D'Amore V, Santolini I, Celli R, Lionetto L, De Fusco A, Simmaco M, van Rijn C M, Vieira E, Stauffer S R, Conn P J, Bosco P, Nicoletti F, van Luijtelaar G, Ngomba R T
I.R.C.C.S., NEUROMED, Neuropharmacology Unit, Parco Tecnologico, Località Camerelle 86077 Pozzilli, Isernia, Italy.
Department of Neuroscience and Mental Health, St. Andrea Hospital, Rome, Italy.
Neuropharmacology. 2014 Oct;85:91-103. doi: 10.1016/j.neuropharm.2014.05.005. Epub 2014 May 20.
Acute treatment with positive allosteric modulators (PAMs) of mGlu1 and mGlu5 metabotropic glutamate receptors (RO0711401 and VU0360172, respectively) reduces the incidence of spike-and wave discharges in the WAG/Rij rat model of absence epilepsy. However, from the therapeutic standpoint, it was important to establish whether tolerance developed to the action of these drugs. We administered either VU0360172 (3 mg/kg, s.c.) or RO0711401 (10 mg/kg, s.c.) to WAG/Rij rats twice daily for ten days. VU0360172 maintained its activity during the treatment, whereas rats developed tolerance to RO0711401 since the 3rd day of treatment and were still refractory to the drug two days after treatment withdrawal. In response to VU0360172, expression of mGlu5 receptors increased in the thalamus of WAG/Rij rats after 1 day of treatment, and remained elevated afterwards. VU0360172 also enhanced mGlu5 receptor expression in the cortex after 8 days of treatment without changing the expression of mGlu1a receptors. Treatment with RO0711401 enhanced the expression of both mGlu1a and mGlu5 receptors in the thalamus and cortex of WAG/Rij rats after 3-8 days of treatment. These data were different from those obtained in non-epileptic rats, in which repeated injections of RO0711401 and VU0360172 down-regulated the expression of mGlu1a and mGlu5 receptors. Levels of VU0360172 in the thalamus and cortex remained unaltered during the treatment, whereas levels of RO0711401 were reduced in the cortex at day 8 of treatment. These findings suggest that mGlu5 receptor PAMs are potential candidates for the treatment of absence epilepsy in humans.
分别用代谢型谷氨酸受体mGlu1和mGlu5的正变构调节剂（PAMs）（分别为RO0711401和VU0360172）进行急性治疗，可降低失神癫痫WAG/Rij大鼠模型中棘波和慢波放电的发生率。然而，从治疗角度来看，确定这些药物的作用是否会产生耐受性很重要。我们每天给WAG/Rij大鼠皮下注射VU0360172（3mg/kg）或RO0711401（10mg/kg）两次，持续十天。VU0360172在治疗期间保持其活性，而大鼠从治疗第3天起对RO0711401产生耐受性，停药两天后仍对该药物无反应。对VU0360172的反应是，WAG/Rij大鼠在治疗1天后丘脑mGlu5受体表达增加，之后一直保持升高。治疗8天后，VU0360172还增强了皮质中mGlu5受体的表达，而mGlu1a受体的表达未发生变化。用RO0711401治疗3 - 8天后，WAG/Rij大鼠丘脑和皮质中mGlu1a和mGlu5受体的表达均增强。这些数据与非癫痫大鼠不同，在非癫痫大鼠中，重复注射RO0711401和VU0360172会下调mGlu1a和mGlu5受体的表达。治疗期间，丘脑和皮质中VU0360172的水平保持不变，而治疗第8天时，皮质中RO07(11401的水平降低。这些发现表明，mGlu5受体PAMs是治疗人类失神癫痫的潜在候选药物。
