Neuroprotective actions of a histidine analogue in models of ischemic stroke.
Histidine is a naturally occurring amino acid with antioxidant properties, which is present in low amounts in tissues throughout the body. We recently synthesized and characterized histidine analogues related to the natural dipeptide carnosine, which selectively scavenge the toxic lipid peroxidation product 4-hydroxynonenal (HNE). We now report that the histidine analogue histidyl hydrazide is effective in reducing brain damage and improving functional outcome in a mouse model of focal ischemic stroke when administered intravenously at a dose of 20 mg/kg, either 30 min before or 60 min and 3 h after the onset of middle cerebral artery occlusion. The histidine analogue also protected cultured rat primary neurons against death induced by HNE, chemical hypoxia, glucose deprivation, and combined oxygen and glucose deprivation. The histidine analogue prevented neuronal apoptosis as indicated by decreased production of cleaved caspase-3 protein. These findings suggest a therapeutic potential for HNE-scavenging histidine analogues in the treatment of stroke and related neurodegenerative conditions.
Tang
Sung-Chun
SC
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224, USA.
Arumugam
Thiruma V
TV
Cutler
Roy G
RG
Jo
Dong-Gyu
DG
Magnus
Tim
T
Chan
Sic L
SL
Mughal
Mohamed R
MR
Telljohann
Richard S
RS
Nassar
Matthew
M
Ouyang
Xin
X
Calderan
Andrea
A
Ruzza
Paolo
P
Guiotto
Andrea
A
Mattson
Mark P
MP
D000818:Animals; D000831:Animals, Newborn; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D002336:Carnosine / Q000031:analogs & derivatives / Q000627:therapeutic use; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004195:Disease Models, Animal; D005947:Glucose / Q000172:deficiency; D006639:Histidine / Q000031:analogs & derivatives* / Q000378:metabolism; D000860:Hypoxia / Q000188:drug therapy; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000517:prevention & control*; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
C521122:AG-01 compound; D018696:Neuroprotective Agents; D006639:Histidine; D002336:Carnosine; D053148:Caspase 3; D005947:Glucose