Disease relevance of rasagiline

• Activation of tyrosine kinase receptor signaling pathway by rasagiline facilitates neurorescue and restoration of nigrostriatal dopamine neurons in post-MPTP-induced parkinsonism [1].
• The results on the activation of the transcription factor by rasagiline are discussed in relation to its possible application as a neuroprotective drug to halt declining of neurons in neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases [2].
• Specifically rasagiline activates Bcl-2, Bcl-xl, protein kinase C (PKC) and reduces Bax in a variety of cells including PC-12 and neuroblastoma human dopamine derived SH-SY5Y cells [3].
• Neuroprotective effect of rasagiline, a selective monoamine oxidase-B inhibitor, against closed head injury in the mouse [4].
• In alpha-methyl-p-tyrosine (alpha-MpT)-induced hypokinesia (100-120 mg/kg, i.p.) pretreatment with rasagiline at 2.5 mg/kg i.p. restored motor activity to control level [5].

Psychiatry related information on rasagiline

• Effects of N-propargyl-1-(R)aminoindan (rasagiline) in models of motor and cognition disorders [5].
• We have therefore developed a number of novel drugs based on rasagiline (N-propargyl-1R-(+)-aminoindan), a potent anti-Parkinson-propargyl-containing MAO-B inhibitor drug with structural resemblance to selegiline, for the treatment of Alzheimer's disease [6].
• In the case of M30 the pharmacophore of brain permeable iron chelator VK-28 plus the MAO inhibitor-neuroprotective propargylamine moiety of rasagiline are combined in a single molecule as a potential treatment for Alzheimer's disease, Lewy body disease, and Parkinson's disease with dementia [7].

High impact information on rasagiline

• To circumvent this obstacle, a novel MAO-B inhibitor, rasagiline, was developed [8].
• Rasagiline and its derivatives also process amyloid precursor protein (APP) to the neuroprotective-neurotrophic soluble APP alpha (sAPPalpha) by PKC and MAP kinase-dependent activation of alpha-secretase [9].
• Structure activity studies have shown that the neuroprotective activity is associated with the propargyl moiety of rasagiline which protects mitochondrial viability and MPTp by activating Bcl-2 and protein kinase C (PKC), and down regulating pro-apoptotic FAS and Bax [9].
• The anti-Parkinson monoamine oxidase (MAO)-B inhibitor rasagiline (Azilect) was shown to possess neuroprotective activities, involving the induction of brain-derived- and glial cell line-derived neurotrophic factors (BDNF, GDNF) [1].
• Employing conventional neurochemical techniques, transcriptomics and proteomic screening tools combined with a biology-based clustering method, we show that rasagiline, given chronically post-MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), exerts neurorescue/neurotrophic activity in mice midbrain dopamine neurons [1].

Chemical compound and disease context of rasagiline

• Iron chelators (desferal, Vk-28 and clioquinol) but not copper chelators have been shown to be neuroprotective in the 6-hydroxydoapmine and MPTP models of Parkinson's disease (PD), as are monoamine oxidase B inhibitors such as selegiline and rasagiline [10].
• Furthermore, rasagiline, TV3326 and TV3279 are able to influence the processing of amyloid precursor protein by activation of alpha-secretase and increasing the release of soluble alpha APP in rat PC-12 and human neuroblastoma SH-SY5Y cells and in rat and mice cortex and hippocampus [11].
• To test safety, tyramine challenges (50-75 mg) were performed in 72 rasagiline-treated and 38 placebo-treated Parkinson's disease (PD) patients at the end of two double-blind placebo-controlled trials of rasagiline [12].
• Two novel neuroprotective cholinesterase (ChE) inhibitors, TV3326, (N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate, and TV3279, (N-propargyl-(3S) aminoindan-5-yl)-ethyl methyl carbamate, were derived from rasagiline for the treatment of Alzheimer's disease (AD) [13].
• Ladostigil combines the neuroprotective effects of the antiparkinson drug rasagiline, a selective monoamine oxidase (MAO)-B inhibitor, with the cholinesterase (ChE) inhibitory activity of rivastigmine in a single molecule, as a potential treatment for Alzheimer's disease (AD) and Lewy Body disease [14].

Biological context of rasagiline

• Altogether, mitochondrial PT plays a key role both in NM(R)Sal-induced cell death and the neuroprotective effect of rasagiline [15].
• Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and rasagiline, N-propargyl-1(R)-aminoindan [15].
• These results suggest that GAPDH may accumulate in nuclei as a consequence of signal transduction, which is antagonized by anti-apoptotic Bcl-2 protein family and rasagiline [16].
• These structural studies may guide future drug design to improve selectivity and efficacy by introducing appropriate substituents on the rasagiline molecular scaffold [17].
• The areas of high uptake were absent from scan 2, on which activity throughout the brain was comparable to that in white matter, presumably because of blocking of MAO-B binding sites by rasagiline [18].

Anatomical context of rasagiline

• Rasagiline also inhibited the NM(R)Sal-induced loss of DeltaPsim and swelling in the isolated mitochondria, proving that rasagiline directly targets the mitochondria also [15].
• Administration of rasagiline (0.1 mg/kg) to male C57/BL mice for 14 days significantly decreased membrane-bound holoprotein APP levels in the hippocampus [19].
• CONCLUSION: (11)C-l-deprenyl PET showed binding of rasagiline to MAO-B, confirming blocking of MAO-B sites after 10 d of treatment with 1 mg of rasagiline per day, with immediate post-rasagiline treatment tracer uptake and metabolism in the basal ganglia compatible only with nonspecific binding [18].
• Rasagiline, a monoamine oxidase-B inhibitor, protects NGF-differentiated PC12 cells against oxygen-glucose deprivation [20].
• Both doses of rasagiline markedly increased the survival of dopaminergic neurons in the lesioned substantia nigra, compared to controls (+97% and +119%, respectively) [21].

Associations of rasagiline with other chemical compounds

• The respective rasagiline- and selegiline-related series were designed to combine inhibitory activities of both acetylcholine esterase (AChE) and monoamine oxidase (MAO) by virtue of their carbamoyl and propargylamine pharmacophores [22].
• The crystal structure of N-methyl-1(R)-aminoindan bound to MAO B shows that its aminoindan ring adopts a different orientation compared to that of rasagiline [23].
• 3. Amphetamine-induced increase in striatal extracellular dopamine level was attenuated by one day and by chronic (21 days) treatment with selegiline (0.25 mg kg(-1), s.c.). 4. Striatal levels of DAT were elevated after 1 and 21 days treatment with selegiline, but were not affected by clorgyline, rasagiline, nomifensine or amphetamine [24].
• No effect on NA efflux was seen when the tissue was treated with rasagiline (0.005 microM; selective inhibitor of MAO-B), but rasagiline, AGN-1133 and clorgyline increased basal efflux of dopamine (DA) following L-DOPA [25].
• The modification of L-3,4-dihydrooxyphenylalanine- (L-DOPA-) induced turning response by the new selective monoamine oxidase type B (MAO-B) inhibitor rasagiline was studied in guinea-pigs bearing a unilateral 6-hydroxydopamine-induced lesion in the substantia nigra [26].

Gene context of rasagiline

• N-Propargyl-1 (R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma SH-SY5Y cells through activation of NF-kappaB transcription factor [2].
• Moreover, rasagiline dose dependently (0.1-10 microM) increased the phosphorylation of p44 and p42 MAPK, which was abolished by PD98059 (30 microM) and GF109203X (2.5 microM) [27].
• Rasagiline (N-propargyl-1-(R)-aminoindan) is a selective, irreversible monoamine oxidase B (MAO B) inhibitor which has been developed as an anti-Parkinson drug [11].
• A dose of 2.5 mg kg(-1) l-deprenyl and 1 mg kg(-1) rasagiline was shown to result in over 90% inhibition of the monoamine oxidase (MAO)-B from rat liver and striatum, whereas the inhibition of MAO-A was about 60 and 40% in liver and striatum, respectively [28].
• In this study, we investigate the inhibition of recombinant human MAO A and MAO B by several rasagiline analogues [23].

Analytical, diagnostic and therapeutic context of rasagiline

• The neuronal survival properties of rasagiline (R(+)-N-propargyl-1-aminoindane mesylate or TVP-1012), a novel monoamine oxidase B inhibitor, have been investigated using neuronal cell cultures from fetal rat and human ventral mesencephalon [29].
• N-Propargyl-1(R)-aminoindan (rasagiline) is now under phase III clinical trials for Parkinson's disease (PD), and it rescues dopamine neurons from cell death in animal and cellular models of PD [30].
• Pretreatment of PC12 cells in absence of serum and NGF for 24 h with either rasagiline (1 microM) or selegiline (1 microM) is neuroprotective and anti-apoptotic as determined by ELISA and MTT tests [31].
• The ability of rasagiline to reduce the rate of neuronal cell loss in vitro was tested using primary neuronal cell lines and immunohistochemistry to quantify the reduction in cell death [29].
• Rasagiline was generally well tolerated in clinical trials as both monotherapy and when administered with other antiparkinsonian drugs [32].

References