Rasagiline, a monoamine oxidase‐B inhibitor, protects NGF‐differentiated PC12 cells against oxygen‐glucose deprivation

Abstract

In our in vitro model, rasagiline a selective irreversible monoamine oxidase-B (MAO-B) inhibitor, protected nerve growth factor (NGF)-differentiated PC12 cells from cell death under oxygen and glucose deprivation (OGD). The severity of the OGD insult, as expressed by cell death, was time-dependent. Exposure of the cells to OGD for 3 hr followed by 18 hr of reoxygenation caused about 30-40% cell death. Under these conditions, the neuroprotective effect of rasagiline was dose-dependent: rasagiline reducing OGD-induced cell death by 68% and 80% at 100 nM and 1 microM, respectively. The neuroprotective effect of rasagiline was also observed when added after the OGD insult (55% reduction in cell death). Under rasagiline treatment, there was a lesser decrease in ATP content in cultures exposed to OGD compared with that in untreated cultures. OGD followed by reoxygenation resulted in a several fold increase in PGE(2) release into the extracellular medium. Rasagiline (100 nM-1 microM) markedly inhibited OGD-induced PGE(2) release. Clorgyline, a monoamine oxidase-A (MAO-A) inhibitor, did not protect NGF-differentiated PC12 cells against OGD-induced cell death. As NGF-differentiated PC12 cells contain exclusively MAO type A, these data suggest that the neuroprotective effect of rasagiline under OGD conditions is independent of MAO inhibition.

In vitro ischemia decreases histone H4K16 acetylation in neural cells

“…Typical in vitro ischemia experiments include exposure of cells to OGD for 0.5-15 h [8,[47][48][49]. Previously it was shown that 6 h OGD has minor effects on viability and can be used for ischemic preconditioning of PC12 cells, while development of ischemic tolerance occurs after 15-24 h of re-perfusion [8].…”

Clinical Pharmacology of Rasagiline: A Novel, Second‐Generation Propargylamine for the Treatment of Parkinson Disease

“…28,72,73 In addition, the neuroprotective activity of rasagiline is observable at concentrations below the MAO inhibition threshold and is observable in cell systems that do not contain MAO-B, such as human neuroblastoma SH-SY5Y. 74,75 In addition to SH-SY5Y, other isolated cell systems in which rasagiline has shown neuroprotective effects against a variety of challenges include NGFdifferentiated rat pheochromocytoma PC-12 cells, 5,76 fetal rat mesencephalic neurons, 77,78 rat hippocampal neurons, 31 rat cerebellar granule cells, 79 and fetal human mesencephalon cells 77 (Table IV). Under experimental conditions, rasagiline attenuates damage from toxins relevant to PD models such as 6hydroxydopamine, 80,81 N-methyl(R)salsolinol, 80,82 and N-morpholino sydonimine (SIN-1, a peroxynitrite donor).…”

Pharmacokinetics and safety of single and multiple doses of rasagiline in healthy Japanese and caucasian subjects

“…There was also a significant and beneficial effect in quality of life (as assessed by the Parkinson's disease Quality of Life scale) compared to placebo. 13 In addition, non-clinical studies using multiple experimental models have shown that, independent of its MAO-B inhibitory activities, rasagiline is neuroprotective, as demonstrated by both in vitro [14][15][16] and in vivo animal models. [17][18][19] As monotherapy, rasagiline is considered safe and well tolerated, with frequency and types of adverse events for patients receiving rasagiline similar to those receiving placebo at daily doses of 1 and 2 mg, 8 and pain, headache and dizziness being the most common adverse events in both patients 20 and healthy volunteers.…”