Aldehyde load in ischemia-reperfusion brain injury: neuroprotection by neutralization of reactive aldehydes with phenelzine.
In ongoing studies of the neuroprotective properties of monoamine oxidase inhibitors, we found that phenelzine provided robust neuroprotection in the gerbil model of transient forebrain ischemia, with drug administration delayed up to 3 h post reperfusion. Since ischemia-reperfusion brain injury is associated with large increases in the concentrations of reactive aldehydes in the penumbra area, we investigated if the hydrazine function of phenelzine was capable of sequestering reactive aldehydes. Both aminoaldehydes and acrolein are generated from the metabolism of polyamines to putrescine by polyamine oxidase. These toxic aldehydes in turn compromise mitochondrial and lysosomal integrity and initiate apoptosis and necrosis. Previous studies have demonstrated that pharmacological neutralization of reactive aldehydes via the formation of thioacetal derivatives results in significant neuroprotection in ischemia-reperfusion injury, in both focal and global ischemia models. In our studies of acrolein and 3-aminopropanal toxicity, using an immortalized retinal cell line, we found that aldehyde sequestration with phenelzine was neuroprotective. The neuroprotection observed with phenelzine is in agreement with previous studies of aldehyde sequestering agents in the treatment of ischemia-reperfusion brain injury and supports the concept that "aldehyde load" is a major factor in the delayed cell losses of the ischemic penumbra.
Wood
Paul L
PL
The Falk Center for Molecular Therapeutics, Dept. of Biomedical Engineering, McCormick School of Engineering and Applied Sciences, Northwestern University, 1801 Maple Ave., Suite 4306, Evanston, IL 60201, USA. p-wood@northwestern.edu
Khan
M Amin
MA
Moskal
Joseph R
JR
Todd
Kathryn G
KG
Tanay
Véronique A M I
VA
Baker
Glen
G
D000171:Acrolein / Q000378:metabolism / Q000633:toxicity; D000447:Aldehydes / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005849:Gerbillinae; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010624:Phenelzine / Q000494:pharmacology*; D011437:Propylamines / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D015427:Reperfusion Injury / Q000201:enzymology* / Q000517:prevention & control; D012160:Retina / Q000166:cytology; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000201:enzymology; D013997:Time Factors
D000447:Aldehydes; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D011437:Propylamines; D000171:Acrolein; C050862:3-aminopropionaldehyde; D010624:Phenelzine