Blockade of N-acetylaspartylglutamate peptidases: a novel protective strategy for brain injuries and neurological disorders.
The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) is reported to suppress glutamate release mainly through selective activation of presynaptic Group II metabotropic glutamate receptor subtype 3 (mGluR3). Therefore, strategies of inhibition of NAAG peptidases and subsequent NAAG hydrolysis to elevate levels of NAAG could reduce glutamate release under pathological conditions and be neuroprotective by attenuating excitotoxic cell injury. A series of potent inhibitors of NAAG peptidases has been synthesized and demonstrated efficacy in experimental models of ischemic-hypoxic brain injury, traumatic brain injury, inflammatory pain, diabetic neuropathy, amyotrophic lateral sclerosis and phencyclidine-induced schizophrenia-like behaviors. The excessive glutamatergic transmission has been implicated in all of these neurological disorders. Thus, blockade of NAAG peptidases may augment an endogenous protective mechanism and afford neuroprotection in the brain. This review aims to summarize and provide insight into the current understanding of the novel neuroprotective strategy based on limiting glutamate excitotoxicity for a wide variety of brain injuries and neurological disorders.
Department of Neurosurgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Chunlong
C
Zhong
Qizhong
Q
Luo
Jiyao
J
Jiang
D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009422:Nervous System Diseases / Q000188:drug therapy / Q000201:enzymology*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3; D043425:Glutamate Carboxypeptidase II
N-acetylaspartylglutamate (NAAG); brain injury; glutamate excitotoxicity; neurological disorder; neuroprotection