DOI 10.

1007/s11055-018-0579-3
Neuroscience and Behavioral Physiology, Vol. 48, No. 4, May, 2018

The Adaptogenic and Neuroprotective Properties

of Lithium Ascorbate

A. V. Pronin,1 O. A. Gromova,1 I. S. Sardaryan,2 I. Yu. Torshin,3 E. V. Stel’mashuk,4

K. S. Ostrenko,5 O. P. Aleksandrova,4 E. E. Genrikhs,4 and L. G. Khaspekov4

Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Vol. 116, No. 12, Iss. 1, pp. 86–91,
December, 2016.

Objectives. To study the neuroprotective properties of lithium ascorbate (LA) in in vivo and in vitro stress
models. Materials and methods. Neurocytological and behavioral studies were run in models of stress in
nerve cell cultures and experimental animals. Results. LA was shown to have a marked neuroprotective ef-
fect in conditions of glutamate-induced cytotoxicity in vitro and an adaptogenic effect on induction of stress
in vivo. Conclusions. The results obtained here demonstrated that LA has high neuroprotective potential in
stress induced in vivo and in vitro.
Keywords: stress, excitotoxicity, glutamate, lithium ascorbate.

Stress is a state of increased tension in the body arising
as a result of the lack of appropriate adaptive reactions to
external stimuli (stressors). In health, the actions of these
stimuli mobilize the adaptive capacity of the body. When
the resistance of the body decreases for one reason or anoth-
er, the so-called exhaustion stage (distress) starts, long dura-
tions of which can lead to the development of various
chronic diseases [1].
Chronic stress decreases the viability of neurons and
leads to neurodegeneration. Even moderate chronic stress
leads to the appearance of signs of neurodegeneration such
as impairments to synaptic transmission, the accumulation
of γ-amyloid, and hyperphosphorylation of τ protein [2–5].
These effects are mediated on the background of excessive
activation of glutamate NMDA receptors, which leads to
excitotoxic neuron death [6].
1 Ivanovo State Medical Academy, Ivanovo, Russia;
e-mail: doctormchs1978@mail.ru.
2 St. Petersburg State Pediatric Medical University,
St. Petersburg, Russia.
3 Moscow Institute of Physics and Technology (State University),
Moscow, Russia.
4 Neurology Science Center, Moscow, Russia.
5 All-Russia Research Institute of Animal Physiology,
Biochemistry, and Nutrition, Borovsk, Kaluga Region, Russia.
One of the factors promoting the development of stress
is lack of micronutrients, particularly lithium. Lithium is an
essential trace element required for the normal development
of the nervous system. Results from experimental studies
have provided evidence of its neurotropic and neuroprotec-
tive effects. The use of lithium preparations increases the
synthesis of neurotrophic factors, preventing neuron death
by modulating the apoptotic PI3K/Akt/GSK3 cascade. At
very low doses (μg, mg), lithium is extremely important as
an ion specifically (irreplaceably) supporting the activity of
molecular cascades which promote acceleration of neuron
growth and increase their resistance to oxidative stress [7],
improve spatial memory, and prevent the negative influenc-
es of chronic stress on this activity [8]. Use of lithium at
safe low doses increases the volume of gray matter in the
brain [9–11]. Our data indicate that lithium ascorbate was
8.4 times less toxic than the inorganic salt lithium carbon-
ate. Lithium ascorbate is characterized by the best acute
toxicity parameters: the LD50 of lithium ascorbate in Wistar
rats is 6334 mg/kg, such that lithium ascorbate substance
can be identified as a class 5 substance, “essentially nontox-
ic,” LD50 ≥ 5000 mg/kg.
The aim of the present work was to study the neuropro-
tective properties of lithium ascorbate (LA) in in vivo and in
vitro models of stress.

409
0097-0549/18/4804-0409 ©2018 Springer Science+Business Media, LLC
410
Materials and Methods. The protective properties of
LA were studied in vivo using two-month-old Wistar rats in
conditions of transportation and immobilization stress and
in vitro in cultures of cerebellar granule cells subjected to
the cytotoxic action of glutamate.
In vivo studies. The task of this study was to evaluate
the protective properties of parenteral administration of dif-
ferent doses of LA in a stress model. Five groups each of 36
animals were formed on the pairs principle. Animals were
quarantined for seven days before the beginning of the ex-
periment. Rats of all groups were kept in standard animal
house conditions in cages containing 18 animals. Feed was
PLZh premix (compliant with state standard GOST R
50258-92) and the litter was fine dry shavings. Group 1
were controls (the rats received water); group 2 received LA
at a dose of 120 mg/kg; group 3 received LA at a dose of 60
mg/kg; group 4 received LA at a dose of 30 mg/kg; group 5
were intact rats (stress not modeled). LA was given at the
same time of day in groups 2–4, 2 h after the morning feed,
as solution administered via tube; the solvent was water for
injection (Bufus, Novosibkhimfarm) and the volume was
1.5 ml. Animals of groups 2–4 received LA for three weeks.
The protective effect was measured daily using the suspen-
sion test and a simulated transportation test.
Suspension test. The animal was suspended for 24 h
and whole blood was collected from the sublingual vessels
on completion of the experiment. Eosinophil counts were
determined using the Duncker method in whole capillary
blood collected by clipping the tip of the tail. The method is
based on persistence of eosinophils in acetone solution,
which destroys all other blood cells. Cell counts were per-
formed using a Goryaev chamber no more than 30 min after
collection of blood. Eosinophils were counted in 100 large
squares and values were multiplied by 50 to give the num-
ber per μl. Serum adrenaline and noradrenaline were as-
sayed, these being specific markers for stress actions. Six
animals were selected from each group and were placed in
a desiccator chamber containing diethyl ether for spinal de-
capitation for studies of the abdominal cavity and assess-
ment of the number of ulcers in the gastric mucosa.
Simulated transportation stress test. This was run on a
Unimax-1010 universal rotary shaker. A cage was attached
to the shaker platform and five animals were placed in the
cage, in free movement. Three sequential experiments were
performed with intervals of seven days; each experiment
lasted 240 min, during which the shaker was run at 120 rpm.
At the end of the test, the methods described above were
used to study the state of the body. Alanine aminotransfer-
ase (ALT), aspartate aminotransferase (AST), and creati-
nine were assayed in serum using a Konelab-20i (Finland,
USA) automatic biochemical analyzer.
Open field test (OFT). Horizontal and vertical move-
ment activity was recorded, along with grooming, sniffing
of apertures, and defecation boluses. Motor abnormalities
such as unsteady gait, tremor, etc., were also recorded.
Pronin, Gromova, Sardaryan, et al.
Fig. 1. Effects of glutamate (Glu) on culture survival (number of morpho-
logically unaltered neurons on fixed preparations stained with trypan blue).
In vitro studies. Experiments were performed using
cells cultured for 7–8 days and prepared by enzymatic-me-
chanical dissociation of cerebellar neurons from seven-day-
old rats as described previously [12]. Animals were sacrificed
using a lethal dose of ether, followed by sterilization with
70% ethanol; the cerebellum was harvested and transferred to
a plastic Petri dish containing phosphate buffer lacking Ca2+
and Mg2+ ions. Tissue fragments were incubated at 37°C for
15 min in phosphate buffer containing 0.05% trypsin, 0.02%
EDTA, and 0.8% glucose. After incubation, tissue was
washed with two changes of phosphate buffer and once with
the nutrient medium used for cultivation, in which cells were
then mechanically dissociated. This contained 90% Eagle’s
medium, 10% embryonic calf serum, 2 mM glutamine, 5 mM
KCl, and 10 mM HEPES buffer pH 7.2–7.4.
Cell suspensions were centrifuged for 1 min at 1000
rpm, supernatants were removed and pellets were resuspend-
ed in nutrient medium. Cells were cultured in plastic 96-well
plates coated with polyethyleneimine or polylysine, where
the potassium chloride level was adjusted to 25 mM. Each
well was supplemented with 0.1 ml of cell suspension.
Cultivation was continued for 7–8 days in an incubator
filled with a gas mix containing 95% air and 5% CO2 at a
temperature of 35.5°C and a relative humidity of 98%. By
this time, the cultured granule neurons (CGN) reached mor-
phological and neurochemical maturity. The condition of
cultures was monitored daily by visual examination under
an inverted phase contrast microscope.
LA solution was prepared from fresh dry substance im-
mediately before addition to culture medium. Solution was
sterilized by filtration and added to the nutrient medium on
day 2 in vitro for the whole of the cultivation period (up to
The Adaptogenic and Neuroprotective Properties of Lithium Ascorbate 411

TABLE 1. Number of Gastric Ulcers in Suspension Test

Number of ulcers
Group
day 7 day 14 day 21

1 23.5 ± 0.9 21.2 ± 0.2* 21.2 ± 0.2*

2 4.0 ± 0.5* 2.5 ± 1.1 2.1 ± 0.7

3 4.1 ± 0.8 2.6 ± 0.4* 2.4 ± 0.5

4 4.5 ± 0.9 2.4 ± 0.2* 1.9 ± 0.4*

5 1.0 ± 0.1* 1.5 ± 0.5 1.0 ± 0.5*

Here and Table 2: *Statistically significant differences compared with control, Dunn’s test (p < 0.05).

TABLE 2. Whole Blood Eosinophil Counts in Suspension Test (per μl)

Number of eosinophils
Group
day 7 day 14 day 21

1 311 ± 58 285 ± 15 291 ± 2

2 768 ± 67 885 ± 38 911 ± 82

3 791 ± 12* 866 ± 94 910 ± 41*

4 764 ± 65 897 ± 72 954 ± 97

5 953 ± 29 975 ± 5* 981 ± 54*

seven days). In some experiments, LA was added to the me-
dium on in vitro day 7, 3 h before exposure to glutamate.
The following concentrations were used: 0.1, 0.2, 0.5, and
1.0 mM. As CGN have glutamate receptors, and as these
cells have matured by in vitro day 7, hyperstimulation with
exogenous glutamate induces death of CGN, which pro-
vides a convenient model for neurodegeneration [13, 14].
Glutamate (Sigma, USA, N.G.-1626) added to cultures on
day 7 produced a dose-dependent toxic effect (Fig. 1). Con-
centrations were selected in each experiment such that CGN
survival was 30–80% of that in controls. This level of sur-
vival allows the actions of substances on cell death to be
detected. Neuroprotective effects cannot be detected at sur-
vival rates of less than 30% or more than 80%. Cell count-
ing was used to assess potential neuroprotectors, adding
selected toxic concentrations of glutamate (50–250 μM) to
the nutrient medium.
Three cultures were taken at each time point; in each,
five fields were sequentially photographed and counted (45
fields from nine cultures in three independent experiments).
Distributions of results were normal. The number of neu-
rons with unaltered morphology in control cultures was tak-
en as 100%.
Statistical analysis was run by analysis of variance
(ANOVA) with the Bonferroni/Dunnett corrections and the
nonparametric Kolmogorov–Smirnov test, which is highly
sensitive and suitable for analysis of cohorts independently
of whether the distribution is normal. Between-group differ-
ences were regarded as significant at p < 0.05. Results are
presented as M ± SD.
Results and Discussion. In vivo experiments. The
number of gastric ulcers in the suspension test, which cor-
relates directly with the severity of stress, was significantly
decreased by LA. Longer periods of treatment with LA led
to more marked decreases in the number of ulcers (Table 1).
Differences between group 1 and controls were statistically
significant (t test, p < 0.05).
The number of eosinophils in whole blood and the
adrenaline and noradrenaline concentrations are specific
markers of the actions of various stress factors. Increases in
distress led to decreases in eosinophil counts (eosinopenia a
characteristic biomarker of stress), while adrenaline and
noradrenaline levels increased (stress simulates catechol-
amine secretion by the sympathetic ganglia and adrenal cor-
tex). Use of LA led to preservation of the eosinophil pool
(Table 2) and decreases in the adrenaline and noradrenaline
concentrations (Table 3).
Transportation stress model. Use of LA was effective
in transportation stress, conditions which are unnatural for
animals and therefore elicit marked behavioral reactions.
Treated animals made more active efforts to decrease the
unfavorable actions of stress and adapt to the altered condi-
412 Pronin, Gromova, Sardaryan, et al.

TABLE 3. Serum Adrenaline and Noradrenaline in Suspension Test (μg/liter)

Serum adrenaline and noradrenaline concentrations

Group day 7 day 14 day 21

adrenaline noradrenaline adrenaline noradrenaline adrenaline noradrenaline

1 27 ± 3.9 68.6 ± 1.5 28.3 ± 1.2 68.9 ± 9.41 27.7 ± 2.46 70.5 ± 3.54

2 7.6 ± 0.38* 20.2 ± 5.67 8.7 ± 3.82 20.3 ± 4.83 9.6 ± 3.28* 18.4 ± 5.27*

3 7.9 ± 0.21* 22.1 ± 1.98 7.1 ± 1.19 20.3 ± 3.49 7.3 ± 2.14* 19.3 ± 6.13

4 8.1 ± 0.52* 24.3 ± 2.2* 6.9 ± 2.77* 18.2 ± 5.28 6.9 ± 0.97* 17.9 ± 0.95*

5 6.7 ± 0.65* 18.6 ± 1.95 6.1 ± 0.51* 17.9 ± 0.85* 6.4 ± 2.42 17.2 ± 0.56*

TABLE 4. Whole Blood Eosinophil Counts in Transportation Simulation Test (per μl)

Whole blood eosinophil count

Group
day 7 day 14 day 21

1 428 ± 11 401 ± 81 425 ± 69

2 856 ± 42 901 ± 16* 907 ± 43*

3 822 ± 87 919 ± 41* 922 ± 93

4 794 ± 69 921 ± 91 928 ± 107

5 978 ± 51 991 ± 6* 979 ± 38*

TABLE 5. Effects of LA on Blood ALT and Creatinine Conditions in Transportation Simulation Stress

day 7 day 14 day 21

Group
ALT, mM Creatinine, μmol/liter ALT, mM Creatinine, μmol/liter ALT, mM Creatinine, μmol/liter

1 13.2 ± 5.97 19.4 ± 2.45* 13.5 ± 4.84 17.9 ± 5.31 14.0 ± 4.91 19.1 ± 2.12

2 32.4 ± 7.75 39.8 ± 6.13 31.7 ± 7.32 47.8 ± 1.46 30.1 ± 7.42 42.1 ± 2.97*

3 31.0 ± 3.15* 39.6 ± 7.98 33.1 ± 2.84* 48.3 ± 8.27 32.4 ± 6.37 45.6 ± 2.73*

4 29.8 ± 8.45 36.5 ± 3.84 32.1 ± 9.10 48.1 ± 3.82* 31.7 ± 3.14 46.3 ± 3.26*

5 36.3 ± 2.64* 48.8 ± 4.50 38.1 ± 1.49* 50.1 ± 4.86 36.9 ± 3.87* 49.2 ± 4.61

TABLE 6. Effects of LA on the Behavior of Rats in the OFT

Vertical movement Horizontal Number of glances Number of Number of excursions Number of

Group
activity movement activity into openings grooming acts to central zone boluses
1 7.21 ± 2.75 3.48 ± 0.75 2.96 ± 0.42 23.47 ± 2.38 0.9 ± 0.42 6.46 ± 0.16

2 29.46 ± 3.74 6.75 ± 0.68* 9.98 ± 0.96* 8.44 ± 4.76 2.84 ± 0.14* 2.54 ± 0.68*

3 27.32 ± 2.87* 6.18 ± 0.42* 9.32 ± 3.13 9.43 ± 4.12 3.12 ± 2.17 2.12 ± 0.48*

4 17.24 ± 4.86* 5.56 ± 1.24* 4.76 ± 2.41 17.25 ± 3.61 1.21 ± 1.82* 5.14 ± 0.23*

tions: they tried to find the place least subject to vibrations Blood test data and biochemical measures confirmed
and grouped tightly together such that oscillations of the the behavioral criteria of the adaptogenic action of LA. LA
group compensated for oscillations of the shaker platform. promoted retention of the blood eosinophil pool (Table 4)
The Adaptogenic and Neuroprotective Properties of Lithium Ascorbate 413

Fig. 2. Empirical distribution functions for the numbers of surviving CGN at different lithium ascorbate concentrations (mM).
Kolmogorov–Smirnov test.

Fig. 3. Neuroprotective effect of lithium ascorbate on the cytotoxic action of glutamate (100 mM) on CGN. Empirical distri-
bution functions for the numbers (Kolmogorov–Smirnov test) of surviving CGN on exposure to glutamate in the absence of
(Glu) and presence (Glu+) lithium ascorbate (0.1–1.0 mM). Significant differences are shown for all the lithium ascorbate
concentrations used as compared with glutamate alone. Maximum deviations (D) are shown, as used for determination of the
statistical significance of differences between distribution functions.

and normalized the ALT and creatinine concentrations,
pointing to decreases in the negative action of stress on the
liver (Table 5). Thus, the experimental results provide evi-
dence that oral LA produced a rapid, over the first seven
days, adaptation of the body to stress models. The lowest
dose of LA (30 mg/kg) was not significantly less effective
than higher doses (60–120 mg/kg).
The level of arousal of rats in distress was determined
using the OFT. Animals received LA for five days immedi-
ately before testing. LA was found to produce dose-depen-
dent improvements in motor and exploratory activity and
decreased the severity of distress (Table 6).
In vitro experiments. Analysis of empirical distribu-
tion functions of mean values using the Kolmogorov–
414 Pronin, Gromova, Sardaryan, et al.

Fig. 4. Neuroprotective effects of LA on the cytotoxic action of glutamate. White columns: LA (0.1–1.0 mM) in the
absence of glutamate; dark columns: same concentration in the presence of 100 μM glutamate (Glu). Each column is
the mean of 30 fields. *p < 0.01 compared with glutamate alone.

Fig. 5. Neuroprotective action of LA on the neurotoxic action of glutamate (100 μM, 24 h) in cerebellar cell cultures.
Arrows – CGN. Fixed cultures stained with trypan blue. Scale bar: 1:0.000015.

Smirnov test showed that LA (without addition of gluta- At a cytotoxic concentration of glutamate (100 μM),
mate) to concentrations of 0.1–1.0 mM were nontoxic for this range of LA concentrations had marked neuroprotective
CGN (Fig. 2). effects. Analysis of the distribution function of mean num-
The Adaptogenic and Neuroprotective Properties of Lithium Ascorbate
bers of surviving neurons showed significant differences for
all LA concentrations from results obtained on exposure to
glutamate alone (Fig. 3). Use of LA even at the lowest con-
centration (0.1 mM) led to significant changes (D = 0.19,
p = 0.049). An increase in the concentration led to an in-
crease in the magnitude of the difference (the maximum
change in D increased and p decreased), while at the great-
est concentration (1.0 mM), the difference between gluta-
mate toxicity and controls was at the margin of statistical
significance (D = 0.17, p = 0.059). Thus, all LA concentra-
tions (0.1–1.0 mM) increased neuron survival in conditions
of glutamate stress.
Analysis of data by ANOVA showed that neuron sur-
vival in conditions of glutamate toxicity in the presence of
LA over the concentration range 0.1–1 mM, starting from
0.2 mM, produced a significant and dose-dependent in-
crease in the mean level by 12% (Fig. 4). Counts of surviv-
ing CGN in stained preparations (Fig. 5) clearly showed
that LA in the culture medium prevented cell destruction
due to glutamate.
Conclusions. Our data provide evidence of the marked
adaptogenic properties of the nontoxic standardized organic
lithium salt substance, lithium ascorbate, and the close rela-
tionship between stress and neurodestructive processes at
the cellular level. In in vivo experiments, the agent promot-
ed preservation of the eosinophil pool, decreased blood
adrenaline and noradrenaline levels, improved measures of
adaptation of animals in the suspension test, the OFT, and a
transportation stress model. In conditions of in vitro gluta-
mate cytotoxicity, all the lithium ascorbate concentrations
tested (0.1–1.0 mM) had protective effects. Thus, the results
of our studies widen our knowledge of the neuroprotective
potential of small doses of lithium preparations, as demon-
strated previously in experiments on cells cultured from the
striatum [15], hippocampus [16, 17], neocortex [17–19],
and cerebellum [20], and in craniocerebral trauma [21].
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