Fig. 10

mGluR5 and CB₁ cooperatively activate cell signaling pathways to promote neuroprotection. Glutamate release causes activation of N-methyl-D-aspartate receptor (NMDAR), which increases intracellular Ca²⁺, and metabotropic glutamate receptor 5 (mGluR5), which activates various cell signaling pathways. mGluR5 is present at the postsynaptic site and can be stimulated by CDPPB, leading to the activation of different neuroprotective effectors, such as the extracellular-signal-regulated kinase 1/2 (ERK1/2) and AKT. Moreover, mGluR5 is part of a signalosome that contains the two key enzymes for 2-arachidonoylglycerol (2-AG) synthesis and, thus, mGluR5 activation can increase 2-AG levels. However, both MPEP, an mGluR5 blocker, and AM251, a CB₁ antagonist, can block mGluR5-mediated activation of ERK1/2 and AKT and, thus, neuroprotection. The cannabinoid receptor 1 (CB₁), which is present at the presynaptic site, is stimulated by 2-AG and anandamide (AEA), leading to activation of extracellular-signal-regulated kinase (ERK1/2) and AKT. CB₁ activation can also inhibit presynaptic glutamate release and, therefore, blunt mGluR5 activation by glutamate. JZL184 and URB597, which are monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH) inhibitors, respectively, increase the levels of anandamide and 2-AG, leading to activation of ERK1/2 and AKT and promoting neuroprotection. However, this effect can be blocked by both MPEP and AM251. Therefore, mGluR5 and CB₁ are part of the same cell signaling pathway, working cooperatively to trigger activation of ERK1/2 and AKT and promote neuroprotection. AA arachidonic acid