Effect of rasagiline on the molecular composition of the excitatory postsynaptic density

Abstract

In the last decade, several neuroprotective therapies have been proposed for Parkinson's disease and rasagiline was indicated as one of the most promising candidates by preclinical studies. The drug has already been tested in phase III clinical studies (the ADAGIO study). The mechanism underlying rasagiline-dependent neuroprotection is complex and almost unknown. Here, we show that rasagiline is involved in the regulation of the molecular composition of the postsynaptic density of glutamatergic synapses. In hippocampus as well as in striatum, rasagiline induces a significant reduction of synaptic levels of NR2A-containing NMDA receptors and in hippocampal slices it also significantly decreases synaptic levels of GluR1-containing AMPA receptors. This capability of rasagiline to modulate ionotropic glutamate receptors composition at synaptic sites strengthens the rationale for its clinical use to slow the progression of Parkinson's disease.

Effect of long-term treatment with rasagiline on cognitive deficits and related molecular cascades in aged mice

“…Various molecular mechanisms appear to be associated with the neuroprotective effects of rasagiline, including upregulation of cellular antioxidant activity; induction of neurotrophic factors and neuroactive ligand receptors (Maruyama et al, 2004;Weinreb et al, 2009); prevention of the decline in mitochondrial membrane potential and nuclear translation of glyceraldehyde 3-phosphate dehydrogenase, activation of prosurvival antiapoptotic molecules (e.g., , and suppression of cell death cascades initiated by proapoptotic Bcl-2 family molecules (e.g., Bax and Bad) and caspase-3 (Akao et al, 2002b;Blandini, 2005;Maruyama et al, 2001a, Weinreb et al, 2004. Moreover, it was demonstrated that rasagiline may be involved in the regulation of the molecular composition of the excitatory postsynaptic density (Gardoni et al, 2011).…”

Protective effect of rasagiline in aminoglycoside ototoxicity

“…It also increases antioxidant enzyme (glutathione peroxidase and catalase) activities (Kitani et al, 2000) and inhibits mPTP opening, mitochondrial swelling and cytochrome c release (Youdim et al, n.d.;Maruyama et al, 2001;Akao et al, 2002) and caspase 3 activation (Bar-Am et al, 2005). A decrease in the synaptic density of NMDA-and AMPA receptors, responsible for initiating excitotoxicity, has also been reported with rasagiline treatment (Gardoni et al, 2011). These cellular mechanisms are considered responsible for the positive in vivo effects of rasagiline.…”