Mechanisms of Action of Other Potential Neuroprotective Treatments

*Neuroprotection - New Approaches and Prospects*

brain injury. Frontiers in Cellular Neuroscience. 2017 Jul 12;**11**:199 Available from: http://journal. frontiersin.org/article/10.3389/

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fncel.2017.00199/full

**250**

**Chapter 12**

**Abstract**

neuroprotective activity

**1. Introduction**

**253**

Glyproline Pro-Ampakine with

*Anna V. Tallerova, Yulia N. Firsova, Sergei V. Nikolaev,*

*Tatiana A. Antipova, Anna V. Nadorova, Larisa G. Kolik,*

Previously it was shown that neuropeptide cyclo-L-prolylglycine (CPG) is a positive modulator of AMPA receptors, which increases BDNF level in neuronal cell cultures. The spectrum of CPG's pharmacological effects corresponds to that of BDNF. Dipeptide N-phenylacetyl-glycyl-L-proline ethyl ester (GZK-111) was designed and synthesized as a linear analog of CPG. The aim of the present work was to reveal the pharmacological profile of GZK-111. Dipeptide GZK-111 was shown to metabolize into CPG in vitro and increased cell survival by 28% at concentrations of 10-7–10-6 M in a Parkinson's disease cell model. In a model of cerebral ischemia, GZK-111, at a dose of 0.5 mg/kg, i.p., was found to have neuroprotective effects, reducing the cerebral infarct volume by 1.6 times. Similar to CPG, GZK-111, at the range 0.1–1.0 mg/kg, i.p., possessed a stereospecific antiamnesic activity. A significant anxiolytic effect was observed at a dose of 1.5 mg/kg. GZK-111, at the range 0.5–4.0 mg/kg, i.p., demonstrated analgesic activity. GZK-111, at a dose of 10 mg/kg/7 days, i.p., possessed antidepressant-like activity. So, the neuroprotective, nootropic, antihypoxic, anxiolytic, antidepressant-like, and analgesic effects of GZK-111 were revealed. Thus, GZK-111 can be considered as a pharmacologically active pro-ampakine with a BDNF-ergic mechanism of action.

**Keywords:** glyproline GZK-111, pro-ampakine, cyclo-prolylglycine, BDNF,

Cyclo-*L*-prolylglycine (CPG) was designed as a potential peptide prototype of

piracetam, the classic nootropic drug [1] and was subsequently discovered as endogenous compound in the brain of intact rats in micromolar concentration [2]. CPG is similar to piracetam both in structure and main pharmacological effects; it possesses nootropic [3], anxiolytic [4, 5], antihypoxic [6], neuroprotective [6, 7], analgesic [8], and antidepressant [9, 10] activities at central administration at doses 100–1000 times smaller than those for piracetam. Recently, we have demonstrated CPG to be ampakine, i.e., a positive modulator of AMPA receptors [11]. Like other ampakines, it increases brain-derived neurotrophic factor (BDNF) content in

Neuroprotective Activity

*Ksenia N. Koliasnikova, Polina Yu. Povarnina,*

*Tatiana A. Gudasheva and Sergei B. Seredenin*

**Chapter 12**
