ABSTRACT
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.
Subject(s)
Aldehydes/metabolism , Neuroprotective Agents/pharmacology , Phenelzine/pharmacology , Reperfusion Injury/enzymology , Retinal Ganglion Cells/drug effects , Acrolein/metabolism , Acrolein/toxicity , Aldehydes/toxicity , Animals , Brain/drug effects , Brain/enzymology , Brain/pathology , Brain Ischemia/drug therapy , Brain Ischemia/enzymology , Brain Ischemia/pathology , Cells, Cultured , Disease Models, Animal , Gerbillinae , Male , Monoamine Oxidase Inhibitors/pharmacology , Propylamines/metabolism , Propylamines/toxicity , Rats , Reperfusion Injury/prevention & control , Retina/cytology , Retinal Ganglion Cells/enzymology , Time FactorsABSTRACT
Acute administration of the stimulant dextro-amphetamine produces multiple physiological, subjective cognitive and biochemical changes. These effects are similar to those seen in mania, and may be a useful model for mania. The aim of the present study was more fully to determine the multiple effects of dextro-amphetamine and to relate these to changes in plasma levels of the drug. In a double-blind, placebo-controlled crossover study in 25 healthy volunteers (ages 18-45), the effects of 25 mg of oral dextro-amphetamine were examined. Physiological, subjective, cognitive changes, concentrations of amino acids and metabolites of biogenic amines period were related to changes in plasma amphetamine concentrations over 500 min. Peak concentrations of dextro-amphetamine occurred at 2.5-3.5 h post-administration and levels decreased to 75% of peak value after 500 min. The results from the present study indicate that the subjective psychological, cognitive and blood pressure changes frequently did not mirror the time course of plasma levels of the drug. Thus, there was no clear-cut relationship between plasma levels and effects. In addition, dextro-amphetamine caused no significant changes in amino acids or amino metabolite concentrations. In conclusion, while dextro-amphetamine administration definitely causes several changes which are seen in mania, there remain some physiological and metabolic differences between these two conditions.
