Potentiation of mGlu5 receptors with the novel enhancer, VU0360172, reduces spontaneous absence seizures in WAG/Rij rats

Abstract

Absence epilepsy is generated by the cortico-thalamo-cortical network, which undergoes a finely tuned regulation by metabotropic glutamate (mGlu) receptors. We have shown previously that potentiation of mGlu1 receptors reduces spontaneous occurring spike and wave discharges (SWDs) in the WAG/Rij rat model of absence epilepsy, whereas activation of mGlu2/3 and mGlu4 receptors produces the opposite effect. Here, we have extended the study to mGlu5 receptors, which are known to be highly expressed within the cortico-thalamo-cortical network. We used presymptomatic and symptomatic WAG/Rij rats and aged-matched ACI rats. WAG/Rij rats showed a reduction in the mGlu5 receptor protein levels and in the mGlu5-receptor mediated stimulation of polyphosphoinositide hydrolysis in the ventrobasal thalamus, whereas the expression of mGlu5 receptors was increased in the somatosensory cortex. Interestingly, these changes preceded the onset of the epileptic phenotype, being already visible in pre-symptomatic WAG/Rij rats. SWDs in symptomatic WAG/Rij rats were not influenced by pharmacological blockade of mGlu5 receptors with MTEP (10 or 30 mg/kg, i.p.), but were significantly decreased by mGlu5 receptor potentiation with the novel enhancer, VU0360172 (3 or 10 mg/kg, s.c.), without affecting motor behaviour. The effect of VU0360172 was prevented by co-treatment with MTEP. These findings suggest that changes in mGlu5 receptors might lie at the core of the absence-seizure prone phenotype of WAG/Rij rats, and that mGlu5 receptor enhancers are potential candidates to the treatment of absence epilepsy.

Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

“…Reduced expression of NR1 subunits of NMDA receptors in the somatosensory cortex in comparison to non-epileptic ACI rats both at 3 and 6 months of age (van de BovenkampJanssen et al, 2006) Lower expression of the NR2B subunit of the NMDA receptors in both 2-month-old and 6-month-old WAG/Rij rats in different layers of the somatosensory cortex in comparison to Wistar rats of the same age (Karimzadeh et al, 2013) AMPA-GluA4 subunit density is lower in WAG/Rij rats than in ACI rats in S1po layers independently from age and seizure development GluA2 subunits are not expressed around cell bodies in thalamic nuclei with the exception of the NRT, whereas, they are widely expressed in the two cortical sites examined (S1po and the forelimb region of the primary somatosensory cortex (Citraro et al, 2006b) Reduced expression and function of mGlu5 receptors in the thalamus has been observed in pre-epileptic WAG/Rij rats, while an increased receptor expression in the sensorimotor cortex was described (D'Amore et al, 2013) Ion Channels Altered HCN channel expression and cAMP sensitivity of I h has been shown in WAG/Rij rats in the postnatal age continuing into the chronic epilepsy state; HCN1 channel expression decreases, mainly in the dendrites of cortical layer V pyramidal neurons that occurs temporally before the developmental onset of SWDs, and at a cellular level plays a direct role in promoting dendritic Ca 2+ electrogenesis and burst firing (Budde et al, 2005;Kuisle et al, 2006) …”

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

“…Finally, we examined whether chronic treatment with VU0360172 in Wistar rats could induce the appearance of SWDs as a result of the down-regulation of mGlu5 receptors in the thalamus (see D’Amore et al, 2013). No SWDs were recorded in Wistar rats treated for 8 days with VU0360172 (3 mg/kg, s.c. twice daily).…”

“…VU0360172 was administered at the centrally active dose of 3 mg/kg (Rodriguez et al, 2010), which was also effective in reducing SWD number and mean duration (D’Amore et al, 2013), taken into consideration that very high doses (30 mg/kg and more) of mGlu5 PAMs [e.g. 5PAM523 = (4-Fluorophenyl){(2R,5S)-5-[5-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-3-yl]-2-methylpiperidin-1-yl}methanone), has been reported to show neurotoxic and seizure side effects in Female Wistar Hannover rats (Parmentier-Batteur et al, 2013).…”

“…By definition, PAMs amplify receptor function only in the presence of an orthosteric agonist, and therefore recruit only mGlu receptors activated by endogenous glutamate (reviewed Niswender and Conn, 2010). Acute systemic treatment with mGlu1 and mGlu5 receptor PAMs (RO0711401 and VU030172, respectively) reduces the incidence of SWDs in the WAG/Rij rat model (Ngomba et al, 2011b; D’Amore et al, 2013), a genetic model of absence epilepsy with excellent predictive validity (Coenen and van Luijtelaar, 2003; van Luijtelaar and Sitnikova, 2006). Because RO0711401 and VU030172 do not affect motor behaviour, there are interesting for the development as anti-absence drugs for humans.…”

The effects of agomelatine and melatonin on ECoG activity of absenceepilepsy model in WAG/Rij rats

“…The molecular mechanisms underlying antiepileptic activity of melatonin were suggested as enhancement of norepinephrine secretion through adrenergic receptors (Reiter et al, 2007), reduction of striatal dopaminergic activity through dopaminergic D1 and D2 receptors (Sweis, 2005), downregulation of glutamate secretion through blockage of nitric oxide generation (Munoz Hoyos et al, 1998), and upregulation of GABA release in hippocampus (Stewart and Leung, 2005). However, none of these studies explained the antiepileptic activity of melatonin in absence epilepsy, since absence epilepsy is related to a predominance of inhibitory activity in contrast to convulsive seizures, where an excess of excitatory activity is present (Tolmacheva and van Luijtelaar, 2007;Ngomba et al, 2011;D' Amore et al, 2013;Kovacs et al, 2015). Generation of absence seizures is thought to be associated with excessive thalamic oscillations, due to abnormal intrinsic neuronal properties under the control of an inhibitory GABAergic mechanism (Steriade et al, 1993;Manning et al, 2003;Kovacs et al, 2015).…”