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Crocin as a vision supplement

Authors:

Abstract

Crocin is a natural ingredient of saffron (Crocus sativus L.) flower 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 briefly discusses the role of crocin in different eye diseases. The underlying pathophysiological pathways involved in the effect of crocin on ophthalmic diseases are also reviewed. Preclinical evidence shows the cytoprotective, antioxidative, anti-inflammatory, and blood-flow enhancing effects of crocin in retinal tissue. Crocin also affects 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 confirm the current evidence.
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 saron (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 briey discusses the role of crocin in dierent eye diseases. The underlying
pathophysiological pathways involved in the eect of crocin on ophthalmic diseases are also reviewed.
Preclinical evidence shows the cytoprotective, antioxidative, anti-inammatory, and blood-ow enhancing
eects of crocin in retinal tissue. Crocin also aects 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 conrm 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 signicant economic burden.
1
In 2020, 1.1 billion people were
living with vision loss,
2
which is projected to aect 1.7 billion
people in 2050.
2,3
The prevalence of vision loss has increased
signicantly 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-inammatory eects.
8
Inammation
can aect dierent 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 saron (Crocus sativus
L.) ower. It is a water-soluble carotenoid pigment respon-
sible for the red colour
11–13
of the saron ower (Figure 1).
Saron 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 saron with multiple pharmacological, antioxidant, anti-
neoplastic, anti-atherosclerotic, aphrodisiac, and anti-
ischaemic eects.
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 dierent eye
diseases (Table 1) and the underlying pathophysiological path-
ways involved in the eect of crocin on ophthalmologic
diseases.
Literature search strategy
A comprehensive search was performed to retrieve any study
evaluating the eect of crocin or saron (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 ‘saron’ 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 eect
Crocin has shown a protective eect on dierent retinal cells,
including retinal pigment epithelial cells (RPE), photoreceptors,
Muller cells, and retinal nerve bre layers, in dierent animal and
in-vitro models. The synergistic eect of resveratrol on the
cytoprotective and antioxidative eect 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 eect has yet to be be
evaluated. The cytoprotective eects 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 reex 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 eect of crocin on H
2
O
2
induced apoptosis and LDH release.
24
The protective eect 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 eect 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
aected 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 signicant contribution of
oxidative stress to dierent 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 dierent mod-
els of oxidative stress in the eye. Chen et al. evaluated the
antioxidant eect 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 eect 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 eect.
Bochang et al. showed the antioxidative eect of crocin on
retinal ganglion cells in an animal model of H2O2-induced
oxidative damage. Crocin demonstrated an anti-apoptotic
eect in retinal ganglion cells and a preventive eect on
ROS and LDH production. These eects 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
eect of crocin in retinal injury in an animal model of diabetic
retinopathy. These researchers also demonstrated the protec-
tive eect 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 eect of saron (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 signicantly
increased in the saron-treated group compared to the control
group. Therefore, they showed that saron extract could pre-
vent selenite-induced cataract formation in Wistar rats.
29
In con-
trast to the positive eect of saron in an animal model of
cataract, the eect of this natural product in an experimental
model of uveitis was not promising. Talebnejad et al. evaluated
the eect of saron in lipopolysaccharide-induced uveitis in
rabbits. The results showed no signicant dierence in the
clinical and pathological severity score between rabbits receiv-
ing intraperitoneal saron.
30
The underlying mechanism of the antioxidative eect 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 inammatory response
The pathogenic inammatory response is an important back-
ground in many eye ailments. It is also supported by multiple
studies that inammation has a signicant role in the patho-
genesis of dierent retinal diseases, including age-related
macular degeneration, retinal vascular diseases, and diabetic
retinopathy.
32
Anti-inammatory therapies have been inves-
tigated for the prevention and treatment of these diseases.
Crocin has been suggested to treat dierent inammatory
ocular diseases.
33
Yang et al. has demonstrated the anti-
inammatory 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 signicantly reduced gene expression of
the pro-inammatory markers in microglial cells. They showed
that crocin reduces nitric oxide release in retinal tissue as a factor
associated with inammatory response.
34
Saron, the main
medicinal plant involving crocin as the major ingredient, has
shown a suppressing eect on neuro-retinal inammation asso-
ciated with increased intraocular pressure, thereby preventing
retinal ganglion cell death. Anti-inammatory 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 dierent 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 dierent 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 eect 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 eect 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 eect of crocin was through the opioid receptors. The
authors observed no naloxone-induced reversal of crocin
analgesic eect and concluded that analgesic eect 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 deciency 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 eect of a formulation
containing crocin, cross-linked hyaluronic acid, and liposomes
in treating an experimental model of dry eye. These authors
assessed cytoprotective eects against inammation and oxi-
dative stress in epithelial cells of the human cornea. The results
showed a signicant reduction in IL-1β and TNFα as inamma-
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 eect 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 eect 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 eect of crocin on inhibition of
oxidative stress and the pro-inammatory response of microglial
cells. This eect 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 inammatory
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 benecial eect 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 dierent 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 signicant 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 eect of saron (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 saron
(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 signicant dierence was only observed in elec-
troretinogram results, and visual acuity does not show any
dierence between the groups.
Age-related macular degeneration
Falsini et al. evaluated the eect of saron on retinal icker
sensitivity in early age-related macular degeneration
(ARMD).
58
They showed that 3-months saron supplementa-
tion could improve retinal icker sensitivity in patients suer-
ing ARMD. They have enrolled 25 patients with early ARMD
and assigned them to receive saron 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 saron compared to placebo control.
Another report by Broadhead et al. showed the superiority
of saron (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 benecial eects 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 saron for 6 months in patients with age-
related macular degeneration. They showed a signicant
improvement in ocular coherence tomography and electroreti-
nogram outcomes in patients receiving saron.
60
In another
eort, Riazi et al. evaluated the impact of saron 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
saron for 12 weeks. There was a signicant increase in visual
acuity and contrast sensitivity in the saron group compared to
the control group.
61
Glaucoma
Jabbarpoor et al. showed the ocular hypotensive eect of aqu-
eous saron 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 saron 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 signicant reduc-
tion in intraocular pressure in patients of the saron group
compared to placebo, which was maintained after stopping
supplementation for the second 1-month follow-up.
Discussion
Natural products may have therapeutic eects in various
disorders.
63
The pathogenesis mechanism of disorders is
very important in selecting an eective treatment.
Inammation 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. Saron is com-
posed of many molecules, including crocin safranal,
picrocrocin, and crocetin, which all possess antioxidant
properties.
65
Saron is usually used as a avour. Because of heat or
chemical reactions in the cooking process, the eects 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 eective molecules of saron may
also be dierent. For example, some eective molecules may
aect the cardiovascular system, while others may have better
penetration to the eye and show their eect in the retina. These
variations must be included in analysing the studies and using
these products as eective drugs for a specic disease.
Some adverse eects are also reported for saron-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
eects on various diseases, including ocular diseases.
67
As
a main active constituent of saron, crocin is studied as
a visual supplement for dierent eye diseases, especially retinal
pathologies.
68
Preclinical evidence showed the cytoprotective,
antioxidative, anti-inammatory, and blood ow-raising eects
of crocin in retinal tissue (Table 1). It is also shown that crocin
aects 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 ecacy of crocin in ocular diseases.
These studies should include larger sample sizes and longer
follow-ups to conrm 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 conict 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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8M. HEYDARI ET AL.
... Additionally, crocin and crocetin enhance retinal blood flow and oxygen diffusion, which inhibits VEGF production and neovascularization [38]. Several studies have reported that oral saffron supplements are safe and well tolerated [39][40][41]. ...
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Background: Age-related macular degeneration (ARMD) leads to impaired vision and potential blindness. Globally, it accounts for approximately 9% of vision loss cases, and a projected 288 million individuals will be affected by 2040. Current treatments have limitations such as variable effectiveness, high costs, and potential side effects. Additionally, atrophic ARMD management remains challenging. As saffron has shown promising neuroprotective and antioxidant effects by potentially delaying disease progression, this study aims to review the mechanistic, pre-clinical, and clinical evidence of the effects, safety, and tolerability of saffron in ARMD treatment. Methods: The Scale for the Assessment of Narrative Review Articles was applied in this narrative review. To find relevant literature, the syntax “(saffron OR crocus) AND (retin* OR “geographic atrophy” OR “choroidal neovascular*” OR “macular degeneration”)” was searched in PubMed/MEDLINE. Pre-clinical and clinical original investigations of the effects of saffron in ARMD along with the eligible studies cited in their reference lists were identified and included. Results: Saffron and its active compounds, crocin and crocetin, have shown promising results in improving visual function and delaying ARMD progression. Several clinical studies have found that daily supplementation with 20–50 mg of saffron or 5–15 mg of crocin for 3–12 months significantly improved best-corrected visual acuity, contrast sensitivity, and retinal function as measured by electroretinogram and microperimetry, with benefits observed in both dry and wet forms of ARMD. The effects were independent of genetic risk factors and maintained during the follow-up periods, suggesting the potential role of saffron as a long-term treatment option. Saffron reduces ARMD progression via anti-angiogenic, neuroprotective, and antioxidant mechanisms. Moreover, saffron is safe and well tolerated. Conclusions: Although further research is needed to confirm long-term safety and efficacy, current evidence supports the use of saffron or crocin supplements as a safe and tolerable adjunct therapy for ARMD management.
... Because of its antioxidant properties, crocin inhibits the chemical alteration of irradiated cells and reduces oxidative stress significantly [19]. Recent studies have shown that crocin alone can reduce the chemical damage caused by light radiation in animal retinal cells [20][21][22] and play an essential role in cell division and cytotoxic function of T lymphocytes in childhood leukemia. Additionally, some studies have indicated that crocin can significantly inhibit cell division in tumors [23][24][25]. ...
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Background High-dose radiation altering the genetic material in patients’ bone marrow cells can lead to hematopoietic radiation syndrome. Accordingly, the presence of radiation protections agents is critical to preventing these adverse effects. Objective This study aimed to evaluate the radioprotection of the exclusive or combination effect of resveratrol and crocin extracts at various concentrations on irradiated human lymphocytes. Material and Methods In this experimental study, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method was used to evaluate the cell viability in pre-treatment with resveratrol, crocin, or a combination of both, using a concentration range of 5 to 4800 μM / ml in 24 h. The chromosomal aberration test was employed to determine the aberration frequency in 48 h. This study was performed on human peripheral blood lymphocytes treated with 2 Gy radiation and reliability of measurements performed by the triplicate repeat. Results MTT results showed that the groups treated with either resveratrol or crocin at concentrations of 5 to 4800 µM had no significant reduction in cell viability. The cytogenetic analysis of irradiated lymphocytes with 2 Gy X-rays revealed a reduction in the frequency of dicentric chromosomes in all treated groups in contrast with the control group. The most significant reduction occurred in those treated with a single agent at the concentration of 100 µM and a combined drug at the concentration of 50 µM. Conclusion The combination of resveratrol and crocin is considered a potential radioprotector and prophylactic for patients before radiation therapy.
... Crocin Anti-schizophrenia, Antifatigue, Anti-Alzheimer's, Neuroprotective, Anti-depressant, Anti-diabetic, Therapeutics for multiple sclerosis, Antioxidative, Anti-tumor, Therapeutics for neuro-retinal diseases, Anti-inflammatory, Anti-apoptotic, Mitigates blood pressure and heart rate [66][67][68][69][70][71][72][73][74][75][76][77][78] ...
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Plants are an important source of essential bioactive compounds that not only have a beneficial role in human health and nutrition but also act as drivers for shaping gut microbiome. However, the mechanism of their functional attributes is not fully understood despite their significance. One such important plant is Crocus sativus, also known as saffron, which possesses huge medicinal, nutritional, and industrial applications like food and cosmetics. The importance of this plant is grossly attributed to its incredible bioactive constituents such as crocins, crocetin, safranal, picrocrocin, and glycosides. These bioactive compounds possess a wide range of therapeutic activities against multiple human ailments. Since a huge number of studies have revealed negative unwanted side effects of modern-day drugs, the scientific communities at the global level are investigating a large number of medicinal plants to explore natural products as the best alternatives. Taken into consideration, the available research findings indicate that saffron has a huge scope to be further explored to establish alternative natural-product-based drugs for health benefits. In this review, we are providing an update on the role of bioactive compounds of saffron as therapeutic agents (human disorders and antimicrobial activity) and its nutritional values. We also highlighted the role of omics and metabolic engineering tools for increasing the content of key saffron bioactive molecules for its mass production. Finally, pre-clinical and clinical studies seem to be necessary to establish its therapeutic potential against human diseases.
... The main coloring and biologically active components of saffron are the water-soluble carotenoids crocin and crocetin. The high biological activity of crocin and the prospect of using it for the treatment of eye diseases (glaucoma, macular degeneration, diabetic retinopathy, and age-related macular degeneration) [61], as an antidepressant [62], and an anticancer substance [63] have been revealed. ...
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Background: Saffron is an enriched pool of bioactives including crocins, crocetin, safranal, picrocrocins, essential oils, minerals and trace amounts of B1 and B2 vitamins. Obtaining any valuable ingredients like bioactive compounds which are naturally present in plants is completely depending on the extraction and purification procedures. An efficient extraction method of bioactives should meet the green chemistry aspects including safety, environment-friendly, run-down or at least little impurities, efficiency, and economic requirements. On the other hand, efficient entrapment of saffron bioactive compounds into the protected carriers is indispensable owing to their liability to the operational (process), environmental, and body digestive conditions. Scope and approach: This review will present recent advances on the extraction and encapsulation of saffron bioactive components which could result in value-added products from the so-called red gold (saffron)as the most expensive spice in the world for different purposes such as food, pharmaceutical, and cosmetic formulations. Key findings and conclusions: Many different extraction methods, alone or in combination, have been exploited to produce the bioactives from saffron such as convectional routes (e.g. maceration and solvent extraction)and the modern routes (e.g. supercritical fluids, pulsed electric field, emulsion liquid extraction, microwave, sonication, etc.). Encapsulation techniques are strongly proposed to shelter the bioactive compounds found in saffron, over the other protective techniques. In this regard, microencapsulation (spray drying, freeze drying, extrusion, emulsion systems)and nanoencapsulation (nanoemulsions, solid lipid nanoparticles and nanodispersions, nanohydrogels, electrospinning, nano spray drying)procedures have been investigated for saffron bioactives.