Mystixin-7 Peptide Protects Ionotropic Glutamatergic Mechanisms against Glutamate-Induced Excitotoxicity In Vitro.

Anatoly A Mokrushin

doi:10.1155/2016/5151843

Abstract

Hyperactivation of the N-methyl-D-aspartic acid type glutamate receptors (NMDARs) causes glutamate excitotoxicity, a process potentially important for many neurological diseases. This study aims to investigate protective effects of the synthetic corticotrophin-releasing factor-like peptide, mystixin-7 (MTX), on model glutamate-induced excitotoxicity in vitro. The technique online monitoring of electrophysiological parameters (excitatory glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPAR) and NMDAR-dependent postsynaptic mechanisms) in the olfactory cortex slices was used. Application of L-glutamate in toxic concentration (20 mM) on slices evoked hyperactivation of NMDARs and weaker activation of the AMPARs. Upon further action agonist, the excessive activation of glutamate receptors was replaced by their irreversible blockade. Pretreatment of the slices using MTX in different concentrations (50 and 100 mg/mL) protected both NMDARs and AMPARs from glutamate-induced damage. An enzymatic treatment of MTX reduced hyperactivation of both NMDARs and AMPARs. The present study demonstrated that MTX minipeptide protected the functioning of both NMDARs and AMPARs against glutamate-induced damage. The MTX peptide is a prospective candidate for elaborated medication in treatment of neurological diseases.

Highlights

Glutamate is a major excitatory neurotransmitter in the central nervous system of mammals
The acute phase of the development of glutamateinduced excitotoxicity was nonlinear for changing both of the AMPARs and N-methyl-D-aspartic acid type glutamate receptors (NMDARs) activity. These findings indicate that glutamate in toxic concentration affected both subtypes of ionotropic glutamate receptors, but the strongest action it had was on the NMDARs
The maximal protective effect was at concentration of 100 mg/mL for both receptor mechanisms (Figure 2). These results indicate that the protective effect of MTX may be enhanced for both AMPARs and NMDARs in a dosedependent manner

Summary

Introduction

Glutamate is a major excitatory neurotransmitter in the central nervous system of mammals. This substance plays a key role in various adaptive functions, including learning, memory, emotional reactivity, sensory perception, and control of locomotion [1,2,3]. Powerful stress (e.g., trauma, ischemia, epilepsy, and anoxia) induces massive release of intracellular glutamate into the extracellular space [4]. It results in hyperactivation of glutamate receptors, impairment of glutamate reuptake, and an excessive influx of Ca2+ entry into cells [5]. An important and practically significant problem of modern neurobiology is in searching reliable, effective medicines without side effects, which protect the functioning of glutamatergic mechanisms

Objectives

Methods

Results

Conclusion