Abstract
HIV-associated neurocognitive disorder (HAND) consists of motor and cognitive dysfunction in a relatively large percentage of patients with AIDS. Prior work has suggested that at least part of the neuronal and synaptic damage observed in HAND may occur due to excessive stimulation of NMDA-type glutamate receptors (NMDARs). Here, we compared pharmacological and genetic manipulation of NMDAR activity using an improved derivative of the NMDAR antagonist memantine, termed NitroMemantine, and the modulatory NMDAR subunit GluN3A in the HIV/gp120 transgenic (tg) mouse model of HAND. Interestingly, we found that while both NitroMemantine and GluN3A have been shown to inhibit NMDAR activity, NitroMemantine protected synapses in gp120-tg mice, but overexpression of GluN3A augmented the damage. Given recent findings in the field, one explanation for this apparently paradoxical result is the location of the NMDARs primarily affected, with NitroMemantine inhibiting predominantly extrasynaptic pathologically activated NMDARs, but GluN3A disrupting normal NMDAR-mediated neuroprotective activity via inhibition of synaptic NMDARs.
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Acknowledgments
We thank James Parker for graphic assistance. This work was supported in part by NIH grants P01 HD29587, P30 NS076411, R21 NS083415, and R01 EY09024 to S.A.L. Additional support was provided by a Distinguished Investigator Award from the Brain & Behavior Research Foundation to S.A.L.
Conflict of interest
S.A.L. is the named inventor on worldwide patents for memantine (Namenda®) and NitroMemantine for the treatment of neurodegenerative diseases. Following Harvard University guidelines, he participates in a royalty sharing agreement with his former institution Harvard Medical School/Boston Children’s Hospital for the licensing of the memantine patents to Forest Laboratories/Actavis. He is also a Scientific Co-Founder of Adamas Pharmaceuticals, Inc., which has agreements with Forest Laboratories/Actavis for co-developing long-lasting formulations of memantine. The authors declare that they have no other competing interests.
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Nakanishi, N., Kang, YJ., Tu, S. et al. Differential Effects of Pharmacologic and Genetic Modulation of NMDA Receptor Activity on HIV/gp120-Induced Neuronal Damage in an In Vivo Mouse Model. J Mol Neurosci 58, 59–65 (2016). https://doi.org/10.1007/s12031-015-0651-1
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DOI: https://doi.org/10.1007/s12031-015-0651-1