Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury.
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.
Slusher
B S
BS
Guilford Pharmaceuticals, Department of Research, Baltimore, Maryland 21224, USA. slusher_b@guilfordpharm.com
Vornov
J J
JJ
Thomas
A G
AG
Hurn
P D
PD
Harukuni
I
I
Bhardwaj
A
A
Traystman
R J
RJ
Robinson
M B
MB
Britton
P
P
Lu
X C
XC
Tortella
F C
FC
Wozniak
K M
KM
Yudkoff
M
M
Potter
B M
BM
Jackson
P F
PF
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000517:prevention & control*; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D046508:Culture Techniques; D004151:Dipeptides / Q000378:metabolism; D004195:Disease Models, Animal; D004361:Drug Tolerance; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D043425:Glutamate Carboxypeptidase II; D018698:Glutamic Acid / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism
C402107:2-(phosphonomethyl)pentanedioic acid; D004151:Dipeptides; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; C027172:isospaglumic acid; D018698:Glutamic Acid; D002268:Carboxypeptidases; D043425:Glutamate Carboxypeptidase II