Rasagiline Promotes Regeneration of Substantia Nigra Dopaminergic Neurons in Post-MPTP-induced Parkinsonism via Activation of Tyrosine Kinase Receptor Signaling Pathway

Abstract

The anti-Parkinson drug rasagiline (Azilect), an irreversible and selective monoamine oxidase (MAO)-B inhibitor, was shown to possess neuroprotective activities, involving multiple survival pathways among them the up-regulation of protein kinase C (PKC)alpha, PKCepsilon, the anti-apoptotic Bcl-2, Bcl-xL, and Bcl-w and the induction of brain-derived- and glial cell line-derived neurotrophic factors (BDNF, GDNF). More recently, employing conventional neurochemical techniques, as well as transcriptomic and proteomic screening tools, combined with a biology-based clustering method, it was shown that rasagiline also possesses neurorescue/neurogenesis activity in mice midbrain dopaminergic neurons when given chronically, post-MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). This action was attributed to the activation of cell signaling mediators associated with neurotrophic factors responsive-tyrosine kinase receptor (Trk) pathway, including ShcC, SOS, AF6, Rin1, and Ras and the increase in the Trk-downstream effecter phosphatidylinositol 3 kinase (PI3K) protein and its substrate, Akt/PKB. It is interesting to determine whether a similar effect is seen in Parkinsonian patients after long-term treatment with rasagiline, which may have implications as a possible disease modifying agent.

Docosahexaenoic acid provides protective mechanism in bilaterally MPTP-lesioned rat model of Parkinson's disease

“…The inhibitor of MAO-B, rasagiline, has been found to slow the functional decline in patients with an early, mild form of PD [26,115]. In MPTP-treated mice, rasagiline was shown to protect against the toxin, a neuroprotective effect associated with activation of Akt [116,117]. Our results show protection against MPTP toxicity by DHA involving the PI3K/Akt pathway.…”

The TrkB-Positive Dopaminergic Neurons are Less Sensitive to MPTP Insult in the Substantia Nigra of Adult C57/BL Mice

“…Third, up-regulation of BDNF or BDNF-mediated signaling was involved in neuroprotection process of dopaminergic neurons against inflammatory, MPTP, and 6-OHDA-induced degeneration by mediating retinoic acid receptor stimulation, cystamine administration and acupuncture [16,23,33]. The rasagiline and selegiline, two anti-PD monoamine oxidase-B inhibitors, possessed neuroprotective activities and promoted regeneration of nigral dopaminergic neurons in MPTP model by inducing production of BDNF, activating of Trk receptor pathway and increasing of downstream effector phosphatidylinositol 3 kinase protein [18,25]. Fourth, the aging-related changes in gene expression of nigra and striatum were observed in BDNF heterozygous mice [39] and inhibition of BDNF expression by antisense oligonucleotide infusion also confirmed a loss of nigral dopaminergic neurons [34].…”

Stimulation, protection and regeneration of dopaminergic neurons by 9-methyl-β-carboline: a new anti-Parkinson drug?

“…They should elucidate whether 9-me-BC merits further development as an investigational new drug. and iron chelators [190][191][192][193]. 9-me-BC has emerged as a potential multimodal agent with not only neurostimulatory, neuroprotective and neuroregenerative, but also anti-inflammatory properties.…”