Halogenated aromatic amino acid 3,5-dibromo-D: -tyrosine produces beneficial effects in experimental stroke and seizures.
The effects of the halogenated aromatic amino acid 3,5-dibromo-D: -tyrosine (3,5-DBr-D: -Tyr) were studied in rat models of stroke and epileptic seizures caused by middle cerebral artery occlusion (MCAo) through respective intracerebral injection of endothelin-1 (ET-1) and intraperitoneal (i.p.) injection of pentylenetetrazole (PTZ). 3,5-DBr-D: -Tyr was administered as three bolus injections (30 or 90 mg/kg, i.p.) starting at 30, 90, and 180 min after ET-1 administration or as a single bolus (30 mg/kg, i.p.) 15 min prior to PTZ administration. Neurological deficits and infarct volume were estimated 3 days after ET-1 administration and seizure score was assessed during the first 20 min after PTZ administration. The safety of 3,5-DBr-D: -Tyr was evaluated in control animals using telemetry to measure cardiovascular parameters and immunostaining to assess the level of activated caspase-3. 3,5-DBr-D: -Tyr significantly improved neurological function and reduced infarct volume in the brain even when the treatment was initiated 3 h after the onset of MCAo. 3,5-DBr-D: -Tyr significantly depressed PTZ-induced seizures. 3,5-DBr-D: -Tyr did not cause significant changes in arterial blood pressure, heart rate and spontaneous locomotor activity, nor did it increase the number of activated caspase-3 positive cells in the brain. We conclude that 3,5-DBr-D: -Tyr, by alleviating the deleterious effects of MCAo and PTZ in rats with no obvious intrinsic effects on cardiovascular parameters and neurodegeneration, exhibits promising potential as a novel therapeutic direction for stroke and seizures.
Cao
Wengang
W
Department of Anesthesiology, University of Florida, Gainesville, FL, 32610-0254, USA.
Glushakov
Alexander
A
Shah
Hina P
HP
Mecca
Adam P
AP
Sumners
Colin
C
Shi
Peng
P
Seubert
Christoph N
CN
Martynyuk
Anatoly E
AE
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D053148:Caspase 3 / Q000032:analysis; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000009:adverse effects; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006842:Hydrocarbons, Brominated / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000139:chemically induced; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D020521:Stroke / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D014443:Tyrosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use
D019332:Endothelin-1; D006842:Hydrocarbons, Brominated; D014443:Tyrosine; C082610:3,5-dibromotyrosine; D053148:Caspase 3; D010433:Pentylenetetrazole