ISSN 0006-2979, Biochemistry (Moscow), 2026, Vol. 91, No. 8, pp. 1406-1416 © Pleiades Publishing, Ltd., 2026.
1406
Age-Related Alterations
in Retinal Monoamine Neuromodulation
during AMD-Like Retinopathy Development in Rats
Darya V. Telegina
1,a
, Alena O. Kutlimetova
2,b
, Arseniy E. Izyurov
2,c
,
Alexander V. Kulikov
2,d
, and Nataliya G. Kolosova
2,e
*
1
Sirius University of Science and Technology, 354340 Sirius Federal Territory, Russia
2
Institute of Cytology and Genetics Siberian Branch of Russian Academy of Sciences,
630090 Novosibirsk, Russia
a
e-mail: telegina.dv@talantiuspeh.ru
b
e-mail: burnyasheva@bionet.nsc.ru
c
e-mail: IzyurovAE@bionet.nsc.ru
d
e-mail: v_kulikov@bionet.nsc.ru
e
e-mail: kolosova@bionet.nsc.ru
Received March 23, 2026
Revised June 24, 2026
Accepted June 24, 2026
Abstract— Aging is the major risk factor for age-related macular degeneration (AMD), a leading cause of
vision loss in aging populations. Increasing evidence suggests that alterations of neurotransmitter systems
contribute to the pathogenesis of AMD. Although biogenic amines in the retina were first detected over
50 years ago, their age-related dynamics and role in AMD development are still poorly understood. Here,
we compare age-related changes in the concentrations of norepinephrine, serotonin, dopamine, and their
main metabolites in the retinas of senescence-accelerated OXYS rats that develop an AMD-like retinopathy
and Wistar rats. We also assessed activities of monoamine oxidases (MAOs) and tyrosine hydroxylase and
compared changes in these activities with transcriptome data on genes associated with biogenic amine
pathways. The results revealed that in OXYS rats, retinal aging and progression of AMD-like retinopathy
are primarily associated with alterations in the dopaminergic system. Specifically, dopamine and its main
metabolite DOPAC were present in the retinas at higher levels than serotonin and 5-hydroxyindoleacetic
acid. Furthermore, the development of retinopathy in OXYS rats was accompanied by elevated dopamine
and DOPAC levels, decreased MAO activity, and changes in the expression of genes associated with the
dopaminergic synapse signaling.
DOI: 10.1134/S0006297926600870
Keywords: retina, aging, age-related macular degeneration, biogenic amines, OXYS rats
* To whom correspondence should be addressed.
INTRODUCTION
Aging is a predominant risk factor for the devel-
opment of age-related macular degeneration (AMD),
a progressive neurodegenerative retinal disease that
leads to severe central vision impairment. By 2040,
AMD is projected to affect approximately 288 million
older adults worldwide. Besides aging, the develop-
ment of AMD has been associated with various other
factors, including genetic susceptibility and environ-
mental influences [1]. Despite decades of extensive
research, the etiology of AMD remains unknown,
which explains the lack of effective and affordable
treatments. Recent introduction of therapies target-
ing vascular endothelial growth factor (VEGF) has
significantly improved clinical outcomes in patients
with neovascular (“wet”) AMD, a form characterized
by pathological proliferation of new blood vessels in
the retina [2]. However, no treatment currently exists
for patients with “dry” AMD (a progressive loss of
the region of highest visual acuity in the macula) or
geographic atrophy, other than vitamin supplements,
which can only slow the progression of vision loss[3].
One of possible strategies for treating and preventing
AMD and for reversing age-related changes in the ret-
ina is the use of agonists and antagonists of mono-
CHANGES IN RETINAL MONOAMINE LEVELS IN RETINOPATHY 1407
BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026
amines, such as dopamine (DA), serotonin (5-HT), and
noradrenaline (NA), which act as neuromodulators
in the retina [4-6]. Several retrospective studies have
shown that levodopa (L-DOPA), a DA precursor com-
monly used in Parkinson’s disease therapy, reduces
the incidence of AMD and slows down its progression
to geographic atrophy [7-9]. However, interpretation
of these findings is limited, as patients in these stud-
ies received L-DOPA to compensate for DA deficiency
associated with Parkinson’s disease and, therefore,
had initially lower DA levels in the central nervous
system. Onthe contrary, the use of selective serotonin
uptake inhibitors (SSRIs), which are the most frequent-
ly prescribed antidepressants globally, has been asso-
ciated with reduced visual acuity [4] and decreased
thickness of the foveal and perifoveal macular gangli-
on cell complex [10] and, in rare cases, maculopathy
[11]. It is important to note that patients with major
depressive disorder, bipolar disorder, or schizophre-
nia, i.e., diseases characterized by dysregulation of
monoaminergic systems, often exhibit structural and
functional retinal abnormalities [12]. Although bio-
genic amines were first detected in the retina over
50 years ago, age-dependent changes in these systems
in this structure remain unclear, particularly in the
context of neurodegenerative disease progression.
To elucidate the role of monoamines in retinal aging
and AMD development, we used senescence-accelerat-
ed OXYS rats, which develop retinopathy that closely
resembles human AMD in its clinical presentations,
morphology, and ultrastructural features [13]. The
first clinical manifestations of retinopathy can be de-
tected by ophthalmoscopic examination in ~20% of
OXYS rats at the age of 5-6 weeks and are recorded
in all animals at the age of 3-4 months. Pathological
changes progress and reach advanced stages associat-
ed with the loss or significant deterioration of visual
acuity by 14-18 months of age. The type of retinopa-
thy developing in OXYS rats corresponds to the “dry”
form of AMD and is manifested by dystrophic changes
and thinning of the retina, impaired microcirculation
in the choroid, changes in neurotrophic support, ac-
cumulation of lipofuscin and amyloid β, as well as
structural abnormalities of the retina characteristic of
AMD[13]. Themain aim of this study was to compare
levels and metabolism of biogenic amines, as well as
the expression of their receptors in the retina of male
OXYS and Wistar rats at the preclinical (20days) and
early (3-5months) stages, as well as during pathology
progression (16-18 months).
MATERIALS AND METHODS
Animals. The study was performed on OXYS and
Wistar rats aged 20 days, 3 months, and 16 months,
obtained from the Conventional Animal Vivarium
of the Institute of Cytology and Genetics. The ani-
mals were housed under standard laboratory condi-
tions (22 ± 2°C and a 12-h light/dark cycle) in cages
(57×36×20 cm; five animals per cage) with adlibitum
access to standard rodent chow (PK-120-1; Labora-
torsnab, Russia) and water. The rats were euthanized
by CO
2
asphyxiation followed by decapitation. Next,
retinas from both eyes of each rat were carefully
excised (n = 8 per group), transferred into microfuge
tubes, flash-frozen in liquid nitrogen, and stored
at −80°C.
Sample preparation. The retinas were homoge-
nized in 150 μL of 50 mM Tris-HCl, pH 6.0, contain-
ing 1 mM dithiothreitol (DTT) (Sigma-Aldrich, USA).
A 50-μL aliquot of the homogenate was immediately
mixed with 150 μL of 0.6 M HClO
4
and centrifuged
for 15 min at 12,700 rpm (4°C). The resulting su-
pernatant was diluted twofold with water and used
for quantification of biogenic amines by high-per-
formance liquid chromatography (HPLC). The pellet
was resuspended in 1 mL of 0.1 M NaCl and used for
protein quantitation by the Bradford assay (Bio-Rad,
USA) in accordance with the manufacturer’s protocol.
The remaining 100 µL of homogenate was centrifuged
for 15 min at12,700g (4°C). The supernatant was then
transferred into a transparent microfuge tube. The
supernatant and the pellet were stored at −80°C for
subsequent monoamine oxidase (MAO) activity assay.
Monoamine assay by HPLC was performed as
described previously [14]. In brief, concentrations
of NA, DA, 3,4-dihydroxyphenylacetic acid (DOPAC),
serotonin (5-HT), and 5-hydroxyindoleacetic acid
(5-HIAA) were determined in the diluted supernatant
by HPLC on a Luna C18(2) column (length × internal
diameter 10; particle size, 5 μm) with electrochemical
detection at 750 mV with a DECADE II™ electrochem-
ical detector (Netherlands). Calibration curves were
generated using standard mixtures containing 0.5,
1, and 2 ng of each biogenic amine (Sigma-Aldrich).
Peak areas were estimated using LabSolution LG/GC
software, version 5.54 (Shimadzu Corporation, Japan)
and quantified against the corresponding standard
curves. Monoamine concentrations were normalized
to the total protein content determined by the Brad-
ford assay.
Tyrosine hydroxylase (TH) activity assay. TH
activity was measured as previously described [15].
A 15-μL aliquot of the supernatant was incubated for
15 min at 37°C in the presence of 0.3 mM L-tyrosine
(Sigma-Aldrich), 0.3 mM 6,7-dimethyl-5,6,7,8-tetrahy-
dropteridine (cofactor) (Sigma-Aldrich), decarboxylase
inhibitor m-hydroxybenzylhydrazine (Sigma-Aldrich),
5 μM catalase (Sigma-Aldrich), and 1 mM DTT in
a final volume of 25 μL. The reaction was termi-
nated by adding 75 μL of 0.6 M HClO
4
, followed
TELEGINA et al.1408
BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026
by centrifugation at 14,000g for 15 min. The superna-
tant was diluted twofold with water, and the L-DOPA
concentration was determined in the diluted super-
natant by HPLC as described above using standard
solutions of L-DOPA (25, 50, and 100 pmol; Sigma,
USA). Additional 10 μL of the supernatant was com-
bined with 90 μL of 0.1 M NaOH for protein quanti-
tation by the Bradford method. The TH activity was
expressed in pmol of L-DOPA formed per minute per
mg of protein.
MAO activity assay. The MAO activity was as-
sessed using 5-HT as a substrate as described in
[16, 17], with modifications, and was defined as the
amount of 5-hydroxyindoleacetic aldehyde synthe-
sized per minute per mg of protein. In brief, the
pellet was resuspended in 100 μL of 50 mM Tris-HCl,
pH 7.6, using a motor-driven grinder (Z359971, Sigma-
Aldrich) and centrifuged for 15 min at 435g (4°C).
A 10-μL aliquot of the turbid supernatant was in-
cubated for 10 min at 37°C with 0.1 mM 5-HT in a
final volume of 25 μL. The reaction was terminated
by adding 75 μL of 0.6 M HClO
4
, followed by a 15-
min centrifugation at 14,000g The supernatant was
diluted twofold with water, and the concentration
of 5-hydroxyindoleacetic aldehyde was determined
by HPLC using 5-hydroxyindoleacetic aldehyde stan-
dards (500, 1000, and 2000 pmol; Cymit Quimica S.L.,
Spain). Additional 10 μL of the turbid supernatant
was combined with 90 μL of 0.1 M NaOH for protein
quantitation by the Bradford method. MAO activity
was expressed in pmol of 5-hydroxyindoleacetic alde-
hyde formed per minute per mg of protein.
Transcriptome data analysis. Retinal gene ex-
pression profiles in OXYS and Wistar rats at 20 days,
3 months, and 18 months (n = 3 in each group) have
been previously characterized via high-throughput
transcriptome sequencing (RNA-seq) on the Illumina
platform (see [18] and [19] for detail). Differences in
the expression levels were considered significant at
p-value < 0.01. Differentially expressed genes were
then compared with a list of genes associated with
the dopaminergic synapse (rno04728), serotoniner-
gic synapse (rno04726), and tryptophan and tyrosine
metabolism (rno00380 and rno00350, respectively) in
the KEGG pathway database (https://www.genome.jp/
kegg/).
Statistical analysis was performed using the
STATISTICA 10.0 software package (StatSoft, USA). The
normality of data distribution was assessed by the
Shapiro–Wilk test, and the homogeneity of varianc-
es was evaluated by the Levene’s test. Outliers were
identified by the Dixon’s Q test and excluded from
subsequent analysis. Comparisons between groups
were performed using factorial analysis of vari-
ance (ANOVA) and the nonparametric Kruskal–Wal-
lis test with a post hoc comparison of group means.
It should be noted that both parametric and non-
parametric statistical methods produced comparable
results. The genotype (strain) and age were consid-
ered independent factors. Results are presented as
mean ± standard deviation (SD). Differences were
considered statistically significant at p < 0.05.
RESULTS
Changes in monoamine concentrations in the
rat retina during aging and in the development of
AMD-like retinopathy. First, we assessed biogenic
amine levels in the retina of Wistar and OXYS rats
of different ages (20 days, 5 months, and 16 months)
by HPLC. We reliably detected NA, DA, DOPAC,
5-HT, and 5-HIAA in the retina, whereas the concen-
tration of homovanillic acid was below the detection
level.
According to two-way ANOVA, retinal concentra-
tions of NA (F
2,48
= 5.88, p < 0.01), DA (F
2,47
= 106.551,
p < 0.001), DOPAC (F
2,48
= 42.32, p < 0.001), and
5-HIAA (F
2,45
= 11.77, p < 0.001) depended on age.
In addition, the levels of DA (F
1,47
= 19.48, p < 0.001),
DOPAC (F
1,48
= 11.41, p < 0.01), and 5-HT (F
1,47
= 5.19,
p < 0.05) depended on the rat genotype (Fig. 1).
Despite these overall effects, pairwise compari-
sons of group mean revealed no changes in the NA
and 5-HT levels. The concentration of 5-HIAA was
found to be significantly increased in the retinas of
both Wistar and OXYS rats at the age of 16 months
(p < 0.05). To evaluate 5-HT turnover, we calculated
the 5-HIAA : 5-HT ratio. Two-way ANOVA revealed
significant effects of both age (F
1,46
= 4.14, p < 0.05)
and genotype (F
1,46
= 8.59, p < 0.01) on this ratio.
The 5-HIAA : 5-HT ratio was higher in 20-day-old
OXYS rats compared with age-matched Wistar rats
(p < 0.05) and decreased in OXYS rats by 4 months of
age (p < 0.05).
DA levels were elevated at the age of 5 months
(p < 0.05), whereas DOPAC concentration progressive-
ly increased up to 16 months of age in the retina of
both strains (p < 0.05). Moreover, the levels of both
DA and DOPAC were higherin the retina of OXYS rats
at the age of 5 and 16 months compared with age-
matched Wistar rats (p < 0.05). The index of DA turn-
over (estimated as the DOPAC : DA ratio) depended
on age (F
1,47
= 8.45, p < 0.001) but not on genotype.
This ratio decreased at the age of 4months in Wistar
rats (p < 0.05), while no significant difference in the
DOPAC : DA ratio was observed between the strains.
TH and MAO activities. Next, we analyzed the
activity of TH, which catalyzes L-tyrosine hydroxyl-
ation to L-DOPA, and MAOs, which catalyze the oxi-
dative deamination of monoamines such as DA, sero-
tonin, and epinephrine, in the rat retina. MAO activity
CHANGES IN RETINAL MONOAMINE LEVELS IN RETINOPATHY 1409
BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026
Fig. 1. Concentrations of biogenic amines and activities of TH and MAO in the retina of Wistar and OXYS rats at different
ages. Data are presented as mean ± SD (n = 7-8); * p < 0.05 vs. strain; # p < 0.05 vs. previous age.
showed a significant age dependence (F
2,48
= 32.11,
p < 0.0001) but was not influenced by the animal
genotype. In Wistar rats, MAO activity increased pro-
gressively with age (significant differences were de-
tected between 20 days and 5 months and between 5
and 16 months, p < 0.05). In OXYS rats, MAO activity
also increased significantly from 20 days to 5months
(p < 0.05) but remained stable thereafter. Significant
differences between the rat strains were found only
at the age of 16 months, when MAO activity was
approximately 1.3-fold lower in OXYS rats than in
Wistar rats (p < 0.05). In contrast, TH activity was
unaffected by either age or genotype, with no signif-
icant differences detected across the groups (Fig. 1).
TELEGINA et al.1410
BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026
Fig. 2. a) Differences in the expression of monoamine-associated genes between Wistar and OXYS rats at the age of 20days,
3 months, and 18 months. b) GO chord plot showing a relationship between differentially expressed genes and associated
Gene Ontology(GO) terms. c) Venn diagrams illustrating the overlap of differentially expressed monoamine-associated genes
at the age of 20 days, 3 months, and 18 months. Colors indicate upregulated (red) or downregulated (blue) genes.
CHANGES IN RETINAL MONOAMINE LEVELS IN RETINOPATHY 1411
BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026
Fig. 3. GO chord diagram showing associations between differentially expressed genes and their corresponding GO terms.
Alterations in monoaminergic signaling path-
ways in the rat retina during retinopathy develop-
ment. Next, we analyzed changes in gene expression
associated with the dopaminergic synapse (rno04728),
serotoninergic synapse (rno04726), and tryptophan
(rno00380) and tyrosine (rno00350) metabolism path-
ways in the retina of 20-day-old and 3- and 18-month-
old OXYS and Wistar rats using RNA-seq data.
Of 132 genes annotated to “dopaminergic syn-
apse,” differential expression was observed for 35
genes at the age of 20days, 5genes at 3 months, and
7 genes at 18 months in OXYS rats compared to age-
matched Wistar rats (Fig. 2). Notably, Drd4(DA recep-
tor D4) expression was higher in OXYS rats than in
Wistar rats across all examined ages. In addition, in
OXYS rats, expression of Drd1, Drd2 (DA receptors D1
and D2, respectively), Fos, and Mapk12 was elevated
at both 20 days and 4 months of age, while expres-
sion of Gnao1, Gng12, Kcnj9, and Th showed consis-
tent directional changes at 20 days and 18 months
(Fig. 2).
We identified 17 differentially expressed genes
associated with the term “serotonergic synapse” in
the retina of 20-day-old OXYS rats compared with
Wistar rats, whereas only three and six genes were
detected at 3 and 18 months of age, respectively. Five
genes in OXYS rats exhibited age-consistent changes:
Htr3a was upregulated at 20 days and 3 months;
Alox12 was downregulated at 3 and 18months; while
Gnao1 and Kcnj9 were upregulated and Gng12 was
downregulated at 20 days and 18 months.
In the “tryptophan metabolism” pathway, seven
differentially expressed genes were found at the age
of 20 days, five at 3 month, and seven at 18 month
in OXYS rats compared to age-matched Wistar rats.
Expression of Acat2 was reduced, whereas expres-
sion of Cyp1b and Ehhadn was higher in OXYS rats
compared to Wistar controls at all ages. In addition,
Aanat mRNA level was elevated in 3-month-old OXYS
rats vs. Wistar rats.
For “tyrosine metabolism”, three genes were
downregulated at 20 days, and Th expression was re-
duced at 18 months in OXYS rats relative to Wistar
controls.
Importantly, several genes were shared across
the pathways (Fig. 3). At 20 days of age, Maoa and
Maob genes coding for MAOs inactivating monoamine
neurotransmitters (5-HT, DA, melatonin, and NA) and
common to all four pathways were downregulated
in OXYS rats compared to Wistar rats. Expression of
the Th (tyrosine hydroxylase) gene shared between
“dopaminergic synapse” and “tyrosine metabolism”
pathways, was reduced in 20-day-old and 18-month-
old OXYS rats compared to Wistar rats (Fig. 3).
DISCUSSION
Here, we present the first systematic study on
age-related changes in the levels of biogenic amines
in the retina of healthy Wistar rats and OXYS rats
that develop an AMD-like pathology. We demonstrated
TELEGINA et al.1412
BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026
that retinal aging and the progression of AMD-like
retinopathy are accompanied primarily by alterations
in the dopaminergic system. In contrast, only minor
differences were observed in the retinal content of
NA, 5-HT, and its metabolite 5-HIAA. Overall, the lev-
els of DA and DOPAC in the rat retina were higher
than the levels of 5-HT and 5-HIAA. Neither strain-
nor age-dependent alterations in the 5-HT content
and 5-HIAA : 5-HT ratio were observed. In contrast,
the retinal concentration of 5-HIAA increased by the
age of 18 months.
DA is the most abundant catecholamine in the
vertebrate retina[6], where it plays a key role by me-
diating both light- and circadian rhythm-dependent
signaling via changes in gap junction coupling and
ionic conductance [20]. DA deficit and dysregulated
dopaminergic neurotransmission in the retina have
been implicated in several retinopathies, including
diabetic retinopathy [21] and retinal degeneration
associated with Parkinson’s disease [22]. Postmortem
studies in Parkinson’s disease patients revealed apop-
tosis of retinal dopaminergic neurons, along with oth-
er morphological abnormalities, such as thinning of
the inner nuclear and ganglion cell layers and degen-
eration of the retinal lattice[23]. In addition, patients
with Parkinson’s disease presented with reduced light
sensitivity, decreased spatial acuity, and impaired col-
or vision [20]. Dopaminergic neurons are located in
the inner nuclear layer of the retina [5] that under-
goes age-related alteration, including changes in the
number of these neurons, increased oxidative stress,
and inflammation [6].
Elevated DOPAC levels have been detected in
the aged rat retinal tissue [24]. As a byproduct of DA
metabolism that is subsequently converted to homo-
vanillic acid, increased DOPAC levels in aged rats are
believed to reflect increased DA degradation during
aging [6]. In our work, we registered significantly
elevated DA and DOPAC levels in the retina during
both aging and retinopathy development. Further-
more, analysis of RNA-seq data uncovered elevated
Drd4 expression in OXYS rats at all ages. DRD4 is ex-
pressed in photoreceptors and is involved in circadi-
an rhythm regulation. Ithas been reported that DRD4
mediates circadian regulation of light-adapted electro-
retinogram responses, and knockouts of D4 or D1 re-
ceptors in mice caused distinct visual deficits [25]. Ac-
cordingly, we believe that higher levels of DA, DOPAC,
and Drd4 mRNA in OXYS rats are associated with
dysregulation of circadian signaling both at a whole-
body level and directly in the retina, which possesses
its own circadian clock. The impairment of circadian
rhythms in the retina of OXYS rat is also supported
by previously reported alterations in diurnal expres-
sion patterns of autophagy-related genes[26] and dif-
ferences in the diurnal and nocturnal activities of the
glutamate/GABA system during AMD-like retinopathy
progression [27, 28]. Moreover, starting from the age
of 3 months, the level of melatonin, the main regula-
tor of circadian rhythms, in OXYS rats showed a loss
of normal day–night variation in the plasma, suggest-
ing disruption of systemic circadian regulation [29].
Oral melatonin administration improved retinal mor-
phology parameters and slowed down the develop-
ment of AMD-like retinopathy symptoms in OXYS rats
both during early pathology stages (treatment from
the age of 1.5 to 3 months) [30] and during its active
progression (administration from 12 to 18 months)
[27]. Collectively, these findings support the hypothe-
sis that disruption of temporal organization in retinal
physiology may induce and/or contribute to the reti-
nal degeneration in OXYS rats.
According to recent studies, retinal circadian
regulation is an important physiological process, and
disruption, or even slight perturbation, of the tempo-
ral organization of retinal function may contribute to
retinal degeneration [31], including AMD in humans
[32]. We were able to find only one study reporting
findings comparable to those observed in OXYS rats,
namely an increase in the levels of retinal DA and
DOPAC during retinal pathology in Goto–Kakizaki(GK)
rats, a model of spontaneously occurring polygenic
type II diabetes mellitus [33]. This model is nonobese
and non-insulin-dependent and spontaneously devel-
ops impaired insulin secretion by 2 weeks of age
and impaired fasting hyperglycemia by 4 weeks [34].
GKrats develop retinal dysfunction that precedes cog-
nitive and motor deficits [35]. Moreover, GK rats do
not exhibit vascular retinal pathology typical for di-
abetes [33]. This most likely can be explained by the
fact DA and/or DA agonists have been shown to act
as potent anti-angiogenesis agents due to their ability
to inhibit VEGF, a strong stimulator of angiogenesis.
For instance, in streptozotocin-diabetic rats, treatment
with the DA agonist bromocriptine reduces vascular
permeability [36]. DA also inhibits VEGF secretion,
thereby preventing its binding to VEGF receptor 2
and promoting receptor endocytosis. These processes
collectively reduce proliferation, migration, survival,
and vascular permeability of endothelial cells, thus re-
ducing vascular leakage and neovascularization [37].
Inthis context, our previous paper demonstrated that
in the retina of both Wistar and OXYS rats, VEGF lev-
els significantly declined from the age of 20 days to
3 months, followed by a gradual increase, reaching a
peak at 24 months in rats of both strains [38].
When these findings are compared with the
present data, divergent trajectories become apparent
in the relationship between DA concentrations and
VEGF protein levels. Between 20 days and 5 months
of age, retinal DA and DOPAC concentrations increase
more than 2-fold in both rat strains. In OXYS rats,
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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026
the development of retinopathy is associated with
higher DA and DOPAC levels relative to Wistar rats,
along with reduced VEGF content in the retina [38].
Moreover, in the present study, metabolic efficien-
cy of retinal DA, i.e., DA turnover evidenced by the
DOPAC : DA ratio, did not differ between the rat
strains. Therefore, it can be hypothesized that with
the development of the AMD-like pathology in OXYS
rats, elevated DA levels suppress neovascularization.
In addition, we observed an age-related increase
in the MAO activity in the retina of both rat strains.
Asimilar positive correlation between the MAO activ-
ity and aging has been reported in plasma, platelets,
and various brain regions [39]. MAOs are located in
the outer mitochondrial membrane. They play a ma-
jor role in the regulation of concentrations of several
bioactive amines, in particular, by catalyzing the deg-
radation of 5-HT, DA, NA, and melatonin in the brain.
Two functionally and structurally distinguishable iso-
forms exist – MAO-A and MAO-B – which differ in
tissue distribution and substrate specificity. MAO-A
preferentially metabolizes NA, melatonin, 5-HT, and
DA, whereas MAO-B primarily degrades phenyl-
ethylamine and benzylamine [40]. According to our
RNA-seq data, MAO-A is the predominant isoform in
the retina. ThemRNA levels for both Maoa and Maob
genes were lower in 20-day-old OXYS rats compared
to Wistar rats. Consistent with the MAO enzymatic
activity, expression of both isoforms in the rat ret-
ina increased with age. However, at a late stage of
AMD-like retinopathy development (16 months), we
found a significant decrease in the MAO activities in
OXYS rats relative to Wistar controls. We believe that
this reduction in the MAO activity is likely associated
with a decrease in the mitochondrial number and im-
paired mitochondrial function in the retina of OXYS
rats already at the age of 6 months [41].
DA also plays an indispensable part as a coregu-
latory biomolecule in both the nervous and immune
systems. For example, DA receptors have been found
on membranes of various non-neuronal cells, includ-
ing lymphocytes, macrophages, microglia, and astro-
cytes [42].
It has been demonstrated that microglial cells
express functional DA receptors and, therefore, DA
can directly modulate their activity and function-
al status. For example, DA influences inflammatory
activity, migration, and adhesion of microglia [43].
It was proposed that elevated DA levels can activate
low-affinity DA receptors (including DRD1, DRD2, and
DRD4), thereby initiating anti-inflammatory effects
in microglia. Conversely, diminished DA levels have
been reported to selectively stimulate high-affinity
DA receptors (DRD3 and DRD5), thus promoting in-
flammation [43]. It has been suggested that high DA
levels attenuate inflammatory activation of microglia
by reducing the release of nitric oxide [44] and de-
creasing phagocytic activity [45]. Indeed, in line with
our previous results, retinal microglia of OXYS rats
showed no signs of the proinflammatory status, such
as migration of activated macrophages and microglia
into the photoreceptor layer [46] during retinopathy
development. Furthermore, the level of iNOS (induc-
ible nitric oxide synthase) mRNA in OXYS rats was
seven times lower than in Wistar rats; however, iNOS
protein levels in 3-month-old OXYS rats measured by
ELISA were paradoxically increased. This discrepancy
may reflect reduced immune reactivity in OXYS rats
[47]. Thus, it can be hypothesized that high DA levels
in the retina of OXYS rats help suppress the devel-
opment of a full-scale microglial immune response,
thereby contributing to neurodegeneration. Converse-
ly, proinflammatory stimuli in microglial cells have
been found to enhance DA biosynthesis in animal
models [43]. During aging, the retina is exposed to
chronic low-grade oxidative stress that persists over
decades and progressively increases with advancing
age. As a result, the retinal innate immune system,
specifically microglia and the complement system,
adopts a state of chronic low-level activation (para-in-
flammation), characterized by secretion of proinflam-
matory cytokines and chemokines[48]. Itis therefore
plausible that in the aging retina, microglia constant-
ly secrete low doses of proinflammatory factors, lead-
ing to DA synthesis upregulation. In turn, elevated DA
levels suppress the progression of full-scale inflam-
matory response in the retina, thereby facilitating the
progression of retinal neurodegeneration.
Abbreviations
5-HIAA 5-hydroxyindoleacetic acid
5-HT serotonin
AMD age-related macular degeneration
DA dopamine
DOPAC 3,4-dihydroxyphenylacetic acid
HPLC high-performance liquid
chromatography
MAO monoamine oxidase
NA noradrenaline
TH tyrosine hydroxylase
Contributions
D.V.T. developed the study concept; D.V.T., A.O.K., A.E.I.,
and A.V.K. conducted experiments; A.V.K. developed
the methodology; A.V.K. and N.G.K. supervised the
study; A.V.K. and N.G.K. acquired funding; A.V.K. de-
veloped the software; D.V.T., A.O.K., A.E.I., A.V.K., and
N.G.K. edited the manuscript.
Funding
This work was supported by government-funded proj-
ect FWNR-2022-0016.
TELEGINA et al.1414
BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026
Ethics approval and consent to participate
All experimental procedures were approved by the
Bioethics Commission of the Institute of Cytology and
Genetics (protocol no. 85/1; approved, June 18, 2021)
and are consistent with the Association for Research
in Vision and Ophthalmology statement for the Use of
Animals in Ophthalmic and Vision Research, as well as
European Communities Council Directive 86/609/EES.
Conflict of interest
The authors of this work declare that they have no
conflicts of interest.
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