Neuroprotective action of halogenated derivatives of L-phenylalanine.
OBJECTIVE
The aromatic amino acid L-Phenylalanine (L-Phe) significantly and reversibly depresses excitatory glutamatergic synaptic transmission (GST) via a unique set of presynaptic and postsynaptic mechanisms. Therefore, we hypothesized that endogenous derivatives of L-Phe, which display potent antiglutamatergic activity, may safely and efficaciously protect the brain during conditions characterized by overactivation of glutamate receptors.


METHODS
We tested this hypothesis in vitro with a combination of patch-clamp and lactate dehydrogenase (LDH) analyses in rat cultured neurons exposed to simulated ischemia, and in vivo using a rat model of experimental stroke caused by transient middle cerebral artery occlusion (MCAO).


RESULTS
3,5-diiodo-L-tyrosine (DIT) and 3,5-dibromo-L-tyrosine (DBrT), endogenous halogenated derivatives of L-Phe, attenuated GST by similar mechanisms as L-Phe, but with greater potency. For example, the IC50s for DIT and DBrT to depress the frequency of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor-mediated mEPSCs were 104.6+/-14.1 micromol/L and 127.5+/-13.3 micromol/L, respectively. Depression of GST by DIT and DBrT persisted during energy deprivation. Furthermore, DBrT significantly reduced LDH release in neuronal cultures exposed to oxygen glucose deprivation. In rats subjected to transient MCAO, DBrT decreased the brain infarct volume and neurological deficit score to 52.7+/-14.1% and 57.1+/-12.0% of control values, respectively. DBrT neither altered atrioventricular nodal and intraventricular conduction in isolated heart, nor heart rate and blood pressure in vivo.


CONCLUSIONS
DBrT, an endogenous halogenated derivative of L-Phe, shows promise as a representative of a novel class of neuroprotective agents by exerting significant neuroprotection in both in vitro and in vivo models of brain ischemia.
Kagiyama
Tomoko
T
Department of Anesthesiology, University of Florida, Gainesville, Fla 32610-0254, USA.
Glushakov
Alexander V
AV
Sumners
Colin
C
Roose
Brandy
B
Dennis
Donn M
DM
Phillips
M Ian
MI
Ozcan
Mehmet S
MS
Seubert
Christoph N
CN
Martynyuk
Anatoly E
AE
D000818:Animals; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000517:prevention & control*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018408:Patch-Clamp Techniques; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000502:physiology; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use
D018696:Neuroprotective Agents; D017470:Receptors, Glutamate; C475724:bromotyrosine; D014443:Tyrosine; D010649:Phenylalanine; C082610:3,5-dibromotyrosine; D007770:L-Lactate Dehydrogenase