Gene/Protein
Disease
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Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
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Target Concepts:
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Query: UMLS:C0038454 (
stroke
)
147,016
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
We describe here a new strategy for the treatment of
stroke
, through the inhibition of
NAALADase
(N-acetylated-alpha-linked-acidic dipeptidase), an enzyme responsible for the hydrolysis of the neuropeptide NAAG (N-acetyl-aspartyl-glutamate) to N-acetyl-aspartate and glutamate. We demonstrate that the newly described
NAALADase
inhibitor 2-PMPA (2-(phosphonomethyl)pentanedioic acid) robustly protects against ischemic injury in a neuronal culture model of
stroke
and in rats after transient middle cerebral artery occlusion. Consistent with inhibition of
NAALADase
, we show that 2-PMPA increases NAAG and attenuates the ischemia-induced rise in glutamate. Both effects could contribute to neuroprotection. These data indicate that
NAALADase
inhibition may have use in neurological disorders in which excessive excitatory amino acid transmission is pathogenic.
...
PMID:Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury. 1058 Oct 82
Excessive glutamatergic transmission is thought to be responsible for the injury observed in a variety of neurological disorders such as
stroke
. N-acetylaspartylglutamate (NAAG), a major peptidic component of the brain, has been suggested to serve as a potential storage form of glutamate. N-acetylated-a-linked acidic dipeptidase (
NAALADase
, EC 3.4.17.21) is responsible for the hydrolysis of NAAG into N-acetylaspartate (NAA) and glutamate. If NAAG is a storage form of glutamate, then inhibition of
NAALADase
should be neuroprotective in diseases in which excess glutamatergic transmission is detrimental. In addition, NAAG has been demonstrated to be an agonist at group II metabotropic glutamate receptors and functions as a mixed agonist/antagonist at N-methyl-D-aspartate receptors. Therefore, inhibition of
NAALADase
would also function to increase NAAG levels which, in turn, should provide neuroprotection via the interaction of NAAG with these receptors. Recently, potent and selective inhibitors of the enzyme have been designed and subsequently used to demonstrate that inhibition of
NAALADase
is neuroprotective in animal models of neurodegeneration. As such,
NAALADase
inhibition represents a novel method of regulating extracellular glutamate levels and provides a new avenue for the treatment of neurological disorders.
...
PMID:Design of NAALADase inhibitors: a novel neuroprotective strategy. 1137 62
