(-)Deprenyl-N-oxide, a (-)deprenyl metabolite, is cytoprotective after hypoxic injury in PC12 cells, or after transient brain ischemia in gerbils.

Abstract

BACKGROUND AND AIMS:

(-)-Deprenyl (selegiline) possesses cyto-protective effect in a much lower concentration, than it is needed to inhibit MAO-B activity. In permanent MCA occlusion stroke model in rats, the infarct volume and the number of apoptotic neurons in the penumbra region were decreased by low concentration (-)deprenyl treatment. Augmented Bcl-2 protein expression was documented as the responsible factor of this effect. The stabilization of mitochondrial membrane and diminished ROS production are the further possible consequences of (-)deprenyl treatment. It is not clear however that (-)deprenyl, or its metabolites are the acting neuroprotective molecules in the hypoxic/ischemic conditions. We report here the possible cyto-protective effect of deprenyl-N-oxide (DNO), a recently synthesized (-)deprenyl metabolite.

METHODS:

DNO in a very low dose (10(-5,-8,-12) M) was tested in PC12 cell culture after hypoxia and in gerbils after transient occlusion of bilateral common carotid artery. In PC12 culture the cell death was visualized by PI staining. The level of reactive oxygen species was measured by the Cerium method, and the mitochondrial membrane integrity was labeled by JC1 staining. Apoptotic neurons were counted on formaldehyde fixed gerbil brain slices after TUNEL and caspase-3 immune-staining - NIKON/BIORAD confocal microscopy was used for the quantitative analysis.

RESULTS:

DNO treatment significantly decreased the frequency of cell death in PC12 cultures after hypoxia, increased the mitochondrial transmembrane potential (DeltaY(m)) and decreased the ROS production. In the CA2 regions of gerbil hippocampus, we found significantly less apoptotic neurons than in the untreated controls.

CONCLUSION:

Transient hypoxia or ischemia induced cell damage could be diminished by DNO. This (-)deprenyl metabolite is an active cell protective molecule.

• Authors: Géza Szilágyi, László Simon, Edina Wappler, Kálmán Magyar, Zoltán Nagy
• Journal: Journal of the neurological sciences (J Neurol Sci) Vol. 283 Issue 1-2 Pg. 182-6 (Aug 15 2009) ISSN: 1878-5883 [Electronic] Netherlands
• PMID: 19332347 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Neuroprotective Agents
• Reactive Oxygen Species
• deprenyl-N-oxide
• Selegiline

Topics

• Animals
• Apoptosis (drug effects)
• Brain Ischemia (drug therapy, pathology, physiopathology)
• Carotid Artery Diseases (drug therapy, pathology, physiopathology)
• Cell Death (drug effects)
• Cell Hypoxia (drug effects)
• Gerbillinae
• Hippocampus (drug effects, pathology)
• Mitochondrial Membranes (drug effects, physiology)
• Neurons (drug effects, physiology)
• Neuroprotective Agents (administration & dosage, pharmacology)
• PC12 Cells
• Rats
• Reactive Oxygen Species (metabolism)
• Selegiline (administration & dosage, analogs & derivatives, pharmacology)
• Time Factors