Promising New Antistroke Treatment
Abstract & Commentary
Source: Slusher S, et al. Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury. Nat Med 1999;5:1396-1402.
Excessive glutamate release in acute ischemic stroke leads to a cascade of neuronal excitotoxicity and cell death. Numerous agents, such as the glutamate receptor blocker MK-801, have been shown to attenuate this process in animals, but no drug has yet been found effective in clinical stroke trials.
The neuropeptide NAAG (N-acetyl-aspartyl-glutamate) is a glutamate receptor antagonist and is also a direct source of glutmate when it is hydrolyzed by the enzyme NAALADase (N-acetylated-a-linked-acidic dipeptidase). 2-PMPA, an inhibitor of NAALADase, may afford neuroprotection by increasing NAAG and decreasing its by-product, glutamate.
Slusher and colleagues demonstrate the following:
1. 2-PMPA inhibits cyanide-induced ischemia in tissue culture. The magnitude of this inhibition was 85%, compared with 60% for MK-801.
2. The volume of stroke produced by middle cerebral artery occlusion (MCAO) in rats was reduced by 54% with immediate 2-PMPA administration. 2-PMPA administration delayed by 60 or 90 minutes, but not 120 minutes, produced similar benefits.
3. With 2-PMPA, glutamate levels in the ischemic brain were reduced by 80% in the basal ganglia and 100% in the cerebral cortex. NAAG levels were significantly increased. There effects were not observed in nonischemic controls.
4. No adverse behavioral or histological effects were observed (in contrast to control experiments with MK-801).
NAALDase inhibition may represent a promising "upstream" method of modifying glutamate neurotoxicity by preventing its production and increasing levels of an inhibitory precursor. This effect appears to occur specifically in the ischemic milieu. Unfortunately, in rats, the drug appears to be effective only up to 90 minutes. If a similar time profile applies in humans, it is unlikely to be of clinical use. Nevertheless, given its favorable safety profile, we look forward to human trials. —azs