Research Article| Volume 283, ISSUE 1-2, P182-186, August 15, 2009

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

Published:March 31, 2009DOI:


      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.


      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.


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


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


      CLSM (Confocal laser scanning microscopy), ROS (Reactive oxygen species)


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Olanow C.W.
        • Hauser R.A.
        • Gauger L.
        • Malapira T.
        • Koller W.
        • Hubble J.
        • Bushenbark K.
        • Lilienfeld D.
        • Esterlitz J.
        The effect of deprenyl and levodopa on the progression of Parkinson's disease.
        Ann Neurol. 1995; 38: 771-777
        • Simon L.
        • Szilágyi G.
        • Bori Z.
        • Orbay P.
        • Nagy Z.
        (−)-d-Deprenyl attenuates apoptosis in experimental brain ischemia.
        Eur J Pharmacol. 2001; 430: 235-241
        • Unal I.
        • Gürsoy-Ozdemir Y.
        • Bolay H.
        • Söylemezoglu F.
        • Saribaş O.
        • Dalkara T.
        Chronic daily administration of selegiline and EGb 761 increases brain's resistance to ischemia in mice.
        Brain Res. 2001; 917: 174-181
        • Simon L.
        • Szilágyi G.
        • Bori Z.
        • Telek G.
        • Magyar K.
        • Nagy Z.
        Low dose (−)deprenyl is cytoprotective: it maintains mitochondrial membrane potential and eliminates oxygen radicals.
        Life Sci. 2005; 78: 225-231
        • Szilágyi G.
        • Simon L.
        • Koska P.
        • Telek G.
        • Nagy Z.
        Visualization of mitochondrial membrane potential and reactive oxygen species via double staining.
        Neurosci Lett. May 2006; 399: 206-209
        • Gál A.
        • Szilágyi G.
        • Wappler E.
        • Sáfrány G.
        • Nagy Z.
        Bcl-2 or Bcl-XL gene therapy reduces apoptosis and increases plasticity protein GAP-43 expression in PC12 cells.
        Brain Res Bull. 2008; 76: 349-353
        • Sivenius J.
        • Sarasoja T.
        • Aaltonen H.
        • Heinonen E.
        • Kilkku O.
        • Reinikainen K.
        Selegiline treatment facilitates recovery after stroke.
        Neurorehabil Neural Repair. 2001; 15: 183-190
        • Tatton W.G.
        • Ju W.Y.
        • Holland D.P.
        • Tai C.
        • Kwan M.
        (−)-Deprenyl reduces PC12 cell apoptosis by inducing new protein synthesis.
        J Neurochem. Oct 1994; 63: 1572-1575
        • Tatton W.G.
        • Wadia J.S.
        • Ju, R.M. Chalmers-Redman W.Y.
        • N.A. Tatton
        (−)-Deprenyl reduces neuronal apoptosis and facilitates neuronal outgrowth by altering protein synthesis without inhibiting monoamine oxidase.
        J Neural Transm Suppl. 1996; 48 (Review): 45-59
        • Tatton W.G.
        • Chalmers-Redman R.M.
        • Ju W.J.
        • Mammen M.
        • Carlile G.W.
        • Pong A.W.
        • Tatton N.A.
        Propargylamines induce antiapoptotic new protein synthesis in serum- and nerve growth factor (NGF)-withdrawn, NGF-differentiated PC-12 cells.
        J Pharmacol Exp Ther. 2002; 301: 753-764
        • Yoshida T.
        • Yamada Y.
        • Yamamoto T.
        • Kuroiwa Y.
        Metabolism of deprenyl, a selective monoamine oxidase (MAO) B inhibitor in rat: relationship of metabolism to MAO-B inhibitory potency.
        Xenobiotica. 1986; 16: 129-136
        • Lévai F.
        • Fejér E.
        • Szeleczky G.
        • Szabó A.
        • Eros-Takácsy T.
        • Hajdu F.
        • et al.
        In vitro formation of selegiline-N-oxide as a metabolite of selegiline in human, hamster, mouse, rat, guinea-pig, rabbit and dog.
        Eur J Drug Metab Pharmacokin. 2004; 29: 169-178
        • Magyar K.
        • Pálfi M.
        • Tábi T.
        • Kalász H.
        • Szende B.
        • Szökő E.
        Pharmacological aspect of (−) Deprenyl.
        Curr Med Chem. 2004; 11: 2017-2031
        • Magyar K.
        • Szende B.
        (−)deprenyl, a selective MAO-B inhibitor, with apoptotic and anti-apoptotic properties.
        NeuroToxicol. 2004; 25: 233-242
        • Csonka E.
        • Szemenyi K.
        • Miskulin M.
        • Robert A.M.
        Morphological examinations of aortic endothelial and smooth muscle cells grown in vitro on collagen membranes.
        Artery. 1980; 8: 243-258
        • Kusumoto M.
        • Dux E.
        • Paschen W.
        • Hossmann K.A.
        Susceptibility of hippocampal and cortical neurons to argon-mediated in vitro ischemia.
        J Neurochem. 1996; 67: 1613-1621
        • Dénes L.
        • Szilágyi G.
        • Gál A.
        • Bori Z.
        • Nagy Z.
        Cytoprotective effect of two synthetic enhancer substances, (−)-BPAP and (−)-deprenyl, on human brain capillary endothelial cells and rat PC12 cells.
        Life Sci. Aug 8 2006; 79: 1034-1039
        • Magyar K.
        • Pálfi M.
        • Jenei V.
        • Szökő É.
        Deprenyl: from chemical synthesis to neuroprotection.
        J Neural Transm Suppl. 2006; : 143-156
        • Magyar K.
        • Szatmáry I.
        • Szebeni G.
        • Lengyel J.
        Pharmacokinetic studies of (−)-deprenyl and some of its metabolites in mouse.
        J Neural Transm. 2007; 72 (Suppl): 165-173
        • Youdim M.B.
        • Heldman E.
        • Pollard H.B.
        • Fleming P.
        • McHugh E.
        Contrasting monoamine oxidase activity and tyramine induced catecholamine release in PC 12 and chromaffin cells.
        Neuroscience. 1986; 19: 1311-1318
        • Mandel S.
        • Weinreb O.
        • Amit T.
        • Youdim M.B.
        Mechanism of neuroprotective action of the anti-Parkinson drug rasagiline and its derivatives.
        Brain Res Rev. 2005; 48: 379-387
        • Czerniczyniec A.
        • Bustamante J.
        • Lores-Arnaiz S.
        Modulation of brain mitochondrial function by deprenyl.
        Neurochem Int. 2006; 48: 235-241
        • Czerniczyniec A.
        • Bustamante J.
        • Lores-Arnaiz S.
        Improvement of mouse brain mitochondrial function after deprenyl treatment.
        Neuroscience. 2007; 144: 685-693
        • De Marchi U.
        • Pietrangeli P.
        • Marcocci L.
        • Mondovi B.
        • Toninello A.
        l-Deprenyl as an inhibitor of menadione-induced permeability transition in liver mitochondria.
        Biochem Pharma. 2003; 66: 1749-1754