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Evidence that N-acetylaspartylglutamate is the Astrocyte-Targeted Neurovascular Coupling Agent that Regulates Slow Tonic Control of Brain Blood Flow

Amjad Khan

The presence of high levels of N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) in the mammalian brain, and of most of the enzymes that synthesize and hydrolyze them were discovered more than six decades ago. At that time it was also noted that these substances and their anabolic and catabolic enzymes were highly compartmentalized with most NAA and NAAG and their anabolic enzymes present in neurons, and their catabolic enzymes present in macroglia. These early findings have been reviewed. Subsequently, in a review of the properties of metabotropic glutamate receptors (mGluR’s) found in brain, it was reported that of the eight members of the three groups of mGluR’s, that NAAG was a selective agonist for the group II mGluR3 receptor. At the same time, two papers were published, one that demonstrated for the first time that the enzyme that hydrolyzed NAA was only expressed in oligodendrocytes , and the other that showed that the enzyme that hydrolyzed NAAG was expressed “exclusively in astrocytic glial cells”. The “nagging” question of the function of NAAG was considered in 1997 and revisited in 2015. The hypothesis that NAAG was intimately involved in neuronastrocyte communication was first suggested in 1999 5 and it was speculated that NAAG, via the action of its substratespecific astrocytic peptidase, “may be an important mediary of neuronal-glial communication”. The expanded NAAG functional hypothesis was a logical step in the evolution of the concept in that it considered the entire NAA-NAAG metabolic sequence as a unique linked tri-cellular system and stated that “NAAG in the CNS may have a …primary role” in “neuronal-glial cell-specific signaling and communication”. In 2005 it was observed for the first time that by inhibiting NAAG peptidase in vivo, the astrocytic enzyme that hydrolyzes NAAG, that there was a prolonged global reduction in the proton magnetic resonance blood oxygen level-dependent (BOLD) signal indicating a reduction in global cerebral blood flow (CBF), but with little or no effect on physical activity. In 2006 the hypothesis was expanded to suggest that NAAG functioned “to control focal or regional hyperemia” by stimulating astrocytes to synthesize and release second messengers to the vascular system via cyclooxygenase-1 (COX-1) synthesized