Abstract
A glutamate/NMDA receptor (NMDA-R) antagonist, amantadine (AMA) exhibits a broad spectrum of clinically important properties, including antiviral, antiparkinsonian, neuroprotective, neuro-reparative and cognitive-enhancing effects. However, both clinical and pre-clinical studies have demonstrated that noncompetitive NMDA-R antagonists induce severe schizophrenia-like cognitive deficits. Therefore, this study aims to clarify the clinical discrepancy between AMA and noncompetitive NMDA-R antagonists by comparing the effects of AMA with those of a noncompetitive NMDA-R antagonist, MK801, on rat tripartite glutamatergic synaptic transmission using microdialysis and primary cultured astrocytes. Microdialysis study demonstrated that the stimulatory effects of AMA on L-glutamate release differed from those of MK801 in the globus pallidus, entorhinal cortex and entopeduncular nucleus. The stimulatory effect of AMA on L-glutamate release was modulated by activation of cystine/glutamate antiporter (Sxc). Primary cultured astrocytes study demonstrated that AMA also enhanced glutathione synthesis via Sxc activation. Furthermore, carbon-monoxide induced damage of the astroglial glutathione synthesis system was repaired by AMA but not MK801. Additionally, glutamate/AMPA receptor (AMPA-R) antagonist, perampanel enhanced the protective effects of AMA. The findings of microdialysis and cultured astrocyte studies suggest that a combination of Sxc activation with inhibitions of ionotropic glutamate receptors contributes to neuroprotective, neuro-reparative and cognitive-enhancing activities that can mitigate several neuropsychiatric disorders.
Highlights
An approved glutamate/NMDA receptor (NMDA-R) antagonist, amantadine (AMA), exhibits a broad spectrum of clinically important properties, including antiviral and antiparkinsonian effects.It has been established that blocking the M2 small viral membrane protein is an element of antiviral activity of AMA [1], and inhibiting both NMDA-R and catecholamine transporter plays an important role in the antiparkinsonian effect of AMA [2,3]
The entorhinal cortex plays important roles in attention, conditioning, event and spatial cognition, and it possibly exerts its actions by compressing representations that overlap in time [35]
Damage in the globus pallidus is frequently seen in patients with carbon monoxide poisoning (COP) [38]
Summary
An approved glutamate/NMDA receptor (NMDA-R) antagonist, amantadine (AMA), exhibits a broad spectrum of clinically important properties, including antiviral and antiparkinsonian effects. It has been established that blocking the M2 small viral membrane protein is an element of antiviral activity of AMA [1], and inhibiting both NMDA-R and catecholamine transporter plays an important role in the antiparkinsonian effect of AMA [2,3]. In advanced Parkinson’s disease, AMA is utilized primarily to treat peak-dose L-DOPA-induced dyskinesia [4]. AMA was found to improve speech disturbance in advanced Parkinson’s disease patients with subthalamic nucleus deep brain stimulation resistance [4]. AMA was observed to accelerate the pace of functional recovery during active treatment in patients with post-traumatic
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