The anti-absence effect of mGlu5 receptor amplification with VU0360172 is maintained during and after antiepileptogenesis

Abstract

Ethosuximide (ETX) has become the drug of choice in the treatment of patients with absence seizures taking into account both its efficacy, tolerability and antiepileptogenic properties. However, 47% of subjects treated with ETX failed in therapy, and most antiepileptic drugs have cognitive side effects. VU0360172, a positive allosteric modulator (PAM) of mGluR5, acutely and chronically administered decreased seizures dose dependently in rats of the WAG/Rij strain, a genetic absence model. Here it is investigated whether anti-epileptogenesis induced by ETX alters the sensitivity of VU0360172 as an anti-absence drug, and cognition is affected during and after chronic ETX treatment.Method: Male WAG/Rij rats were chronically treated with ETX for 4 months. EEG's were recorded during and after treatment as well as challenged with VU0360172. Rats were also periodically exposed to a cue discrimination learning task in a Y-maze. mGlu5 receptors were quantified with Western Blot.Results: Antiepileptogenesis was successfully induced by ETX and VU0360172 showed a time and dose dependent anti-absence action. However, chronic ETX treated rats showed a decrease in absences both during and after the end treatment, without clear time and dose related effects. The decrease of sensitivity for VU0360172 was not accompanied by a change in mGluR5 expression in cortex and thalamus. Chronic ETX enhanced motivation to collect sucrose pallets and this was followed by an increase in cued discrimination learning.It is concluded that VU0360172 keeps its antiabsence effects after chronic treatment. Moreover, its differential effects in the two groups cannot be explained by a simple receptor down regulation suggesting a more downstream interaction between ETX and mGluR5. The cognitive enhancing effects of ETX, as found at the end of the experiment might be mediated to the antidepressant action of ETX as expressed by an increase in the rewarding properties of sucrose pallets.

Experimental Treatment Options in Absence Epilepsy

“…In WAG/Rij, 4-month pharmacological treatment with ETX initiated immediately after weaning, i.e., before SWDs onset, suppressed seizures several weeks after treatment was stopped [106]: the agedependent increase in SWDswasdelayed or even prevented, suggesting "antiepileptogenesis". Theseinitial results were replicated several times [32,[107][108][109] and similar effects were also found in GAERS using the same protocol [110]. Initially, it was thought that the molecular changes due to epileptogenesis and antiepileptogenesis were restricted to the initiation site of SWDs [106].…”

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

“…For the purpose of this review, we have included all relevant data also including pharmacological manipulation; however, we focus on any kind of difference encountered before and after seizure appearance, considering that alterations observed in old rats in comparison to agematched controls might be a consequence of seizures more than a cause or an epiphenomenon. Finally, despite some alterations that can be identified in the pre-seizure period, no studies after long-term antiepileptogenic treatments have been performed except some on ion channels (see sections 3.3. and 4) and on mGlu5Rs (D'Amore et al, 2016).…”

Establishing Drug Effects on Electrocorticographic Activity in a Genetic Absence Epilepsy Model: Advances and Pitfalls

“…This was the case after rats were chronically exposed to ETX in order to induce antiepileptogenesis. In that case the drug VU0360372 showed only a rather small decrease compared to the action of the same drug in the untreated sham control group (D'Amore et al, 2016). Considering that 2 months old WAG/Rij have few SWDs, and not all animals show clear and unambiguous SWDs, and the age dependent increase in incidence of SWDs, it is recommended to use WAG/Rij's at an age of 6 months; than it is our experience that they have a sufficient amount of SWD's to find drug and dose related effects and both an increase and decrease in number and mean duration of SWDs can be found (van Luijtelaar and Coenen, 1986;Schridde and van Luijtelaar, 2004;Bouwman et al, 2007;Remen et al, 2016).…”