R‐Deprenyl and R‐2‐Heptyl‐N‐Methylpropargylamine Prevent Apoptosis in Cerebellar Granule Neurons Induced by Cytosine Arabinoside but Not Low Extracellular Potassium

Abstract

R-Deprenyl and R-2-heptyl-N-methylpropargylamine (R-2-HMP) are compounds that have been shown to reduce neuronal death in various in vitro and in vivo models involving apoptosis but do not always prevent apoptosis. In the present study we have examined the effects of these compounds and their S enantiomers on cytosine arabinoside (ara C)-induced apoptosis and low K~-inducedapoptosis in cerebellar granule cells in primary culture. It was found that R-deprenyl and R-2-HMP could prevent ara C-induced apoptosis with an EC 50 around iO-~M but could not prevent low K~-induced apoptosis. S-Deprenyl and S-2-HMP did not prevent apoptosis under any conditions but were found to antagonize the antiapoptotic actions of R-deprenyl and R-2-HMP. Using the fluorescent mitochondrial dye chioromethyltetramethylrhodamine methyl ester it was found that there was a loss of mitochondrial function in cerebelar granule cells exposed to ara C but not low Kmedium. R-Deprenyl and R-2-HMP prevented the ara C-induced loss of mitochondrial function. It is concluded that Rdeprenyl and R-2-HMP prevent apoptosis of cerebetlar granule cells by a mechanism that is independent of monoamine oxidase inhibition and that they act on the same site to prevent specifically apoptosis involving a loss of mitochondrial membrane potential, possibly p53-dependent apoptosis.

Propargylamines Induce Antiapoptotic New Protein Synthesis in Serum- and Nerve Growth Factor (NGF)-Withdrawn, NGF-Differentiated PC-12 Cells

“…The prevention of decreases in BCL-2 and the decreased mitochondrial BAX localization induced by the DRPs may contribute to the maintenance of ⌬⌿ M found with DRP treatment of neurons or neuron-like cells entering apoptosis (Paterson et al, 1998;Wadia et al, 1998). BCL-2 prevents decreases in ⌬⌿ M caused by agents that increase mitochondrial membrane permeability and induce apoptosis in PC-12 cells (Dispersyn et al, 1999).…”

“…DRP antiapoptosis also has been found in other models including partially NGFdifferentiated PC-12 cells after serum and NGF withdrawal, rat hippocampal neurons after ischemia/hypoxia, neuroblastoma cells treated with rotenone, rat cerebellar granule neurons exposed to cytosine arabinoside, serum-deprived human melanoma cells, rat retinal neurons after hypoxia, ischemia, or serum withdrawal, and rat hippocampal neurons, cerebellar neurons, or neuroblastoma cells exposed to okadaic acid (see Tatton et al, 2000 for details and references). Notably, DRPs do not reduce all forms of apoptosis as has been shown in NGF-naive PC-12 cells (Vaglini et al, 1996), thymocytes treated with dexamethasone (Fang et al, 1995), and cerebellar granule neurons exposed to low-media K ϩ levels (Paterson et al, 1998).…”

“…Although some of the protein alterations may contribute to antiapoptosis, the extent of DRP-induced antiapoptotic protein synthesis is not known nor whether any protein synthesis changes are appropriately timed to interrupt apoptosis signaling. DRPs can prevent mitochondrial membrane potential (⌬⌿ M ) dissipation in some forms of apoptosis in which ⌬⌿ M dissipation results from increases in mitochondrial membrane permeability (Paterson et al, 1998;Wadia et al, 1998;Zhang et al, 1999). In some forms of apoptosis, increases in mitochondrial membrane permeability allow the release of mitochondrial factors that signal for apoptotic degradation (Jacotot et al, 1999).…”

Neuroprotective actions of selegiline

“…1). In addition, selegiline protects dopaminergic neurons from toxicity induced by glutathione depletion (Chang et al, 1997), protects against peroxynitrite-and nitric oxide-induced apoptosis (Maruyama et al, 1998), and possesses antiapoptotic actions in a variety of neurons (Paterson et al, 1998). Myllya et al (1992), by studying the efficacy of selegiline as an initial treatment in de novo parkinsonian patients, carried out a placebo-controlled and doubleblind parallel trial.…”

Insulin Rescues Retinal Neurons from Apoptosis by a Phosphatidylinositol 3-Kinase/Akt-mediated Mechanism That Reduces the Activation of Caspase-3

“…p53 also up-regulates glyceraldehyde-3-phosphate dehydrogenase in cerebellar granule neurons during apoptosis (28). However, p53 may not be involved in apoptosis induced by factors that do not lead directly to DNA damage, such as low potassium (29,30). The involvement of p53 in apoptosis of retinal neurons is unclear, but it is elevated after retinal ischemia (31).…”