transmission, stabilizing of sodium channels and blockade of gamma-aminobutyric acid (GABA) reuptake. The action profile of riluzole is dominated by its effects on glutamate transmission which are predominately mediated by N-methyl-D-aspartate (NMDA) receptor-linked processes in vitro. In vivo studies show that blockade and stimulation of the different NMDA receptor complex binding sites or AMPA receptors modulate motor behavior in a characteristic manner. It was therefore interesting to examine if blockade of glutamatergic transmission by riluzole induced similar behavioral effects as direct NMDA/AMPA receptor antagonists and if these effects are mediated by a specific receptor. The effects of riluzole alone and in combination with several other neuroactive compounds on the central nervous system was assessed by behavioral paradigms to evaluate sniffing behavior, locomotion, ataxia and rigidity. Accompanying compounds included the NMDA receptor agonist NMDA, the partial glycine site agonist D-cycloserine (DCS), and the alpha-amino-3-hydroxy-5-phenyl-4-isoxazolepropionic acid (AMPA) receptor antagonist GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzo-diazepine HCl]. Riluzole influenced neither stereotyped sniffing behavior nor locomotion but impaired motor coordination and attenuated rigidity induced by blockade of dopamine D1 and D2 receptor antagonists when given alone. At higher doses spontaneous behavioral activity decreased and motor coordination was more impaired. Augmentation of the riluzole effects were observed when NMDA, but not GYKI 52466, was coadministered. The glycine site agonist DCS increased the anticataleptic properties of riluzole. The results indicate that when given alone, riluzole has a behavioral profile resembling that of competitive NMDA receptor antagonists. However, coadministration of riluzole with NMDA/AMPA receptor ligands suggests that this assumption is incorrect, and that riluzole affects glutamatergic transmission by a more indirect mechanism. Nevertheless, the profile of riluzole together with its pre- and postsynaptic blockade of glutamatergic transmission implies beneficial properties in diseases where an overactive glutamate system induces chronic neurotoxicity and/or acute behavioral effects.
利鲁唑（2-氨基-6-三氟甲氧基苯并噻唑）具有神经保护、抗惊厥、抗焦虑和麻醉特性。这些作用是通过阻断谷氨酸传递、稳定钠通道以及阻断γ-氨基丁酸（GABA）再摄取来介导的。利鲁唑的作用特征主要由其对谷氨酸传递的影响所主导，在体外，这些影响主要由与N-甲基-D-天冬氨酸（NMDA）受体相关的过程介导。体内研究表明，阻断和刺激不同的NMDA受体复合物结合位点或α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体以一种特征性方式调节运动行为。因此，研究利鲁唑阻断谷氨酸能传递是否会诱导与直接NMDA/AMPA受体拮抗剂类似的行为效应，以及这些效应是否由特定受体介导，是很有意思的。通过行为范式评估利鲁唑单独使用以及与其他几种神经活性化合物联合使用对中枢神经系统的影响，以评估嗅探行为、运动、共济失调和强直。伴随化合物包括NMDA受体激动剂NMDA、部分甘氨酸位点激动剂D-环丝氨酸（DCS）以及α-氨基-3-羟基-5-苯基-4-异恶唑丙酸（AMPA）受体拮抗剂GYKI 52466 [1-（4-氨基苯基）-4-甲基-7,8-亚甲基二氧基-5H-2,3-苯并二氮杂卓盐酸盐]。利鲁唑既不影响刻板嗅探行为也不影响运动，但单独给药时会损害运动协调并减轻多巴胺D1和D2受体拮抗剂阻断诱导的强直。在较高剂量时，自发行为活动减少，运动协调受损更严重。当联合给予NMDA而非GYKI 52466时，观察到利鲁唑的效应增强。甘氨酸位点激动剂DCS增强了利鲁唑的抗僵住特性。结果表明，单独给药时，利鲁唑的行为特征类似于竞争性NMDA受体拮抗剂。然而，利鲁唑与NMDA/AMPA受体配体联合给药表明这一假设是不正确的，并且利鲁唑通过更间接的机制影响谷氨酸能传递。尽管如此，利鲁唑的特征及其对谷氨酸能传递的突触前和突触后阻断意味着在谷氨酸系统过度活跃诱导慢性神经毒性和/或急性行为效应的疾病中具有有益特性。
