The mGlu7 receptor provides protective effects against epileptogenesis and epileptic seizures

Girard, B.; Tuduri, P.; Moreno, M. P.; Sakkaki, S.; Barboux, C.; Bouschet, T.; Varrault, A.; Vitre, J.; McCort, I.; Dairou, J.; Acher, F.; Fagni, L.; Marchi, N.; Perroy, J.; Bertaso, F.

doi:10.1101/514844

bioRxiv · 10.1101/514844

The mGlu7 receptor provides protective effects against epileptogenesis and epileptic seizures

Girard, B.·Tuduri, P.·Moreno, M. P.·Sakkaki, S.·Barboux, C.·Bouschet, T.·Varrault, A.·Vitre, J.·McCort, I.·Dairou, J.·Acher, F.·Fagni, L.·Marchi, N.·Perroy, J.·Bertaso, F.

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Abstract

Finding new targets to control or reduce seizure activity is essential to improve the management of epileptic patients. We hypothesized that activation of the pre-synaptic and inhibitory metabotropic glutamate receptor type 7 (mGlu7) reduces spontaneous seizures. We tested LSP2-9166, a recently developed mGlu7/4 agonist with unprecedented potency on mGlu7 receptors, in two paradigms of epileptogenesis. In a model of chemically induced epileptogenesis (pentylenetetrazol systemic injection), LSP2-9166 induces an antiepileptogenic effect rarely observed in preclinical studies. In particular, we found a bidirectional modulation of seizure progression by mGlu4 and mGlu7 receptors, the latter preventing kindling. In the intra-hippocampal injection of kainic acid mouse model that mimics the human mesial temporal lobe epilepsy, we found LSP2-9166 reduced seizure frequency and hippocampal sclerosis. LSP2-9166 also acts as an anti epileptic drug on established seizures in both models tested. Specific modulation of the mGlu7 receptor could represent a novel approach to reduce pathological network remodeling.

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Girard, B., Tuduri, P., Moreno, M. P., Sakkaki, S., Barboux, C., Bouschet, T., Varrault, A., Vitre, J., McCort, I., Dairou, J., Acher, F., Fagni, L., Marchi, N., Perroy, J., Bertaso, F.. 2019-01-09. The mGlu7 receptor provides protective effects against epileptogenesis and epileptic seizures. https://doi.org/10.1101/514844

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