Head-to head comparison of mGlu1 and mGlu5 receptor activation in chronic treatment of absence epilepsy in WAG/Rij rats

Abstract

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

Anti‐absence activity of mGlu1 and mGlu5 receptor enhancers and their interaction with a GABA reuptake inhibitor: Effect of local infusions in the somatosensory cortex and thalamus

“…Systemic administration of compounds RO0711401 and VU0360172, which behave as selective positive allosteric modulators (PAMs) of mGlu1 and mGlu5 receptors, respectively, decrease the incidence of SWDs in symptomatic WAG/Rij rats . No tolerance develops to the antiabsence activity of VU0360172, whereas the activity of RO0711401 declines after the first 3 days of repeated administrations . It is not known precisely where within the C‐T‐C circuit activation of mGlu1 or mGlu5 receptors reduces SWDs.…”

Is There a Future for mGlu5-Positive Allosteric Modulators in Absence Epilepsy? A Comparison with Ethosuximide

“…From a therapeutic standpoint, it is important to establish whether tolerance is developed to the action of these putative anti-absence drugs. Effective doses of VU0360172 (3 mg/kg, s.c.) and RO0711401 (10 mg/kg, s.c.) were administered to rats twice daily for 10 days, and incidence of SWDs was determined across this period (D'Amore et al 2014(D'Amore et al , 2013. As expected (Ngomba et al 2011b), both mGlu1 and mGlu5 receptor PAMs suppressed the incidence of SWDs in the first 2 days of treatment.…”

“…Opposite data were obtained in non-epileptic wistar rats, in which repeated injections of the two PAMs downregulated the expression of mGlu1α and mGlu5Rs. RO0711401 changed the expression of both the mGlu1α and the mGlu5Rs in WAG/Rij and wistar rats, whereas VU0360172 selectively changed the expression of mGlu5Rs only (D'Amore et al 2014). These pharmacody-namic and accompanying pharmacokinetic studies could not explain the large differences between VU0360172 and RO0711401 in terms of tolerance to the SWD-suppressing effects.…”

Metabotropic glutamate receptors as drug targets for the treatment of absence epilepsy

“…The rats developed complete tolerance to RO0711401 after 2 days, while VU0360172 maintained its anti-SWD effects throughout this period and even after 48 hours from ceasing treatment [15] (see also Table 1). The mechanism for this tolerance remains unclear, but it limits the clinical usefulness of RO0711401.…”

“…MPEP mGlu5 NAM with an mGlu4 NAM component reduces SWDs in Ih/Ih mice [33] Development of tolerance: VU0360172 (NON after 10 days), while RO0711401 did develop after 2 days [15] Local infusion of either RO0711401 or VU0360172 suppressed SWDs independently both in the cortex and thalamus [16 ] LY341495 an orthosteric antagonist reduces SWDs in WAG/Rij rats [17] LY379268 an orthosteric agonist increases SWDs in WAG/Rij rats [17]. LY389795 and LY379268 both reduces SWDs in Ih/Ih mice [45] PHCCC enhances SWDs in WAG/Rij rats [9 ] ADX71743 produces lethargic effects similar to SWDs in WT mice [19].…”