Allosteric modulators of NR2B-containing NMDA receptors: molecular mechanisms and therapeutic potential

N-methyl-D-aspartate receptors (NMDARs) are ion channels gated by glutamate, the major excitatory neurotransmitter in the mammalian central nervous system (CNS). They are widespread in the CNS and are involved in numerous physiological and pathological processes including synaptic plasticity, chronic pain and psychosis. Aberrant NMDAR activity also plays an important role in the neuronal loss associated with ischaemic insults and major degenerative disorders including Parkinson''s and Alzheimer''s disease. Agents that target and alter NMDAR function may, thus, have therapeutic benefit. Interestingly, NMDARs are endowed with multiple extracellular regulatory sites that recognize ions or small molecule ligands, some of which are likely to regulate receptor function in vivo. These allosteric sites, which differ from agonist-binding and channel-permeation sites, provide means to modulate, either positively or negatively, NMDAR activity. The present review focuses on allosteric modulation of NMDARs containing the NR2B subunit. Indeed, the NR2B subunit confers a particularly rich pharmacology with distinct recognition sites for exogenous and endogenous allosteric ligands. Moreover, NR2B-containing receptors, compared with other NMDAR subtypes, appear to contribute preferentially to pathological processes linked to overexcitation of glutamatergic pathways. The actions of extracellular H⁺, Mg²⁺, Zn²⁺, of polyamines and neurosteroids, and of the synthetic compounds ifenprodil and derivatives (‘prodils’) are presented. Particular emphasis is put upon the structural determinants and molecular mechanisms that underlie the effects exerted by these agents. A better understanding of how NR2B-containing NMDARs (and NMDARs in general) operate and how they can be modulated should help define new strategies to counteract the deleterious effects of dysregulated NMDAR activity.     

Effects of betaxolol and latanoprost on ocular blood flow and visual fields in patients with primary open-angle glaucoma

PURPOSE: To evaluate the effects of betaxolol and latanoprost on ocular blood flow and visual fields in patients with primary open-angle glaucoma (POAG) by means of an observer-masked, prospective clinical study. METHODS: Thirty-two patients with newly diagnosed POAG were included in the study. The patients were randomized into two groups. The first group was treated with betaxolol 0.50% twice daily and the second group with latanoprost 0.005% once daily. Baseline and posttreatment examinations on the first and third months of treatment included intraocular pressure (IOP) measurement, automated visual field testing, and ocular blood flow assessment. For evaluation of visual fields, mean defect and pattern standard deviation indices were used. Ocular blood flow was assessed by means of color Doppler imaging of the central retinal artery (CRA) and the temporal short posterior ciliary artery (PCA). For each vessel, peak systolic (PSV) and end-diastolic (EDV) blood flow velocities were measured and resistivity index (RI) calculated. RESULTS: After exclusion of one noncompliant patient, the study was completed with 31 eyes of 31 patients. Both drugs significantly reduced IOP (p<0.05). The mean IOP lowering effect of latanoprost was significantly higher than that of betaxolol (p=0.03). Visual field indices exhibited no significant changes in either group (p>0.05). There were no significant changes in PSV or EDV measurements of CRA or PCA in either group (p>0.05). RI decreased in both CRA and PCA with both drugs. The mean changes between baseline and 3 month blood flow measurements were not significantly different between betaxolol and latanoprost (p>0.05). CONCLUSIONS: Over a treatment period of 3 months, both betaxolol and latanoprost tended to improve ocular blood flow without one of them being superior to the other. The results suggest that the direct (non IOP-dependent) influence on ocular circulation is better for betaxolol than for latanoprost. In addition, neither drug caused significant generalized improvements in visual fields during this period.     

Fractionation of Spatial Memory in GRM2/3 (mGlu2/mGlu3) Double Knockout Mice Reveals a Role for Group II Metabotropic Glutamate Receptors at the Interface Between Arousal and Cognition

Group II metabotropic glutamate receptors (mGluR2 and mGluR3, encoded by GRM2 and GRM3) are implicated in hippocampal function and cognition, and in the pathophysiology and treatment of schizophrenia and other psychiatric disorders. However, pharmacological and behavioral studies with group II mGluR agonists and antagonists have produced complex results. Here, we studied hippocampus-dependent memory in GRM2/3 double knockout (GRM2/3^−/−) mice in an iterative sequence of experiments. We found that they were impaired on appetitively motivated spatial reference and working memory tasks, and on a spatial novelty preference task that relies on animals'' exploratory drive, but were unimpaired on aversively motivated spatial memory paradigms. GRM2/3^−/− mice also performed normally on an appetitively motivated, non-spatial, visual discrimination task. These results likely reflect an interaction between GRM2/3 genotype and the arousal-inducing properties of the experimental paradigm. The deficit seen on appetitive and exploratory spatial memory tasks may be absent in aversive tasks because the latter induce higher levels of arousal, which rescue spatial learning. Consistent with an altered arousal–cognition relationship in GRM2/3^−/− mice, injection stress worsened appetitively motivated, spatial working memory in wild-types, but enhanced performance in GRM2/3^−/− mice. GRM2/3^−/− mice were also hypoactive in response to amphetamine. This fractionation of hippocampus-dependent memory depending on the appetitive-aversive context is to our knowledge unique, and suggests a role for group II mGluRs at the interface of arousal and cognition. These arousal-dependent effects may explain apparently conflicting data from previous studies, and have translational relevance for the involvement of these receptors in schizophrenia and other disorders.