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Invited Symposium: MAOIs: Mulptiple Effects and Sites of Action






Abstract

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Neurochemical and Neuroprotective Effect of Aliphatic N-Methylpropargylamine MAO-B Inhibitors.


Contact Person: Peter H Yu (yup@sask.usask.ca)


Background

* R-Deprenyl can slightly relief the symptoms and delay the on-set of severe disability of Parkinson's disease; It improves cognitive behavior and slows down the progression of disability of Alzheimer’s disease. * Although it cannot be concluded from these clinical studies whether R-deprenyl is neuroprotective (i.e. prevent neurodegeneration), R-deprenyl has been shown to protect neurons against various neurotoxins and insults in different models, such as MPTP and kainate-induced seizures and the rescue of facial neurons following axotomy in young rats. Antiapoptotic mechanism for R-deprenyl has been proposed. * MAO-catalyzed deamination reactions can produce hydrogen peroxide and subsequently enhance oxidative stress. Inhibition of MAO activity would thus decrease oxidative stress and reduce any associated neuronal damage. Dopamine turn-over in the remaining small number of nigrostriatal neurons has been shown to be increased in order to maintain motor function in Parkinsonism. Inhibition of oxidative deamination seems to be a logic approach to prevent progressive neuronal damage due to oxidative stress. * R-Deprenyl and R-2-HMP has been shown to exert neuroprotective and neurorescue effect in different experimental models, however, the mechanism(s) does not seem to be due to inhibition of MAO activity. * R-Deprenyl, a structural analogue of amphetamine, is catabolized to produce desmethyldeprenyl, methamphetamine and amphetamine; this has caused some concern due to amphetamine-like properties. These metabolites have also been claimed to exhibit antagonist effect to the antiapoptotic properties of R-deprenyl.

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Aliphatic Propargylamines as MAO-B Inhibitors

* MAO-B possesses high affinity towards aliphatic amines. * An aliphatic group has been attached to N-methylpropargylamines. The products have been found to be highly potent, selective, irreversible MAO-B inhibitors. For example, the inhibitory activity towards MAO-B of R-2-HMP [N-(2-heptyl)-N-methylpropargylamine] is more potent and selective than that of R-deprenyl. * The MAO-B inhibitory activity is related to carbon chain length and the substitutions. * The MAO-B inhibitory activity is stereospecific with R-enantiomer to be the active form. * 2-HMP is readily cross the blood brain barrier. It is metabolized to desmethyl-2-HMP, N-methyl-2-aminoheptane, 2-aminoheptane, etc.

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Neuroprotective and neurorescue effects

* Effect of R-2-HMP on MPTP-induced depletion of dopaminergic neurons: Aliphatic N-methyl-propargylamines prevent the conversion of MPTP to MPP+ , thererfore, they are capable of protecting the dopaminergic neurons against MPTP-induced nigrostriatal depletion in mouse brain. 2-R-HMP has also been shown to rescue neurons after MPTP washout (i.e. two days after MPTP treatment). * Effect of R-2-HMP on DSP-4-induced degeneration of noradrenergic neurons: DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine], can selectively deplete noradrenergic axon terminals. It subsequently causes ascending cell death of NA neuronal cell bodies in rodents. R-2-HMP is capable of preventing the depletion of noradrenergic axon and terminals against DSP-4. The neuroprotective effect was confirmed by both neurochemical and morphological methods. Such a protective effect is unrelated to inhibition of MAO-B activity. R-2-HxMP has also been shown to prevent the ascending neurodegeneration of locus coeruleus noradrenergic neurons. * Effect of R-2-HMP on HSP70 and delayed c-Fos expression in kainate-induced neurotoxicity: The excitatory neurotoxin kainic acid (KA) induces limbic seizures and subsequently massive and irreversible neuronal injuries and death in many brain regions, particularly in the hippocampal dentate hilus and the pyramidal cell layers of the CA1 and CA3 fields. The expression of heat shock proteins, i.e. the 70 kD protein (HSP70), and a delayed expression of c-Fos are induced and can be served as markers for neuronal injury. R-2-HMP, which are administered four hours after the KA treatment, are capable of preventing the expression of HSP70 and c-Fos and the subsequent neurodegeneration in hippocampal CA1. * Effect of R-2-HxMP on MK-801 induced neuronal damage: MK-801, a non-competitive NMDA antagonist, at higher concentrations can induce apoptotic neuronal death in the limbic system. It has been used as an animal model for dementia and psychosis. We observed that both cycloheximide and R-2-HxMP prevent MK-801-induced neuronal death in the retrosplenial cortex in the rat. The results suggest that the MK-801-induced neuronal death is apoptotic. Unlike cycloheximide, R-2-HxMP does not inhibit protein synthesis, therefore, exerts a different anti-apoptotic mechanism. * Ex vivo neuroprotection of hippocampal slices by R-2-HMP: R-2-HMP can significantly increase cell viability in the hippocampal slices following hypoxic-hypoglycaemic insult based on confocal (LIVE/DEAD stain) examination and on the enhancement of 3H-thymidine incorporation. S-2-HMP enantiomer exhibited significantly reduced neuroprotective effect. R-2-HMP significantly increased 3H-thymidine incorporation of the hippocampal slices. It is unclear, whether the increase in 3H-thymidine was due to cell proliferation or DNA repair in the damaged hippocampal tissues.

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Antiapoptotic Properties

* Effect of R-2-HMP on apoptosis of cerebellar granule cells: Apoptosis of cerebellar granule cells induced by low K+ is p53 independent and those induced by mitotic inhibitor cytosine arabinoside (Ara C) is p53 dependent. R-2-HMP exhibits a dose dependent inhibition of Ara C-induced apoptosis, but has no effect of apoptosis induced by low K+. S-2-HMP does not affect both type of apoptosis in the cerebellar granule cells. * 2-HMP does not affect apoptosis of thymocytes: Apoptosis of thymocytes induced by dexamethasone is p53 independent and those induced by gamma-irradiation is p53 dependent. R-2-HMP fails to affect p53 dependent or independent apoptosis in the thymocytes. The reason why aliphatic N-methylpropargylamines can inhibit apoptotic effects only in some systems but not in others is unclear. It seems to suggest that these agents selectively prevent different subtypes of apoptosis depending on cell types and the mechanism of the apoptotic death. From the pharmacological point of view it is important that any anti-apoptotic neurorescue agent should not affect all programmed cell death processes that are essential for maintaining normal physiology. * Effect on superoxide dismutase (SOD) and free radicals: R-Deprenyl has been claimed to be able to increase rat striatal SOD activity. This observation was not confirmed in our lab. We were unable to detect any increase in SOD activity either in the striata or the cerebral cortex, neither could we detect any increase in the concentration of immuno-reactive SOD antibody in the cortex following chronic treatment with this drug. It has been reported that SOD mRNA can be induced by R-deprenyl. R-Deprenyl has been claim to scavenge free radicals generated during dopamine auto-oxidation, in vitro. This apparent scavenging effect seems to be due to the decrease in pH in the reaction mixture produced by the use of the hydrochloride salt of R-deprenyl. Dopamine auto-oxidation could be reduced by 2-HxMP.HCl, however, the effect disappeared when pH value was carefully adjusted with buffers.

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Conclusion

Aliphatic N-methylpropargylamines, such as R-2-HMP and R-2-HxMP, are highly potent, irreversible and selective MAO-B inhibitors both in vitro and in vivo. Whilst being similar to R-deprenyl they do not possess any amphetamine moiety within their structure. They are able to protect the neuron from damage against toxins and physical assaults in several in vitro, ex vivo and in vivo models. The neurorescue effect seems to be unrelated to inhibition of MAO activity. These compounds may be potentially useful for the treatment of neurodegenerative disorders. The mechanism of neurorescue action remains to be established.

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Yu, PH; Zhang, X; Zuo, DM; Lai, CT; Tieu, K; Davis, BA; Boulton, AA; (1998). Neurochemical and Neuroprotective Effect of Aliphatic N-Methylpropargylamine MAO-B Inhibitors.. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/levant/yu0398/index.html
© 1998 Author(s) Hold Copyright