Potentiation of mGlu5 receptors with the novel enhancer, VU0360172, reduces spontaneous absence seizures in WAG/Rij rats.
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. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
I.R.C.C.S., NEUROMED, Neuropharmacology Unit, Parco Tecnologico, Località Camerelle 86077, Pozzilli, Isernia, Italy.
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D'Amore
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Santolini
C M
CM
van Rijn
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Biagioni
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Molinaro
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Prete
P J
PJ
Conn
C W
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Lindsley
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Zhou
P N
PN
Vinson
A L
AL
Rodriguez
C K
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Jones
S R
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Stauffer
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Nicoletti
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van Luijtelaar
R T
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Ngomba
D000367:Age Factors; D000818:Animals; D058256:Brain Waves / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000379:methods; D004832:Epilepsy, Absence / Q000188:drug therapy* / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006868:Hydrolysis; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013003:Somatosensory Cortex / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D020651:Ventral Thalamic Nuclei / Q000378:metabolism
C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C581972:N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide; D018129:Phosphatidylinositol Phosphates; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; D009536:Niacinamide