Neuroprotective action of halogenated derivatives of L-Phenylalanine

• Published in: Stroke (1970) Vol. 35; no. 5; pp. 1192 - 1196
• Main Authors: KAGIYAMA, Tomoko, GLUSHAKOV, Alexander V, SUMNERS, Colin, ROOSE, Brandy, DENNIS, Donn M, PHILLIPS, M. Ian, OZCAN, Mehmet S, SEUBERT, Christoph N, MARTYNYUK, Anatoly E
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01-05-2004
• Subjects: Animals; Biological and medical sciences; Disease Models, Animal; In Vitro Techniques; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - prevention & control; L-Lactate Dehydrogenase - metabolism; Male; Medical sciences; Neurology; Neurons - enzymology; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Patch-Clamp Techniques; Phenylalanine - analogs & derivatives; Phenylalanine - pharmacology; Phenylalanine - therapeutic use; Rats; Rats, Sprague-Dawley; Receptors, Glutamate - drug effects; Receptors, Glutamate - physiology; Stroke - drug therapy; Stroke - metabolism; Stroke - pathology; Synaptic Transmission - drug effects; Synaptic Transmission - physiology; Tyrosine - analogs & derivatives; Tyrosine - pharmacology; Tyrosine - therapeutic use; Vascular diseases and vascular malformations of the nervous system; Stroke; Nervous system diseases; Phenylalanine; Cardiovascular disease; Glutamate receptor; Glutamate; excitotuxicity; Cerebral disorder; Vascular disease; Aminoacid; neuroprotection; Central nervous system disease; receptors, glutamate; Antidepressant agent; Cerebrovascular disease
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/01.STR.0000125722.10606.07

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.
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).
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.
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.