Previous studies have identified three NMDAR subunits: NR1, NR2 (A–D) and NR3 (A,B). Functional NMDARs are heterotetramers composed of two glycine–biding NR1 subunits and two glutamate-binding NR2 subunits, whereas NR1/NR3 heterotetramers can be combined by glycine (Chatterton et al., 2002; Mayer and Armstrong, 2004; Paoletti, 2011). Different NR2-containing receptors (NR1/NR2A, or NR1/NR2B heterotetramers) exhibit different biophysical and pharmacological properties (Cull-Candy and Leszkiewicz, 2004; Furukawa et al., 2005; Chen and Wyllie, 2006). NR2A subunits are primarily located at intrasynaptic sites, whereas NR2B subunits are predominantly located at extrasynaptic sites (Stocca and Vicini, 1998; Rumbaugh and Vicini, 1999; Tovar and Westbrook, 1999; Traynelis et al., 2010). Functionally, NR2A subunits play a neuroprotective role by activating cellular CREB or Akt pathways (Hardingham and Bading, 2010; Luo et al., 2011; Lai et al., 2014). Activation of NR2A will induce phosphorylation of CREB which is associated with BDNF expression and contributes to neuronal survival (Chen et al., 2008). It has been reported that some drugs may be neuroprotective against ischemia via enhancing CREB activity (Raval et al., 2009; Zhang et al., 2010). Conversely, activation of the extrasynaptic NR2B subunit will trigger apoptotic pathways by increasing ROS levels and prohibiting CREB expression (Léveillé et al., 2008; Hardingham and Bading, 2010; Gladding and Raymond, 2011). When animals experience ischemic insult, nNOS will translocate to the cell membrane to form the NR2B-PSD95-nNOS complex that activates nNOS to produce more NO and causes severe neuronal injury. Some agents have recently been tested in the rat MCAO model and stroke primates showing that disruption of nNOS-PSD95 or NR2B-PSD95 interaction reduced infarct area in ischemic models (Zhou et al., 2010; Cook et al., 2012). Whether both NR2A and NR2B subunits could be simultaneously regulated to achieve neuroprotection by pharmacological drugs remains unknown.