Effects of rasagiline, its metabolite aminoindan and selegiline on glutamate receptor mediated signalling in the rat hippocampus slice in vitro

Abstract

BackgroundRasagiline, a new drug developed to treat Parkinson's disease, is known to inhibit monoamine oxidase B. However, its metabolite R-(-)-aminoindan does not show this kind of activity. The present series of in vitro experiments using the rat hippocampal slice preparation deals with effects of both compounds on the pyramidal cell response after electric stimulation of the Schaffer Collaterals in comparison to selegiline, another MAO B inhibitor.MethodStimulation of the Schaffer Collaterals by single stimuli (SS) or theta burst stimulation (TBS) resulted in stable responses of pyramidal cells measured as population spike amplitude (about 1 mV under control SS conditions or about 2 mV after TBS).ResultsDuring the first series, this response was attenuated in the presence of rasagiline and aminoindan-to a lesser degree of selegiline-in a concentration dependent manner (5-50 μM) after single stimuli as well as under TBS. During oxygen/glucose deprivation for 10 min the amplitude of the population spike breaks down by 75%. The presence of rasagiline and aminoindan, but rarely the presence of selegiline, prevented this break down. Following glutamate receptor mediated enhancements of neuronal transmission in a second series of experiments very clear differences could be observed in comparison to the action of selegiline: NMDA receptor, AMPA receptor as well as metabotropic glutamate receptor mediated increases of transmission were concentration dependently (0,3 - 2 μM) antagonized by rasagiline and aminoindan, but not by selegiline. On the opposite, only selegiline attenuated kainate receptor mediated increases of excitability. Thus, both monoamino oxidase (MAO) B inhibitors show attenuation of glutamatergic transmission in the hippocampus but interfere with different receptor mediated excitatory modulations at low concentrations.ConclusionsSince aminoindan does not induce MAO B inhibition, these effects must be regarded as being independent from MAO B inhibition. The results provide strong evidence for a neuroprotective activity of rasagiline and aminoindan in concert with an extended clinical indication into the direction of other diseases like Alzheimer's disease or stroke.

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

“…Here we show that rasagiline can directly modulate NMDA receptor composition at synapse and, consequently, its function, by decreasing NR2A at synaptic sites. This is confirmed by a very recent report describing significant decreases of glutamate receptors-mediated signaling in hippocampus, following treatment with rasagiline at similar concentrations (Dimpfel and Hoffmann, 2011). Moreover, recent data reported a critical functional role for NR2A-containing NMDA receptors -and a less crucial role for NR2B-containing NMDA receptors -in the depression of glutamatergic synaptic transmission and evoked dopamine release in striatum (Schotanus and Chergui, 2008;Schotanus et al, 2006).…”

“…In vitro studies indicated that the neuroprotective activity of rasagiline can be observed at concentrations below the MAO-B inhibition threshold (Weinreb et al, 2010), mainly between 0.1 and 10 μM ( Bar-Am et al, 2005;Dimpfel and Hoffmann, 2011;Weinreb et al, 2007). On these bases, we treated acute corticostriatal and hippocampal slices with rasagiline 0.1 and 1 μM for 2 hours.…”

Monoamine oxidase inhibitors: Promising therapeutic agents for Alzheimer’s disease (Review)

“…An increasing number of molecular biology and pharmacology studies have shown the neuroprotective effects of MAO inhibitors on the prevention and treatment of AD (21,52,53) (Table I) (15,56,57,61,62,112,114,(131)(132)(133)(134)(135)(136)(137)(138)(139)(140)(141)(142)(143)(144). The main neuroprotective mechanisms of MAO inhibitors in AD include the following: i) Improvement of cognitive impairment (50,54,55), where MAO inhibitors correct chemical imbalances in the brain; ii) antioxidant activities and enhancement of iron-chelating activities (56)(57)(58)(59), where chelators can modulate Aβ accumulation, protect against tau hyperphosphorylation and block metal-associated oxidative stress, thereby holding considerable promise as effective anti-AD drugs (145,146); iii) regulation of APP and Aβ expression processing (56,60), for example ladostigil (TV3326), a selective MAO-B inhibitor, which regulates APP translation and processing (114); iv) the selective MAO inhibitors selegiline and rasagiline have been proven to possess neuroprotective activities in cell cultures and animal models of neurodegenerative diseases through the activation of certain signaling pathways, including p42/44 MAPK and PKC (61); v) inhibition of ChE activity by the MAO inhibitor rasagiline (62)(63)…”

Mechanism of Action of Low Dose Preparations from <i>Coffea arabica</i>, <i>Gelsemium</i> and <i>Veratrum</i> Based on <i>in Vivo</i> and <i>in Vitro</i> Neurophysiological Findings

“…In order to search for answers it seems appropriate to deal initially with some plant-derived preparations in the order of dilutions of D4-D6, where for sure some molecules are left within the preparation after the dilution procedure. A second reason to get engaged into this matter was the availability of two very sensitive physiological methods used for years to characterize successfully classic synthetic drugs as well as plant derived extracts: Tele-Stereo-EEG for in vivo characterization [1] and hippocampus slice for in vitro characterization [2] [3]. The former methodology provides evidence for in vivo characterization of dose and time dependent drug effects including predictions for clinical use; the latter provides information on concentration dependent effects of water-soluble preparations on physiological transmission of brain electric signals including hints on the mechanisms of action.…”