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Parkinson’s & Movement Disorders
November 11-12, 2019 | London, UK
7
th
International Conference on
Parkinson’s 2019
November 11-12, 2019
J Neurol Clin Neurosci . | Volume 3
Volume 3
Journal of Neurology and Clinical Neuroscience
The MAO-B inhibitor Rasagiline induced Neuroprotection in PC12 Dopaminergic
Neuronal model by regulation of the Akt/Nrf2 redox signaling pathway
Philip Lazarovici
The Hebrew University of Jerusalem, Israel
P
arkinson’s disease (PD) is a progressive, neurodegenerative disorder. One strategy for PD treatment relies
on inhibition of dopamine metabolism by inhibiting the monoamine oxidase B (MAO- B). Selegiline
(L-Deprenyl) and Rasagiline (Azilect) are selective MAO-B inhibitors which provide symptomatic benefit in
PD treatment and found to exert neuroprotective effects. However, slowing or halting the neurodegenerative
process has not yet been accomplished in PD patients using these drugs and therefore, neuroprotection is still
considered an unmet clinical need. We investigated in the PC12 dopaminergic neuronal model, exposed to oxygen-
glucose deprivation (OGD), the neuroprotective signalling pathways of these MAO-B inhibitors (1-3). Exposure
of neurons to OGD for 3 hr followed by 18 hr of reoxygenation caused about 30-40% cell death. Rasagiline
induced dose-dependent 50% neuroprotection when added either before or after the OGD insult. Clorgyline, a
monoamine oxidase-A inhibitor, did not protected the neurons towards OGD-induced cell death suggesting that the
neuroprotective effect of Rasagiline is independent of MAO A inhibition (4,5). Selegiline reduced OGD-induced
apo-necrotic cell death by 30%. L-methamphetamine, a major Selegiline metabolite, but not 1-R-aminoindan, the
major Rasagiline metabolite, enhanced OGD-induced cell death by 70%. Concomitant exposure of the cultures
under OGD, to a combination of either Selegiline and L-methamphetamine or Rasagiline and 1-R-Aminoindan,
indicated that L-methamphetamine, but not 1-R-Aminoindan, blocked the neuroprotective effect of the parental
drug. These results suggest a neuroprotective advantage of Rasagiline over Selegiline (6). Both survival kinases
phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinase (MAPK) were
activated by Rasagiline in relation to the neuroprotective effect. Rasagiline-induced nuclear shuttling of transcription
factor Nrf2 and increased the expression of antioxidant heme oxygenase-1 (HO-1). Rasagiline decreased production
of neurotoxic reactive oxygen species and preserved mitochondrial membrane integrity. These results indicate that
Rasagiline provides neuroprotection via improving mitochondrial integrity, as well as increasing mitochondria-
specific antioxidant enzymes by a mechanism involving the Akt/Nrf2 redox signaling pathway. These findings
may be exploited to develop third generation of MAO-B inhibitors with improved neuroprotection in PD therapy.
Biography
Philip Lazarovici graduated in pharmacology and toxicology at the Hebrew University, post graduated on neurobiology at the Weizmann
Institute of Science and conducted neurochemical and molecular research at the National Institutes of Child Health and Human
Development, NIH, Bethesda, USA. He was a visiting professor in the School of Biomedical Engineering, Science and Health Systems,
Drexel University and Faculty of Engineering, Temple University, Philadelphia, USA. He is a member of 15 international and national
academic societies, published about 250 scientific articles and reviews and edited six books.
philipl@ekmd.huji.ac.il