NAAG peptidase inhibitors and deletion of NAAG peptidase gene enhance memory in novel object recognition test

Abstract

The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) is inactivated by the extracellular enzyme glutamate carboxypeptidase II. Inhibitors of this enzyme reverse dizocilpine (MK-801)-induced impairment of short-term memory in the novel object recognition test. The objective of this study was to test the hypothesis that NAAG peptidase inhibition enhances the long-term (24 hr delay) memory of C57BL mice in this test. These mice and mice in which glutamate carboxypeptidase II had been knocked out were presented with two identical objects to explore for 10 minutes on day 1 and tested with one of these familiar objects and one novel object on day 2. Memory was assessed as the degree to which the mice recalled the familiar object and explored the novel object to a greater extent on day 2. Uninjected mice or mice injected with saline prior to the acquisition session on day 1 demonstrated a lack of memory of the acquisition experience by exploring the familiar and novel objects to the same extent on day 2. Mice treated with glutamate carboxypeptidase II inhibitors ZJ43 or 2-PMPA prior to the acquisition trial explored the novel object significantly more time than the familiar object on day 2. Consistent with these results, mice in which glutamate carboxypeptidase II had been knocked out distinguished the novel from the familiar object on day 2 while their heterozygous colony mates did not. Inhibition of glutamate carboxypeptidase II enhances recognition memory, a therapeutic action that might be useful in treatment of memory deficits related to age and neurological disorders.

The Dual Role of Glutamatergic Neurotransmission in Alzheimer’s Disease: From Pathophysiology to Pharmacotherapy

“…The glial enzyme, glutamate caboxypeptidase II (GCPII), converts NAAG into N -acetylaspartate (NAA) and glutamate, which gets transported into glial cells [ 206 ]. GCPII inhibitors increase the extracellular concentration of NAAG and the drugs that increase the NAAG levels are pro-cognitive in object recognition test [ 207 ]. Treatment with GCPII inhibitors, ZJ43 ( N -[[[(1S)-1-Carboxy-3-methylbutyl]amino]carbonyl]-L-glutamic acid) and 2-(phosphonomethyl) pentanedioic acid (2-PMPA) improved cognition in mice.…”

Suppression of Glutamate Carboxypeptidase II Ameliorates Neuronal Apoptosis from Ischemic Brain Injury

“…However, accumulating evidence suggested that excessive glutamate transmission induced neuron damage, and implicated in neurological disorders, such as ischemia stroke. 4 Inhibition of GCPII has been shown to attenuate excitotoxicity associated with enhanced glutamate transmission under pathological conditions. Modulation of GCPII activity with smallmolecule inhibitors has implications for the therapy of cancer 5 and inflammatory pain 6 or neuropathic pain.…”

Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration

“…In support of this, small molecule inhibitors of GCP-II have been demonstrated to be efficacious in multiple preclinical models wherein excess glutamate transmission is implicated including traumatic spinal cord and brain injury [ 10 – 12 ] stroke [ 4 ], neuropathic and inflammatory pain [ 13 – 27 ], ALS [ 28 ], schizophrenia [ 29 ], neuropathy [ 30 , 31 ], drug abuse [ 32 – 35 ] and cognition [ 36 ]. In addition, GCP-II knockout animals have shown to be protected against ischemic brain injury, peripheral neuropathy [ 37 ], and have demonstrated long term memory enhancing effects [ 38 ].…”