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REVIEW
Crocin as a vision supplement
Mojtaba Heydari
a,b
, Mousa zare
b
, Mohammad Reza Badie
b
, Ronald Ross Watson
c
, Mohammad Reza Talebnejad
b
and Mehrdad Afarid
b
a
Research Center for Traditional Medicine and History of Medicine, Department of Persian Medicine, School of Medicine, Shiraz University of
Medical Sciences, Shiraz, Iran;
b
Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University
of Medical Sciences, Shiraz, Iran;
c
Arizona Prevention Center, University of Arizona, Tucson, AZ, USA
ABSTRACT
Crocin is a natural ingredient of saron (Crocus sativus L.) ower that has shown potential for application as
a supplement in eye health and preserving vision. Crocin has been examined for its potential to treat
various eye diseases such as glaucoma, macular dystrophies, diabetic retinopathy, and age-related macular
degeneration. This review briey discusses the role of crocin in dierent eye diseases. The underlying
pathophysiological pathways involved in the eect of crocin on ophthalmic diseases are also reviewed.
Preclinical evidence shows the cytoprotective, antioxidative, anti-inammatory, and blood-ow enhancing
eects of crocin in retinal tissue. Crocin also aects the retinal pathologies by activating PI3K/Akt and
inhibiting NF-κB signalling pathways. Clinical evidence suggests that crocin improves outcomes in patients
with retinal degenerations, retinal dystrophies, and glaucoma. Overall, crocin can be suggested as
a potential vision supplement in healthy populations and patients with eye diseases. However, more
clinical studies with larger sample sizes and longer follow-up durations are needed to conrm the current
evidence.
ARTICLE HISTORY
Received 27 August 2021
Revised 28 January 2022
Accepted 30 January 2022
KEYWORDS
Crocin; eye; natural;
nutrition; retina; saffron;
supplement
Introduction
Loss of vision greatly impacts the quality of life and causes
a signicant economic burden.
1
In 2020, 1.1 billion people were
living with vision loss,
2
which is projected to aect 1.7 billion
people in 2050.
2,3
The prevalence of vision loss has increased
signicantly with the ageing of the world population.
4
Natural supplements are increasingly being investigated
to prevent and treat various diseases, including eye
problems.
4
Antioxidant properties of natural supplements
are considered an important mechanism of their action.
5
It
is suggested that natural supplements can prevent cellular
oxidative damages.
6
Oxidative stress is an important patho-
logic pathway in many eye diseases, including ocular surface
diseases, glaucoma, cataracts, uveitis, retinal diseases, and
eye tumours.
7
Many natural supplements improve eye dis-
eases through their anti-inammatory eects.
8
Inammation
can aect dierent eye parts of the eye from the anterior to
the posterior segment, causing allergic eye disease, dry eye
syndrome, uveitis, and retinal diseases.
9
Ischaemia is also an
important contributor to eye pathologies such as vascular
diseases, which are improved by natural supplements with
the potential to increase blood ow.
10
Crocin is a natural ingredient of saron (Crocus sativus
L.) ower. It is a water-soluble carotenoid pigment respon-
sible for the red colour
11–13
of the saron ower (Figure 1).
Saron is a plant used for its avouring and colouring
properties as a spice.
14
It also has multiple medicinal uses
in traditional medicine,
15
having been used traditionally for
neurological, cardiovascular, metabolic, urogenital, and
musculoskeletal diseases.
16–20
Crocin is the main ingredient
of saron with multiple pharmacological, antioxidant, anti-
neoplastic, anti-atherosclerotic, aphrodisiac, and anti-
ischaemic eects.
21
Crocin is also examined for its potential in treating various
eye diseases such as dry eye disease, glaucoma, macular dystro-
phies, diabetic retinopathy, and age-related macular degenera-
tion. This paper reviews the role of crocin in dierent eye
diseases (Table 1) and the underlying pathophysiological path-
ways involved in the eect of crocin on ophthalmologic
diseases.
Literature search strategy
A comprehensive search was performed to retrieve any study
evaluating the eect of crocin or saron (the medicinal plant
containing crocin as the main ingredient) on ocular tissues or
eye diseases. Both preclinical and clinical studies were included
in the search. The databases of PubMed, EMBASE, Scopus, and
Web of Science were searched up to 1 January 2021. The term
‘crocin’ or ‘saron’ was added to ophthalmic related keywords
including ‘eye’, ‘ocular’, ‘ophthalmology’, ‘retina’, ‘cornea’,
‘macula’, ‘macular’, ‘uveitis’, and ‘retinopathy’ for database
search. This review was restricted to studies reported in the
English language. Also, reviews and other reports that do not
comprise original research were excluded. The details of
retrieved articles in each step of the search are summarised in
Figure 2.
Preclinical evidence
Retinal cytoprotective eect
Crocin has shown a protective eect on dierent retinal cells,
including retinal pigment epithelial cells (RPE), photoreceptors,
Muller cells, and retinal nerve bre layers, in dierent animal and
in-vitro models. The synergistic eect of resveratrol on the
cytoprotective and antioxidative eect of crocin in RPE cells
CONTACT Mojtaba Heydari mheydari@sums.ac.ir
CLINICAL AND EXPERIMENTAL OPTOMETRY
https://doi.org/10.1080/08164622.2022.2039554
© 2022 Optometry Australia
has also been suggested through in-vitro studies.
22
However,
the share of crocin in the observed eect has yet to be be
evaluated. The cytoprotective eects of crocin on the animal
model of Muller and cone cellular light toxicity were shown in an
in-vivo study.
23
Visual function evaluated by the behavioural
optomotor reex method was improved in the crocin-treated
mice.
23
In a histological evaluation of Muller cells, hypertrophic
gliosis and cone cellular damage were also prevented by crocin
treatment.
23
Another in-vitro model of glaucomatous injury to
retinal ganglion cells showed a protective eect of crocin on H
2
O
2
induced apoptosis and LDH release.
24
The protective eect of
crocin against blue light- and white light-mediated photorecep-
tor cell death in bovine and primate retinal primary cell culture
has also been demonstrated.
25
The underlying mechanism of the cytoprotective eect of
crocin has not been completely understood. Some studies have
shown the protective role of crocin in apoptosis by increasing
mitochondrial membrane potential, which is shown to be
aected by oxidative stress mediated mitochondrial change
and DNA damage (24). Crocin downregulate Bax, cytochrome
c, and caspase-3, while upregulate Bcl-2 (24). Cytochrome c is
a mediator of apoptosis activation. Bax increases the cyto-
chrome c release while Bcl-2 decrease it (24). Crocin prevents
mitochondrial pathway-mediated apoptosis through this path-
way, thereby protecting retinal ganglion cells from apoptosis.
24
Retinal oxidative stress
Evidence has shown the mechanisms of biomolecules and
cellular damage by oxidative stress are caused by redox status
imbalance. The involved pathways can activate transcription
factors that result in cellular dysfunction. The eye is one of the
most important organs involved in oxidative damages induced
by reactive oxygen and nitrogen species produced in response
to environmental and internal factors. Light toxicity, UV expo-
sure, increased intraocular pressure, chemical and microbial
injuries are essential sources of oxidative stress in the eye.
Also, some studies have shown the signicant contribution of
oxidative stress to dierent eye diseases such as dry eye syn-
drome, glaucoma, cataract, uveitis, age-related macular
degeneration, and retinopathies. Modulation of the oxidative
stress pathways has become an important target in formula-
tions developed to prevent and treat eye diseases.
Crocin has shown antioxidative properties in dierent mod-
els of oxidative stress in the eye. Chen et al. evaluated the
antioxidant eect of crocin (50 mg/kg) pretreatment before
and after retinal ischaemic reperfusion injury in rats.
26
Oxidative stress has been investigated by measuring superox-
ide dismutase (SOD), reactive oxygen species (ROS), malondial-
dehyde (MDA), and glutathione (GSH) levels. SOD is an
antioxidant enzyme belonging to the family of isoenzymes
involved in the scavenging of O
2
radicals. GSH acts with SOD
to detoxify H
2
O
2
to water. MDA is one of the nal products of
polyunsaturated fatty acids peroxidation in the cells which is
overproduced by increase in the free radicals. SOD, GSH, and
MDA levels are commonly known as markers of oxidative stress.
Oxidative stress usually causes decrease in SOD activity and
reduced form of GSH level and increase in MDA level. However
multiple factors such as the aetiology, context, severity and
duration of oxidative stress may alter the typical response.
7,26
Also, the histological evaluation of retinal thickness and retinal
ganglion cells injury by haematoxylin and eosin and immuno-
uorescence staining has been performed. Apoptosis was also
evaluated by Western blot and immunohistochemical analysis.
The results showed that crocin could prevent oxidative
damage by increasing MAD and GSH and decreasing ROS
and SOD. The protective eect of crocin pretreatment on
retinal thinning and retinal ganglion cells apoptosis resulting
from retinal ischaemic reperfusion injury was also exhibited.
26
Crocin and resveratrol increase human RPE cell viability
and glutathione levels in photo-damaged cells.
27
To the best
of our knowledge, there is no research on the role of crocin in
the observed eect.
Bochang et al. showed the antioxidative eect of crocin on
retinal ganglion cells in an animal model of H2O2-induced
oxidative damage. Crocin demonstrated an anti-apoptotic
eect in retinal ganglion cells and a preventive eect on
ROS and LDH production. These eects were shown to be
induced through down-regulation of NF-κB, Bax, and cyto-
chrome c protein expression, as well as up-regulation of Bcl-2
Figure 1. Chemical structure of crocin.
2M. HEYDARI ET AL.
protein expression. Yang et al. also showed the antioxidative
eect of crocin in retinal injury in an animal model of diabetic
retinopathy. These researchers also demonstrated the protec-
tive eect of crocin on the over-activation of microglial cells
and retinal ganglion cell loss in diabetic retinopathy.
28
Makri et al., in an in vivo study on selenium-induced cataracts
in Wistar rats, investigated the preventing eect of saron (the
main medicinal plant involving crocin as the major ingredient).
They measured the antioxidant activity of superoxide dismutase,
glutathione peroxidase, catalase, and glutathione levels in the
Table 1. Summary of in-vitro and in-vivo studies on the effects of saffron/crocin on eye diseases.
Reference
Type of
study Subject Dosage
Route and duration of
administration Effects
27 In-vitro RPE cells 100 μM 24 hours Cytoprotective effects on human retinal pigment epithelial cells
22 In-vitro RPE cells 100 μM 48 hours Protecting RPE cells from photooxidative damage
23 Animal Mice 0.5-10 mg/kg 30 days/oral Visual performance improvement because of its anti-photodamage and
cytoprotective effects
24 In-vitro RG cells 0.1 and 1 µM 24 hours Preventing H2O2-induced damage to RGCs through the mitochondrial
pathway and activation of NF-κB
25 In-vitro Primary
retinal cell
10–160 μM 32 hours Protecting retinal photoreceptors against light-induced cell death
26 Animal Rat 50 mg/kg 3 days/intraperitoneal Protecting the retina from ischaemia/reperfusion injury and antioxidant
and anti-apoptotic properties in the retina
28 In-vitro Microglial
Cells
0.1 or 1 μM 24 hours Inhibiting oxidative stress and the pro-inflammatory response of
microglial cells associated with diabetic retinopathy through the
activation of PI3K/Akt signalling pathway
34 In-vitro Microglial
Cells
200 μm 24 hours Anti-inflammatory effects of crocin in neuronal degeneration mediated
by its direct effects on microglia homoeostasis
39 Animal Rabbit 50 μL 2 hours/topical Increasing the blood flow due to vasodilation presumably improves
oxygenation and nutrient supply of retinal structures
52 Animal Rat 50 mg/kg 5 days/ intraperitoneal Preventive effect on retinal ischaemia/reperfusion-induced apoptosis of
RG cells by activating the PI3K/AKT signalling pathway
55 In-vitro Microglial
Cells
0.1 to 1 μM 2 hours Suppression of microglial activation and upregulating CX3CR1 expression
by suppressing NF-κB/YY1 signalling
42 Animal Rat 50, 100, and
200 mg/kg
30 seconds/
intraperitoneal and
intracerebroventricular
Non-opioid receptor; significant reduction in corneal pain by both
intraperitoneal and intracerebroventricular injection of crocin
46 In-vitro Human
corneal
epithelial
cells
0.15% 30 minutes Significant reduction in IL-1β and TNFα as inflammation indicators and
reactive oxygen species
49 Animal Rat 100 mg/kg 0, 2, 4, and 6 weeks/
intraperitoneal
Inhibited advanced glycation end products fluorescence, protein cross-
linking, and hydrophobicity in the experimental model of
streptozotocin-induced diabetes
RPE, Retinal Pigment Epithelium; RG, retinal ganglion.
Figure 2. Flow diagram for included studies.
CLINICAL AND EXPERIMENTAL OPTOMETRY 3
isolated lenses. They determined the indicator of lipid peroxida-
tion, malondialdehyde, protein oxidation (sulphhydryl content),
and soluble-to-insoluble protein ratio in the lens. The mean
activities of antioxidant defence markers were signicantly
increased in the saron-treated group compared to the control
group. Therefore, they showed that saron extract could pre-
vent selenite-induced cataract formation in Wistar rats.
29
In con-
trast to the positive eect of saron in an animal model of
cataract, the eect of this natural product in an experimental
model of uveitis was not promising. Talebnejad et al. evaluated
the eect of saron in lipopolysaccharide-induced uveitis in
rabbits. The results showed no signicant dierence in the
clinical and pathological severity score between rabbits receiv-
ing intraperitoneal saron.
30
The underlying mechanism of the antioxidative eect of
crocin has not been completely understood. In this respect,
the nuclear factor kappa B (NF-κB) pathway, which protects
retinal ganglion cells from H
2
O
2
-induced oxidative stress, is
one of the suggested mechanisms.
31
Retinal inammatory response
The pathogenic inammatory response is an important back-
ground in many eye ailments. It is also supported by multiple
studies that inammation has a signicant role in the patho-
genesis of dierent retinal diseases, including age-related
macular degeneration, retinal vascular diseases, and diabetic
retinopathy.
32
Anti-inammatory therapies have been inves-
tigated for the prevention and treatment of these diseases.
Crocin has been suggested to treat dierent inammatory
ocular diseases.
33
Yang et al. has demonstrated the anti-
inammatory properties of crocin in diabetic microangiopathy.
High-glucose and free fatty acid have been used to induce
diabetes models in cultured microglial cells. The results showed
that crocin prevented up-regulation of the expression of CD11b
and Iba-1 microglial cells over-activation.
28
Arikan et al. also
showed that crocin signicantly reduced gene expression of
the pro-inammatory markers in microglial cells. They showed
that crocin reduces nitric oxide release in retinal tissue as a factor
associated with inammatory response.
34
Saron, the main
medicinal plant involving crocin as the major ingredient, has
shown a suppressing eect on neuro-retinal inammation asso-
ciated with increased intraocular pressure, thereby preventing
retinal ganglion cell death. Anti-inammatory properties of cro-
cin are also demonstrated in other organs.
33,35–37
Retinal blood ow
Retinal circulation is regulated by smooth muscle and meta-
bolic interaction that produces vasoactive materials through
the vascular endothelium and periarteriolar cells. The regula-
tion of vascular tone and perfusion pressure in response to
metabolic demands has a vital role in retinal blood ow
autoregulation.
38
Endothelial pericytes and myogenic cells
interaction are essential in retinal blood ow homoeostasis.
Ischaemic insult to the retina activates dierent metabolic
pathways resulting in disturbance in auto-regulation of ret-
inal circulation. Retinal tissue ischaemia injures the retinal-
blood barrier and predisposes retinal vessels to leakage. Also,
vascular leakages may lead to macular oedema.
Neovascularization is a physiological response to these
ischaemic events. This response, in turn, is mediated through
vascular endothelial growth factors.
38
Structural properties of the
newly proliferated vascular tissue are dierent from those of
vessels, and they are susceptible to leakage and haemorrhages.
Increased retinal tissue oxygenation can suppress the expression
of vascular endothelial growth and, therefore, regression of neo-
vascularization and oedema. Targeting the mentioned pathways
in retinal blood ow regulation is a potential technique to nd
new drugs to treat retinal vascular diseases.
38
Xuan et al. studied the eect of crocin (10 mg/kg ip) on
retinal blood ow and retinal function in New Zealand white
rabbits.
39
They designed the animal model of decreased retinal
blood ow by increasing the intraocular pressure, which
decreased about 66% of the retinal blood ow. These research-
ers applied an electroretinogram to assess the retinal function
objectively. The results showed that crocin increases the retinal
and choroidal blood circulation and improves retinal function
evaluated by electroretinogram after ischaemic retinal injury.
39
The study also showed that crocin is a potential therapy for
microangiopathic and ischaemic retinopathies.
Corneal pain
Multiple pathologic pathways can induce corneal pain.
40
Chronic dry eye disease, radiation therapy, extended contact
lens wear, toxicity from preservatives, shingles, diabetes, trigem-
inal neuralgia, chronic conditions that cause facial pain, and any
systemic condition that can lead to nerve damage are among
the major causes of corneal pain.
41
Tamaddonfard et al.
42
eval-
uated the eect of intraperitoneal and intracerebroventricular
crocin on acute corneal pain in rats induced by topical sodium
chloride solution. They considered the number of eye wipes in
the rst 30 seconds as the indicator of corneal pain. The results
showed a considerable reduction in corneal pain by both intra-
peritoneal and intracerebroventricular injection of crocin. They
used naloxone, an opioid receptor antagonist, to assess if the
analgesic eect of crocin was through the opioid receptors. The
authors observed no naloxone-induced reversal of crocin
analgesic eect and concluded that analgesic eect of crocin
was not through the opioid receptors.
Dry eye
Dry eye is a common disease that causes uncomfortable feel-
ings and vision problems.
43
It is considered a multifactorial
condition caused by tear deciency or evaporation excess
that can cause chronic ocular surface damage.
44
Regarding
the lack of permanent and complete treatment for dry eye,
many alleviating treatments have been used for this
condition.
45
Ali et al.
46
evaluated the eect of a formulation
containing crocin, cross-linked hyaluronic acid, and liposomes
in treating an experimental model of dry eye. These authors
assessed cytoprotective eects against inammation and oxi-
dative stress in epithelial cells of the human cornea. The results
showed a signicant reduction in IL-1β and TNFα as inamma-
tion indicators and reactive oxygen species.
Cataract
Cataract is the leading cause of blindness worldwide.
47
Surgical
management is the only current option for the treatment of
cataracts. In this respect, medical treatments have been inves-
tigated for the prevention and treatment of cataracts.
48
Bahmani et al.
49
evaluated the preventive eect of intraperito-
neal crocin on the α-crystallin glycation-induced cataract in an
4M. HEYDARI ET AL.
animal model. α-crystallin is a protein that helps to maintain
the transparency of the eye lens. The compromised function of
α-crystallin by glycation can result in cataract formation in
ageing and diabetes. Cross-linking of crystalline lens proteins
is known as causative factor for cataract formation. Increased
hydrophobicity and decreased solubility of these proteins is
another factor associated with lens opacity and cataract.
Bahmani et al.
49
observed that crocin inhibited advanced gly-
cation end product, protein cross-linking, and hydrophobicity
in the experimental model of streptozotocin-induced diabetes.
Signalling pathways
PI3K/Akt signalling pathway
PI3K-Akt is a pathway that regulates cellular growth, metabo-
lism, life cycle, apoptosis, and angiogenesis. The PI3K-Akt path-
way is regulated by phosphorylation of multiple downstream
substrates. It has been shown that the PI3K/Akt pathway med-
iates retinal progenitor cell survival under hypoxic and super-
oxide stress.
50
It is also suggested that the PI3K/Akt signalling
pathway mediates the high glucose-induced expression of
extracellular matrix molecules in human retinal pigment epithe-
lial cells.
51
According to Qi et al., crocin can activate the PI3K-Akt path-
way in retinal ganglion cells.
52
In the animal model, retinal
ischaemia was stimulated by increasing the intraocular pressure
to more than 100 mmHg for one hour. TUNEL staining was
applied to study the protective eect of the retinal cell by
evaluating apoptosis of the retinal ganglion cells. Also,
a Western blot was applied to quantify the level of phosphory-
lated AKT protein. PI3K inhibitor LY294002 was used to show the
level of contribution of the PI3K/AKT pathway to the observed
outcome. The results showed the preventive role of crocin in
retinal ganglion cells apoptosis and increased survival compared
to the control group. The Western blot showed the PI3K/AKT
neuroprotective activity, which was blocked by LY294002. Yang
et al. also showed a similar eect of crocin on inhibition of
oxidative stress and the pro-inammatory response of microglial
cells. This eect is associated with diabetic retinopathy through
the activation of the PI3K/Akt signalling pathway.
NF-κB signalling pathway
The NF-ĸB-signalling pathway is vital in regulating inammatory
response, cellular metabolism, and proliferation. The NF-
κB-signalling pathway also contributes to glial cell activity and
proliferation of Muller glia-derived progenitor cells. This path-
way inhibits the Muller glia-derived progenitor cells prolifera-
tion. NF-κB-inhibitors can enhance Muller glia-derived
progenitor cells proliferation.
53
Evidence suggests that NF-kB
pathway inhibition can be a potential therapeutic target for
neuro-retinal diseases.
54
Lv et al. showed that crocin upregulates
CX3CR1 expression by suppressing NF-κB/YY1 signalling and
inhibiting lipopolysaccharide-induced microglial activation.
55
Clinical evidence
Diabetic macular oedema
Sepahi et al. reported a benecial eect of crocin supplementa-
tion in patients with refractory diabetic macular oedema.
56
They
evaluated 60 patients with refractory macular oedema not
responding to anti-vascular endothelial growth factor, triamci-
nolone, and photocoagulation. The authors evaluated response
to dierent doses of crocin supplementation (5 and 15 mg/day)
versus placebo for 90 consecutive days in a parallel design
randomised clinical trial. The best-corrected visual acuity and
central macular thickness were considered as primary outcomes.
In addition, they indicated signicant improvement of both
visual acuity and macular thickness in patients receiving
a 15 mg/day dose of crocin (but not in those receiving
5 mg/day).
Stargardt macular dystrophy
Piccardi et al. demonstrated the slowing eect of saron (the
main medicinal plant involving crocin as the major ingredient)
on the progress of Stargardt macular dystrophy visual function
decline determined by functional electroretinogram.
57
The par-
ticipants of this study included 31 patients in both saron
(20 mg/day) and placebo groups, who were followed for
6 months. The results showed the prevention of disease pro-
gression in the intervention group by crocin supplementation.
However, the signicant dierence was only observed in elec-
troretinogram results, and visual acuity does not show any
dierence between the groups.
Age-related macular degeneration
Falsini et al. evaluated the eect of saron on retinal icker
sensitivity in early age-related macular degeneration
(ARMD).
58
They showed that 3-months saron supplementa-
tion could improve retinal icker sensitivity in patients suer-
ing ARMD. They have enrolled 25 patients with early ARMD
and assigned them to receive saron supplementation 20 mg/
d or placebo in a randomised parallel design clinical trial. The
results showed increased amplitude and decreased functional
electroretinogram thresholds in the active study group. They
also demonstrated improved best-corrected visual acuity in
patients receiving saron compared to placebo control.
Another report by Broadhead et al. showed the superiority
of saron (20 mg/day for 12 weeks) to placebo supplementa-
tion in patients with mild to moderate ARMD on 100 patients
in a cross-over design.
59
In addition, these researchers
observed the benecial eects on both functional electrore-
tinogram and visual outcomes.
Lashay et al. conducted a double-blind, placebo-controlled,
randomised trial by evaluating the outcomes of daily supple-
mentation of 30 mg saron for 6 months in patients with age-
related macular degeneration. They showed a signicant
improvement in ocular coherence tomography and electroreti-
nogram outcomes in patients receiving saron.
60
In another
eort, Riazi et al. evaluated the impact of saron on the vision
of patients with ARMD. Visual acuity, contrast sensitivity, and
retinal thickness were measured at the beginning and at the
end in 54 participants with daily supplementation of 50 mg
saron for 12 weeks. There was a signicant increase in visual
acuity and contrast sensitivity in the saron group compared to
the control group.
61
Glaucoma
Jabbarpoor et al. showed the ocular hypotensive eect of aqu-
eous saron extract supplementation in patients with primary
open-angle glaucoma.
62
Their participants were 34 patients with
open-angle glaucoma and clinically controlled intraocular pres-
sure. There were assigned to receive 30 mg/day saron extract,
CLINICAL AND EXPERIMENTAL OPTOMETRY 5
placebo supplementation as adjuvant treatment of timolol, and
dorzolamide eye drops for 1 month and 1 month without treat-
ment as the follow-up. The authors observed a signicant reduc-
tion in intraocular pressure in patients of the saron group
compared to placebo, which was maintained after stopping
supplementation for the second 1-month follow-up.
Discussion
Natural products may have therapeutic eects in various
disorders.
63
The pathogenesis mechanism of disorders is
very important in selecting an eective treatment.
Inammation and oxidative damage are two main patho-
genic causes of many ocular disorders.
64
On the other hand,
natural products can be categorised as antioxidants regard-
ing their chemical and molecular structures. Saron is com-
posed of many molecules, including crocin safranal,
picrocrocin, and crocetin, which all possess antioxidant
properties.
65
Saron is usually used as a avour. Because of heat or
chemical reactions in the cooking process, the eects of this
product may completely change. Therefore, we cannot
extend the results of studies to the usual usage of these
products.
66
Figure 3. Mechanisms involved in retinal protective effects of crocin.
Table 2. Summary of clinical studies on the effects of saffron/crocin on eye diseases.
Refs.
Ophthalmic
Disease
Number of
participants Intervention
Outcome
measure Final effect
Jadad
Score
56 DME 60 Crocin
15 mg/day
12 weeks
BCVA and CMT Improved vision and decreased CMT 4
57 Macular
Dystrophy
(STG/FF
patients)
31 Saffron
20 mg/day
20 weeks
BCVA and fERG Progression of central retinal dysfunction in ABCA4-
related STG/FF
5
58 AMD 25 Saffron
20 mg/day
12 weeks
fERG Improved amplitude and retinal flicker sensitivity 4
59 AMD 100 Saffron
20 mg/day
12 weeks
BCVA and mfERG Improved vision and retinal flicker sensitivity 5
61 AMD 54 Saffron
50 mg/day
12 weeks
BCVA and CMT Improved vision and contrast sensitivity 4
60 AMD 40 Saffron
30 mg/day
24 weeks
BCVA, CMT, and
ERG
Improved retinal function 4
69 AMD 33 Saffron
20 mg/day
12 weeks
fERG Improved retinal flicker sensitivity 4
70 AMD 29 Saffron
20 mg/day
16 weeks
fERG Improved mean fERG sensitivity 4
62 POAG 34 Saffron
30 mg/day
4 weeks
Intraocular
pressure
Reduced intraocular pressure 4
fERG, functional electroretinogram; BCVA, best corrected visual acuity; CMT, central macular thickness.
6M. HEYDARI ET AL.
The site of action of the eective molecules of saron may
also be dierent. For example, some eective molecules may
aect the cardiovascular system, while others may have better
penetration to the eye and show their eect in the retina. These
variations must be included in analysing the studies and using
these products as eective drugs for a specic disease.
Some adverse eects are also reported for saron-like dry
mouth, anxiety, agitation, drowsiness, low mood, sweating,
nausea, vomiting, constipation, changes in appetite, ushing,
and headache. Allergic reactions are also reported in some
people. Accordingly, systemic evaluation of patients before
using this product is recommended.
Conclusion and future direction
Natural products are increasingly being investigated for their
eects on various diseases, including ocular diseases.
67
As
a main active constituent of saron, crocin is studied as
a visual supplement for dierent eye diseases, especially retinal
pathologies.
68
Preclinical evidence showed the cytoprotective,
antioxidative, anti-inammatory, and blood ow-raising eects
of crocin in retinal tissue (Table 1). It is also shown that crocin
aects the retinal pathologies by activating PI3K/Akt and inhibit-
ing NF-κB signalling pathways (Figure 3). Clinical evidence also
showed the potential role of crocin in improving the clinical
outcomes in patients with ARMD, retinal dystrophies, and glau-
coma (Table 2). However, more clinical studies are needed better
to evaluate the potential ecacy of crocin in ocular diseases.
These studies should include larger sample sizes and longer
follow-ups to conrm the current evidence. More pharmaceuti-
cal studies are also required to better formulations targeting
ocular tissues by peri/intraocular injection or bypassing the
blood-retinal barrier.
Disclosure statement
No potential conict of interest was reported by the author(s).
Funding
This study was supported by Shiraz University Medical Sciences (Grant
No. 95-01-01-13605).
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