Translated from Russian to English - www.onlinedoctranslator.

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https://doi.org/10.17116/jnevro201711712253-59

Comparative cerebroprotective activity of metformin,

gosogliptin, citicoline and a new agonist GPR119
with experimental cerebral ischemia on the background of diabetes
mellitus
I.N. TURENKOV1, D.V. Kurkin1*, YES. BAKULIN1, E.V. Volotova1, M.A. SHAFEEV2

Volgograd State Medical University of the Ministry of Health of Russia, Volgograd, Russia; 2CJSC "Research Institute of Chemical
1

Diversity", Khimki, Moscow region, Russia

Purpose of the study. To assess the cerebroprotective activity of metformin, gosogliptin, citicoline and an agonist
GPR119 (compound ZB-16) in a focal cerebral ischemia (GM) model reproduced in animals with 4-week streptozotocin-
nicotinamide-induced diabetes mellitus (DM). Material and methods. The study was carried out on 73 male rats.
Hypoglycemic drugs and compound ZB-16 were administered from the first day of diabetes development, citicoline - after
modeling GM ischemia. Cerebroprotective effect was assessed using the Garcia, Combs and D'Alecy scales, rotarod and open
field tests, as well as by the volume of infarction and the severity of edema of the GM.results
and conclusion. The introduction of metformin with pronounced hypoglycemic activity did not provide significant
cerebroprotective effect in the subsequent modeling of GM ischemia. The introduction of agents affecting the incretin system
(gosogliptin and especially the ZB-16 compound), in addition to the hypoglycemic effect, contributed to a significant decrease in the
volume of infarction, HM edema and the severity of neuropsychiatric deficiency in surviving animals. At the same time, the
introduction of citicoline without correct hypoglycemic therapy slightly reduced the severity of the course of GM ischemia.

Keywords: stroke, diabetes mellitus, metformin, gosogliptin, GPR119, incretins, citicoline.

Cerebroprotective activity of metformin, gosogliptin, citicoline and a novel GPR119 agonist in

cerebral ischemia under experimental diabetes mellitus
IN TYURENKOV, DV KURKIN, DA BAKULIN, EV VOLOTOVA, MA CHAFEEV

Volgograd State Medical University, Department for Pharmacology and Biopharmacy, Volgograd, Russia; Chemical Diversity Research Institute,
Khimki, Moscow Region, Russia

Hypoglycemic agents of some groups: sodium-glucose cotransporter type 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1)
receptor agonists reduce the risk and / or severity of cardiovascular diseases. Studies of such properties are currently focused on
metformin and dipeptidyl peptidase-4 (DPP-4) inhibitors. Agonists of GPR119 receptor, increasing the secretion of GLP-1 and insulin,
are also actively studied as hypoglycemic drugs with endothelial and cerebroprotective potential.Objective... To evaluate the
cerebroprotective activity of metformin, gosogliptin, citicoline and an agonist of GPR119 (ZB-16) in middle cerebral artery occlusion
(MCAO) in animals with 4-week streptozotocin-nicotinamide-induced diabetes.Material and methods... A study included 73 male rats.
Hypoglycemic agents and ZB-16 were administered on the first day of diabetes and citicoline was administered after MCAO.
Cerebroprotective effect was evaluated using Garcia, Combs and D'Alecy score test, "Rotarod" and "open field" test, as well as the
infarct volume and severity of brain edema measurement.Results and conclusion... Preventive administration of metformin resulted
in the pronounced hypoglycemic activity without a significant cerebroprotective effect in subsequent brain ischemia modeling.
Administration of substances with incretin activity (gosogliptin and, in particular, ZB-16) in addition to the hypoglycemic action
promoted a significant reduction of infarct volume, brain edema and severity of neurologic deficit of the surviving animals. At the
same time, the introduction of citicoline without proper glycemic control didn't reduce the brain ischemia severity.

Keywords: stroke, diabetes mellitus, metformin, gosogliptin, GPR119, incretin, citicoline.

Against the background of diabetes mellitus (DM), a significant increase and severity of the course of
vascular complications increases the risk of developing cardiovascular diseases, including disorders of
cerebral hemorrhage. Therefore, in the study of pharmacology (NMC) [1].
the properties of hypoglycemic agents, the There is no consensus on the effect of
assessment of their effect on the risk of developing metformin on the course of ischemic stroke, while its

© Team of authors, 2017 * e-mail: strannik986@mail.ru

JOURNAL OF NEUROLOGY AND PSYCHIATRY, 12, 2017; Issue 2 53

endothelioprotective effect is shown in many St. Petersburg), which were contained in the
In other works, and at present, studies of the free conditions of the vivarium.
influence of metformin on the risk, course of IMC Metformin (400 mg / kg, per os) Is the drug of
and recovery processes are ongoing [2, 3]. first choice for the treatment of type 2 diabetes with
In recent years, incremental high efficiency
tin-mediated therapy of diabetes mellitus, including bliss [7]. due to the presence of incretinomimetics -
agony- Then gosogliptin ("Saterex",
stov receptors of glucagon-like peptide-1 Russia) is a domestic inhibitor of DPP-4 (including (GLP-1) and
dipeptidylpeptidase-4 inhibitors chen in the register of drugs on 05/13/2016). According to (DPP-4) -
pronounced endothelium, cardio and neural activity (in vitro) gosogliptin (IC = 11.3 nM) antiprotective 50
effects, described in detail in, exceeds most of the used inhibitor in a number of reviews [1, 4]. Pleiotropic
properties of DPP-4 moat: sitagliptin (IC = 19 nM), vildaglip- 50
GLP-1 is only partially associated with their hypoglycemic tin (IC =5062 nM), saxagliptin (IC = 50 nM)50
and alo-
action, and their basis is broad gliptin (IC = 24 nM) [8]. According to the50
results of a number of clinically
prevalence of GLP-1 receptors in various scientific studies, the drug has high tissues and the ability to
trigger the most important intraselectivity to DPP-4 type and good pharma-cellular signaling cascades that
support cokinetic parameters: Tmax from 0.5 to 1 , 5 h, the functional activity of the cell and inhibiting T1 / 2
from 15 to 27 h, causes inhibition of DPP-4 and apoptosis in pathological conditions. by 80% within 24 hours
after administration, accompanying
One of the new pharmacological approaches is a twofold increase in the GLP-1 level. According to the re-
influence on the incretin system, the creation of the results of a comparative study [9] is that state agonists
to a number of specific receptors for gliptin are not inferior to vildagliptin in terms of the ability of
enteroendocrine L- and K-cells of the intestine to reduce the level of HbA. Gosogliptin 1c
in the present
(GPR119, GPR43, etc.), the activation of which leads to study [10] was used at a dose of 5 mg / kg per os.
an increase in the production of incretins (GLP-1 and Compound ZB-16 (dipiaron) (CJSC IIHR,
glucose-dependent insulinotropic polypeptide - Russia) is a highly selective yes — GIP) with the subsequent
development of a hypoglycemic receptor agonist GPR119 (EC M-7.25E–09) (rice. 1)... and 50
a number of other
effects. Receptor agonist According to previous studies [5], compound GPR119 is a compound ZB-16,
according to the results of ZB-16, it has a comparable effect as an inhibitor of previous studies, has a
pronounced hypoglycemic-glycemic effect in animals with an experimental effect at a dose of 1 mg / kg,
which does not increase diabetes mellitus [5], as well as cerebroprotective effect when the dose of ZB-16 is
increased to 10 mg / kg (non-interference in modeling cerebral ischemia, glare data). However, in the study
of the brain (GM) in intact animals [6]. cerebroprotective activity of ZB-16 on intact

The aim of the present study was to evaluate influential animals during the ligation of the common carotid
arteries of the therapeutic and prophylactic administration of metforia, it was shown that the compound
(cerebropromin, gosogliptin and a new receptor agonist, the tective action was investigated at doses of 1, 10 and
GPR119 (compounds ZB-16), as well as citicoline 25 mg / kg) exhibits the most pronounced effect of the course of
focal GM ischemia in animals at a dose of 10 mg / kg [6]. It has been suggested that
experimental SD. the hypoglycemic effect of ZB-16 is limited by the
insulin-secreting properties of the pancreas, since it
Material and methods is incretin-mediated and, therefore, insulin-

The study was carried out on 73 male rats, but it may not spread, weighing 280-300 g, at the age of 6-7
months ("Rappolovo", on its pleiotropic effects. Based on this,

F
N
Cl
O O
N
N
S
O
O

Rice. 1... Chemical structure of the GPR119 receptor agonist compound ZB-16.

54 JOURNAL OF NEUROLOGY AND PSYCHIATRY, 12, 2017; Issue 2

 Statistical processing of the received data
compound ZB-16 was administered at a dose of 1 mg / kg (1 time in
day) for 4 weeks of experimental therapy was carried out using the Mi-SD software packages, and after
modeling GM ischemia in a dose of crosoft Office Excel 2013 (Microsoft, USA) and Prism5 10 mg / kg per
day. ("GraphPad Software", USA) by Paint-
Evaluation of the cerebroprotective activity of hypol — Wallis and Dan. The differences were statistically
significant in comparison with glycemic drugs.p<0.05.
with the reference drug citicoline, which is widely used
all over the world for CCD of various origins. Citicoline results
(Ferrer Internacional, Spain) was administered to
animals with experimental diabetes mellitus (500 mg / Assessment of neurological deficits using the Garcia and
kg,per os) [11] only after modeling the occlusion of the Combs and D'Alecy scales
middle cerebral artery (OCMA), In animals of the control group (OCMA + physical
up to this point, they received saline) against the background of GM ischemia, an expression of the solution
developed. female neurological disorders, registered
The study was carried out on animals using the Garcia scales (decrease in spontaneous movement by 4-
week streptozotocin-nicotinamide-inductive activity, asymmetry of movements by co-ordinated (STZ-HA)
DM, which was modeled by impairedness, etc.) and Combs and D'Alecy (weakness of the extremities by
intraperitoneal injection of streptozotocia, inability to maintain equilibrium on neon (65 mg / kg) against the
background of a preliminary (within 15 minutes) movable rod, etc.).
introduction of nicotinamide (230 mg / kg) [12]. For the study, In the groups that received for 4 weeks before and in the
For testing, animals with a glycemic level were selected for 2 days after OCMA hypoglycemic drugs in the
range of 8-16 mmol / L (after 6 hours of fasting), from rats (metformin and gosogliptin), the total score of
which was formed 6 experimental neurological deficits on the Garcia scale was groups (see table)...
significantly lower than in the control group, only
Focal GM ischemia was simulated 48 hours after surgery, while in animals of reversible intravascular
OCMA of prolonged, treated with compound ZB-16, this indicator was 30 min according to J. Koizumi's
method. Chloral hydrate (400 mg / kg, OCMA(rice. 2, a)... When assessing the neurological de-
intraperitoneal). deficit according to Combs and D'Alecy scales total

The level of neurological deficit (according to the scale, the score was lower than in the control group, only in
lamas Garcia and Combs and D'Alecy) and impaired coordination groups OCMA + gosogliptin and OCMA + ZB-16
across the nation of movements (in the Rotarod test) evaluated within 48 hours after OCMA (see fig. 2, b)... Res 24
and 48 h, and motor, orientation-is- The use of citicoline in animals with STZ-NA
investigative activity and distance traveled — for DM who did not receive hypoglycemic drugs, the effect
was assessed in the "open field" test 48 hours before OCMA; the number of neurological deficits in Garcia

At the end of these tests, both Combs and D'Alecy (see fig. 2)...
sampling of GM and analysis of photographs of its
Assessment of impaired coordination of
sections, stained with 2,3,5-triphenyltetrazolium
movements in the rotarod test
chloride and located in the same plane with a
millimeter ruler (section thickness 2 mm, distance to In the rotarod test in animals that did not receive
the objective 30 cm). The relative hypoglycemic therapy (groups OCMA + physical
the volume of necrosis and an increase in the volume of the affected solution and OCMA + citicoline) were
observed with an expanded hemisphere. female violations of strength and coordination of movements.

Groups of animals with STZ-HA diabetes and the average level of glycemia before modeling OCMA

Glycemic level
Group (n - number of animals) 2 hours after glucose load (3 g / kg, per os),
after 6 hours of fasting, mmol / l
mmol / l
LO + saline (n= 10) OCMA + 9.5 ± 0.3 10.9 ± 0.4
saline (n= 15) OCMA + 9.7 ± 0.5 11 ± 0.7
metformin (n= 12) OCMA + 7.5 ± 0.6 7.7 ± 0.6
gosogliptin (n= 12) OCMA + 8.1 ± 0.6 8.8 ± 0.7
ZB-16 (n= 12) OCMA + 7.9 ± 0.4 8.2 ± 0.1
citicoline (n= 12) 9.6 ± 0.5 11.2 ± 0.3

Note. LO + saline - a group of sham-operated animals with STZ-NASD. Data are presented as mean and error of the mean.

JOURNAL OF NEUROLOGY AND PSYCHIATRY, 12, 2017; Issue 2 55

Rice. 2.The level of neurological deficit in animals according to scales Garcia (a) and Combs and D'Alecy (b) (points).
Here and in other pictures: # - the differences are significant relative to the LO group + saline solution at the level p<0.05; * - the differences are significant relative to the
OCMA group + saline solution at the levelp<0.05.

Rice. 3.The time of the latent period of the first fall (a) and retention for 3 attempts (b) on a rotating rod in the rotarod test.

Significant increase in the time of the first fall from (rice. 4, e)... In animals that received before and after
day 1, metformin and gosogliptin, spontaneous dvitin and OCMA + ZB-16 were observed in the OCMA +
gosoglip-OCMA groups.(rice. 3, a)... In the animals of the group, the gating activity, the exploratory
behavior, which received metformin, dynamics was observed, the total distance traveled was a sign of an
increase in the time of the first fall and the total amount of time longer than in the animals of the control
group, the retention time on the rotating rod (for 3 s of OCMA, but less than animals that received
attempts) 48 hours after OCMA (see fig. 3, b)... ZB-16 (see fig. 4, 5)... In rats of the OCMA + citicoline
group, all recorded parameters were insignificantly
Assessment of motor and orientation- higher than in the control group.
exploratory activity in the "open field"
test Assessment of the volume of infarction and the degree of edema of the GM

In the "open field" test, the motor and 48 hours after 30-minute OCMA in the group
orientation-exploratory activity of the abdomen OSMA + saline the volume of necrosis was
in the group OCMA + saline solution was lower than in 33.2 ± 3.6% of the affected hemisphere, which was
sham-operated rats, so the animals, as a result of edema, was increased by 15% relative to the control
group, predominantly moved intact (rice. 6)...
a small area of the field, making rare peeks into In the groups treated with gosogliptin and ZB-16,
burrows and racks (rice. 4)... the volume of necrosis calculated relative to the
In the group of animals OCMA + ZB-16 compared to affected hemisphere was 37% and 43%, respectively.
with the control group were observed significantly less (p<0.05) than in the control group without greater
indices of motor activity (values (see fig. 6)... At the same time, the relative increase is 103%) and the
approximate research behavior of the volume of the affected hemisphere, which characterizes (by 218%)
(rice. 5, a)... The rats of this group boterate the degree of edema; in the groups receiving the completely
examined space of open glyptin and ZB-16, it was 42 and 46% lower (p<0.05), la, more often they performed
stands and looked into burrows than in the control group. In the OCMA + met-

56 JOURNAL OF NEUROLOGY AND PSYCHIATRY, 12, 2017; Issue 2

Rice. 4.Typical trajectory of movement in the open field test.
Groups of animals: a - LO + saline; b - OCMA + saline, c - OCMA + metformin, d - OCMA + gosogliptin, e - OCMA + ZB-16, f — OCMA + citicoline.

Rice. 5.Indicators of motor activity and orientation-exploratory behavior.

formin there was a tendency to a decrease in the size of ischemia [1]. Obviously, not all cerebroprotectors of heart attack
and the severity of edema, which does not reach, are capable of exerting a pronounced effect on IUAC
statistical significance. in the conditions of SD. In the present study, cyticoline
did not have a pronounced cerebroprotective effect in
Discussion animals with DM without previous hypoglycemic
therapy, whereas, according to the literature [6, 11], in
Violations of vasodilating, antithrombotic animals with GM ischemia without
he possessed such anti-inflammatory, anti-inflammatory functions of endothelial diabetes. lia with diabetes contribute
to the violation of the microcircus - Metformin, according to the results of many years
lation, trophism, as well as the resistance of the GM tissue to observation, shows not only a pronounced hypo-

JOURNAL OF NEUROLOGY AND PSYCHIATRY, 12, 2017; Issue 2 57

Rice. 6.The volume of necrosis in the groups treated with gosogliptin ZB-16 and metformin versus controls.
a - an increase in the volume of the affected hemisphere; b - sections of GM, thickness 2 mm, staining with 1% 2,3,5-triphenyltetrazolium chloride.

glycemic activity, but also reduces the risk of differently, it has been suggested that the studied agony of
vascular complications of type 2 diabetes, that nyst of the GPR119 receptor can reduce the severity of those,
is realized due to a decrease in peripheral ischemia of GM both in intact rats and in insulin resistance,
improving the utilization of animals with diabetes.
glucose, lipid profile and endothelioprotein
effective action. However, in the literature [2, 3] there is no lactic administration of the compound ZB-16
provided unambiguous data on its direct effect - a more pronounced cerebroprotective effect on the course
of NMC. In this study, in the case of GM ischemia against the background of diabetes meth- the deficit that
metformin had for me and was comparable to gosoglipti- ty could be a consequence of not only effective
equestrianism. Considering that ZB-16 increases basal and trol glycemia throughout the experiment,
stimulated GLP-1 secretion (unpublished and its endothelioprotective properties. Data), it can be assumed
that cere-

Therapeutic and prophylactic administration of gosoglipbroprotective properties of the Tin receptor agonist
to a lesser extent than compounds ZB-16, the way GPR119 is explained by the effects of GLP-1. contributed to a
decrease in the severity of the course of ischemia Thus, the choice of a drug for hypoglycemia
GM on the background of the SD. This may be due to decreased therapy, which can significantly affect the
production of incretins in animals under conditions of the course and outcome of NMC. Therapeutic and
prophylactic diabetes, which is consistent with the literature [1]. the introduction of metformin causes a
significant decrease in in relation to cerebral pathology of MNC monia. The use of drugs affecting the
growth rate is inferior to synthetic analogues of GLP-1 or a system of incretins (gosogliptin and especially
compounds that increase the production of ZB-16 increment), in addition to hypoglycemic deins.

Compound ZB-16 is an agonist of the receptor-pharct, edema of GM, and the severity of the neuropsychiatric
GPR119; when administered to animals with experimental deficiency in animals with GM ischemia on mental diabetes, a
pronounced decrease in the background of diabetes was noted. At the same time, the introduction of citicoline without a
corrected glycemic level and the normalization of the parameters of co-rectal hypoglycemic therapy does not lead to
walking hemostasis [5, 14], which can be associated with a pronounced cerebroprotective effect.
increased production of incretins upon activation of
this receptor on enteroendocrine cells. Given the The authors declare no conflict of interest.
neuro- and endothelioprotective properties of
agents with incretin activity [1, 4],

58 JOURNAL OF NEUROLOGY AND PSYCHIATRY, 12, 2017; Issue 2

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