The impact of mGlu2 or mGlu5 receptor activators on the production of l-arginine derivatives and the expression of PRMT5 or DDAH1 enzymes in animal models of cognitive decline.

l-arginine derivatives (ADMA, SDMA, NMMA) are endogenous inhibitors of nitric oxide (NO֗) production, which is essential in critical brain processes including blood-brain barrier (BBB) integrity and long-term potentiation (LTP). ADMA and NMMA are degraded by dimethylarginine dimethylaminohydrolase 1 (DDAH1) and protein arginine methyltransferase 5 (PRMT5) is an emerging epigenetic enzyme that mainly represses transcription of target genes via symmetric dimethylation of arginine residues. There is no data concerning the impact of metabotropic glutamate receptors (mGlu) ligands on this aspect of brain physiology. In the present studies the impact of positive allosteric modulators (PAM) of mGlu5 (CDPPB) and mGlu2 (LY487379) receptors on l-arginine derivatives, DDAH1 and PRMT5 expression in mouse models of cognitive dysfunction induced with MK-801(0.3 mg/kg) or scopolamine (1 mg/kg), was investigated. Experiments were performed both after acute and chronic (14 days) administration of the compounds, which were administered at the doses 0.1-5 mg/kg (CDBBB) and 0.1-1 mg/kg (LY487379). The chronic administration of both compounds normalized the level of l-arginine derivatives in MK-801 model (in brain and plasma) and only low dose of CDPPB prevented scopolamine-induced changes. The expression of DDAH1 and PRMT5 was modulated by CDPPB and LY487379, both in MK-801 and scopolamine models. In the novel object recognition (NOR) test low doses of the compounds, inactive after single administration, prevented cognitive decline after chronic injections. Our findings highlight the potential of mGlu receptor modulators in treating schizophrenia and possibly dementia by normalizing l-arginine derivatives production, preventing from nitric oxide synthases uncoupling.