Modulating balance of synaptic and extrasynaptic NMDA receptors as strategy for Alzheimer disease drug discovery

The unbalance between synaptic(Glu N2 A, mediating the protective pathway) and extrasynaptic NMDA receptors(NMDARs)(Glu N2 B, mediating the excitotoxic pathway) has been found in Alzheimer disease(AD), indicating restoring the balance of Glu N2 A and Glu N2 B should be beneficial for AD therapy. In this study, the Glu N2 B-selective antagonist, ifenprodil, and the non-selective NMDAR agonist, NMDA, had little effects on amyloid-beta(Abeta)-induced long-term potentiation(LTP) deficits.Enhancing the activity of Glu N2 A had a protective effect against Abeta, and specific activation of Glu N2 A and inhibition of Glu N2 B showed a better protective effect. The combination of ifenprodil and D-cycloserine(a co-activator of NMDRs similar to D-serine) led to greater improvement in behavior tests than ifenprodil or D-cycloserine alone, meanwhile, the combination of ifenprodil and D-cycloserine reversed the signal pathway more significantly than ifenprodil or D-cycloserine alone. These results indicate that enhancing synaptic NMDARs and inhibiting extrasynaptic NMDARs concurrently showed protective effects against Abeta-induced neurotoxicity, suggesting that modulation of the balance between Glu N2 A and Glu N2 B might be a good strategy for drug discovery against AD.

D-cycloserin,a NMDA-agonist may be a treatment option for anti-NMDAR encephalitis

Anti-N-methyl-D-aspartate receptor(NMDAR)encephalitis is caused by reversible neuron dysfunction associated an autoantibody-mediated decrease of NMDAR in the entire brain.A N-methyl-D-aspartate(NMDA)-agonist treatment for anti-NMDAR encephalitis might have a role considering its specific mechanism.The authors used D-cycloserine,a partial NMDA-agonist in a refractory case with prolonged intensive care unit duration.A 13-year-old female presented with headache,cognitive deterioration,generalized seizures,coma and hypoventilation with required mechanical ventilation.Anti-NMDAR antibodies were identified in cerebrospinal fluid and serum confirming anti-NMDAR encephalitis.The patient was refractory to first-line and second-line immunotherapy and removal of ovary teratoma.D-cycloserine was then administered and her symptoms improved gradually and significantly.This is the first reported case in which D-cycloserine was applied to this disease.D-cycloserine might be a potential option as specific treatment in anti-NMDAR encephalitis.