The Anxiolytic Effect of the Neuropeptide Cycloprolylglycine Is Mediated by AMPA and TrkB Receptors
- PDF / 202,064 Bytes
- 3 Pages / 612 x 792 pts (letter) Page_size
- 112 Downloads / 181 Views
HEMISTRY, BIOPHYSICS, AND MOLECULAR BIOLOGY
The Anxiolytic Effect of the Neuropeptide Cycloprolylglycine Is Mediated by AMPA and TrkB Receptors Corresponding Member of the RAS T. A. Gudashevaa,*, P. Yu. Povarninaa, K. N. Koliasnikovaa, A. G. Alyaevaa, O. N. Vorontsovaa, and Academician S. B. Seredenina Received March 20, 2020; revised March 23, 2020; accepted March 23, 2020
Abstract—Previously we have shown that the neuropeptide cycloprolylglycine is an endogenous positive modulator of AMPA receptors and assumed that the pharmacological effects of CPG are associated with the brain neurotrophic factor. In this paper, we have first demonstrated that DNQX, an inhibitor of AMPA receptors, and K252A, an ihibitor of Trk receptors, prevented the anxiolytic effect of CPG, which confirms the formulated hypothesis. Keywords: cyclo-L-prolyl-glycine, anxiolytic activity, brain derived neurotrophic factor (BDNF), TrkB, AMPA DOI: 10.1134/S1607672920040067
Cyclo-L-prolylglycine (CPG) was designed at the Zakusov Research Institute of Pharmacology as a topological analogue and presumable endogenous peptide prototype of the classical nootropic piracetam [1]. In 1996, CPG was indeed identified in the rat brain as an endogenous compound at a concentration of ∼10–6 M [2]. Recently, CPG was also found in human blood plasma and cerebrospinal fluid at concentrations of ∼10–7 M [3]. It is assumed that CPG is formed in the body from the tripeptide Gly-Pro-Glu, an N-terminal metabolite of the insulin-like growth factor [4]. In animal experiments, CPG exhibits pharmacological effects characteristic of piracetam, though at doses 2–3 orders of magnitude lower. In particular, the nootropic [1, 2], anxiolytic [5], neuroprotective [4], analgesic [6], and antidepressant [7] activities of this cyclodipeptide were detected. In 2016, we found [8] that CPG increases AMPA currents in isolated rat cerebellar Purkinje cells and, thus, exhibits the properties of a positive modulator of glutamate AMPA receptors. It is known that piracetam and some other racetams affect AMPA receptors and mediate the deceleration of desensitization and deactivation of the latter [9]. In addition, using neuronal cell cultures, it was shown [10] that CPG increases the level of the brain-derived neurotrophic factor (BDNF), which is characteristic of positive AMPA receptor modulators [11]. The stimulation of BDNF synthesis by CPG was a Zakusov
Research Institute of Pharmacology, Moscow, Russia *e-mail: [email protected]
also observed in experiments in vivo on a rat model of Alzheimer’s disease induced by intracerebral injection of β-amyloid, where the neuroprotective effect of CPG was accompanied by an increase in the BDNF mRNA level and activation of the ERK signaling pathway [12]. These data suggest that the pharmacological effects of CPG are determined by the stimulation of the BDNF/TrkB signaling pathway, mediated by the activation of AMPA receptors. To test this hypothesis, in this work we studied the effect of the AMPA receptor blocker DNQX and the TrkB receptor blo
Data Loading...
