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Biomedicine & Pharmacotherapy 170 (2024) 115999
Available online 12 December 2023
0753-3322/© 2023 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Review
Effect of salidroside on neuroprotection and psychiatric sequelae during the
COVID-19 pandemic: A review
Ting Zhu
a
,
1
, Hui Liu
e
,
f
,
1
, Shiman Gao
g
, Ning Jiang
c
,
*
, Shuai Chen
d
,
*
, Weijie Xie
b
,
**
a
Institute of Neuroregeneration & Neurorehabilitation, Department of Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
b
Clinical Research Center for Mental Disorders, Shanghai Pudong New Area Mental Health Center, Tongji University School of Medicine, Shanghai 200122, China
c
Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China
d
School of Public Health, Wuhan University, Donghu Road No. 115, Wuchang District, Wuhan 430071, China
e
Guizhou Provincial Key Laboratory of Pharmaceutics & State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang
550004, Guizhou, China
f
Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University, Guiyang 550004,
Guizhou, China
g
Department of Clinical Pharmacy, Women and Children’s Hospital, Qingdao University, Qingdao 266034, China
ARTICLE INFO
Keywords:
Psychiatric sequelae
Salidroside
Neuroprotection
Mental disorder
Neuroinammation
Brain plasticity
ABSTRACT
The coronavirus disease 2019 (COVID-19) pandemic has affected the mental health of individuals worldwide,
and the risk of psychiatric sequelae and consequent mental disorders has increased among the general popula-
tion, health care workers and patients with COVID-19. Achieving effective and widespread prevention of
pandemic-related psychiatric sequelae to protect the mental health of the global population is a serious chal-
lenge. Salidroside, as a natural agent, has substantial pharmacological activity and health effects, exerts obvious
neuroprotective effects, and may be effective in preventing and treating psychiatric sequelae and mental dis-
orders resulting from stress stemming from the COVID-19 pandemic. Herein, we systematically summarise,
analyse and discuss the therapeutic effects of salidroside in the prevention and treatment of psychiatric sequelae
as well as its roles in preventing the progression of mental disorders, and fully clarify the potential of salidroside
as a widely applicable agent for preventing mental disorders caused by stress; the mechanisms underlying the
potential protective effects of salidroside are involved in the regulation of the oxidative stress, neuro-
inammation, neural regeneration and cell apoptosis in the brain, the network homeostasis of neurotransmis-
sion, HPA axis and cholinergic system, and the improvement of synaptic plasticity. Notably, this review
innovatively proposes that salidroside is a potential agent for treating stress-induced health issues during the
COVID-19 pandemic and provides scientic evidence and a theoretical basis for the use of natural products to
combat the current mental health crisis.
Abbreviations:
α
-syn,
α
-synuclein; ACTH, adreno-cortico-tropic-hormone; AD, Alzheimer’s disease; AMPK, activate AMP-activated protein kinase; APP, amyloid
precursor protein; BACE1, β-secretase; BBB, blood–brain barrier; BDNF, brain-derived neurotrophic factor; CAM, complementary and alternative medicine; CIRI,
cerebral ischaemia-reperfusion injury; CMS, chronic mild stress; COVID-19, coronavirus disease 2019; CORT, corticosterone; CRH, corticotropin-releasing hormone;
CREB, cAMP response element-binding protein; DA, dopamine; DJ-1, mitogen-dependent oncogene-1; ER, endoplasmic reticulum; GCLc, glutamate-cysteine ligase
catalytic; GPCR, G-protein coupled receptor; GPx, glutathione peroxidase; GRs, glucocorticoid receptors; GSK-3β, glycogen synthase kinase 3β; GSH, glutathione;
HPA, hypothalamic-pituitary-adrenal; IL, interleukin; IR, insulin receptor; iNOS, inducible nitric oxide synthase; JNK, c-Jun NH2-terminal kinase; LTP, long-term
potentiation; LPS, lipopolysaccharide; MAP2, microtubule-associated protein 2; MAPK, mitogen-activated protein kinase; MCAO, middle cerebral artery occlusion;
MDA;, malondialdehyde; MDD, major depressive disorder; MQC, mitochondrial quality control; MPP, 1-Methyl-4-phenylpyridinium; NAMPT, nicotinamide phos-
phoribosyltransferase; ND6, NADH dehydrogenase 6; NE, noradrenaline; NGF, nerve growth factor; NMDAR, N-methyl-D-aspartate receptor; nNOS, nitric oxide
synthase; Nrf2, nuclear factor E2-related factor 2; OBX, olfactory bulbectomy; OGD, oxygen/glucose deprivation; PD, Parkinson’s disease; PI3K, phosphatidylino-
sitide 3-kinase; PTSD, posttraumatic stress disorder; ROS, reactive oxygen species; 5-HT, serotonin; SIRT1, silent information regulator 1; SNpc, substantia nigra pars
compacta; SOD, superoxide dismutase; TH, tyrosine hydroxylase; TNF, tumour necrosis factor; WHO, World Health Organization.
* Corresponding authors.
** Correspondence to: Clinical Research Center for Mental Disorders, Shanghai Pudong New Area Mental Health Center, Tongji University School of Medicine,
Shanghai, China.
E-mail addresses: jiangning0603@163.com (N. Jiang), chenshuai2016@hotmail.com (S. Chen), xwjginseng@126.com (W. Xie).
1
These authors contributed equally to this work.
Contents lists available at ScienceDirect
Biomedicine & Pharmacotherapy
journal homepage: www.elsevier.com/locate/biopha
https://doi.org/10.1016/j.biopha.2023.115999
Received 20 September 2023; Received in revised form 22 November 2023; Accepted 6 December 2023
Biomedicine & Pharmacotherapy 170 (2024) 115999
2
1. Introduction
The global coronavirus disease 2019 (COVID-19) pandemic has
caused a series of public health problems, including restriction of human
activity and social isolation, and social stress caused by socioeconomic
pressures and concerns about being infected [1–3]. These
pandemic-related social stressors not only exacerbate the psychiatric
symptoms of anxiety [4,5], depression [1,6], acute stress exposure and
post-traumatic stress (PTSD) [5,7] as well as motor dysfunction [8,9],
sleep disturbances [4,6], cognitive impairment [10,11] and suicidal
tendencies [1,2] in the general population but also may aggravate psy-
chopathological processes in patients with mental disorders [7,12] and
COVID-19 patients [13]; COVID-19 may exacerbate the symptoms of
underlying medical conditions, such as cardiovascular diseases and
cancers [14,15], and may be accompanied by a number of psychiatric
complications, such as anxiety, depression-like behaviours [4,5,16],
vascular cognitive impairment, stress-related behaviours, and addiction
behaviour [9,12]. Overall, the COVID-19 pandemic has increased the
risk of mental disorders and psychiatric sequelae and caused social stress
[17–19].
In addition, pathological factors that can cause physical sequelae
may persist in the human body after recovery from COVID-19 [20,21].
Current clinical evidence suggests that these pathological factors can
lead to damage to the brain and nervous system [3,20,21] and poten-
tially to the development of mental disorders, such as anxiety, depres-
sion and PTSD, and brain injuries [18,20,22]. Therefore, mental
disorders have become the largest contributors to the nonfatal health
burden worldwide, and their occurrence and development may be
related to biological factors such as genetics, disruption of neural cir-
cuits, and neurodevelopmental abnormalities, as well as environmental
factors through biological-psycho-social interactions [23–25].
Fluoxetine, a common rst-line psychiatric drug, is effective in
treating most adolescents with major depressive disorder [26,27];
meanwhile the pharmacotherapy of uoxetine may accompany poten-
tial adverse effects. Therefore, the pharmacotherapy on market is
currently not recommended for direct adjuvant treatment in people with
anxiety-and depressive-like symptoms or psychiatric sequelae caused
social stress. Due to concerns related to safety and costs, currently
available antidepressant medications such as uoxetine, imipramine
and citalopram have not been widely used to treat psychiatric symptoms
caused by stress stemming from the COVID-19 pandemic [27,28].
Despite their rapid antidepressant effects, the use of novel N-methyl--
D-aspartate receptor (NMDAR) antagonists such as ketamine has been
highly controversial in recent years due to uncertainties about their
long-term efcacy, their risk of side effects, and the potential for abuse
during long-term treatment [29], which urgently need to be explored.
Given the limitations of currently available antidepressants, patients
with mild mental illnesses or symptoms have become increasingly in-
clined to use complementary and alternative medicine (CAM) strategies
because they are generally well tolerated, have fewer side effects and are
efcacious [30–32]. Traditional herbal remedies, which are important
in the eld of CAM, have been increasingly recognised as the most
promising medical agents for managing many chronic diseases [28,31,
33].
Currently, due to studies on the chemical composition of natural
plants and experimental research, such prescriptions have been widely
integrated into mainstream medicine for the treatment of various dis-
eases. Considering the negative inuences of the current COVID-19
pandemic, new drugs or natural agents for the prevention and treat-
ment of mental disorders are urgently needed, and their mechanisms of
action need to be identied [31,34]. Several existing natural agents,
such as Jinhua Qinggan Granules[35], and Lianhua Qingwen capsules [36,
37], have been reported to have great potential in the prevention and
adjunctive treatment of COVID-19; thus, they may represent new agents
for treating mental health conditions. However, there are no new natural
product-based interventions or therapeutic agents that have been
developed to prevent psychiatric sequelae and subsequent brain damage
in the age of the COVID-19 pandemic.
Salidroside, a natural phenolic compound, is one of the main active
ingredients of the rhizomes of Rhodiola rosea L. (Crassulaceae) (chemical
structure as shown in Fig. 1) [38–40]. Recent studies have shown that
salidroside has various pharmacological activities, including
anti-inammatory, antioxidant, anticancer, antimetabolic, and neuro-
protective activities [41–44], demonstrating its great potential for pre-
venting mental health disorders and improving mental health in
humans. However, it has not yet been determined whether salidroside
can be used in the treatment of mental disorders caused by stress
stemming from the COVID-19 pandemic. Moreover, the efcacy, safety
and applicability of this natural compound have not been fully
demonstrated.
Aiming to explore the potential efcacy and application value of
salidroside, we searched for all existing studies and reports related to the
use of salidroside for the treatment of psychiatric disorders and
adequately summarised and analysed the therapeutic value and poten-
tial mechanisms of salidroside in preventing and treating the exacer-
bation of mental disorder-related symptoms, conditions or types of brain
damage caused by stress stemming from the COVID-19 pandemic,
including anxiety, depression, Alzheimer’s disease (AD), Parkinson’s
disease (PD), and brain injuries. The papers were also divided into
several sections according to the effects of salidroside on the following
processes: (a) neurotransmitter homeostasis; (b) hypothalamic-
pituitary-adrenal axis activity; (c) neuroinammation and pyroptosis;
(d) oxidative injury and cell apoptosis; (e) neuroinammation and cell
damage; (f) Aβ generation and aggregation; (g) Aβ-induced neurotox-
icity and cell death; and so on.
2. Effects of salidroside on depression and anxiety
Depression and anxiety are both highly prevalent and debilitating
disorders, with many sufferers not adequately responding to current
anti-depressant therapy [45]. In recent years, mounting evidence has
shown Salidroside have been used widely around the world and have
demonstrated benecial anxiolytic and antidepressant-like effects and a
high safety prole. The effects may be related to regulation of neuro-
transmitters and hypothalamic-pituitary-adrenal axis, inhibition of
neuroinammation and pyroptosis, and so on [39,46–50].
2.1. Salidroside regulates neurotransmitter homeostasis
Clinical trials have demonstrated that salidroside can alleviate the
symptoms of generalised anxiety, stress, and depression in humans
[51–53]. Preclinical studies have shown that salidroside exerts potent
antidepressant-like effects in various animal models of depression and
anxiety, including animal models of olfactory bulbectomy (OBX)-,
chronic mild stress (CMS)-, and lipopolysaccharide (LPS)-induced
depression and anxiety [39,46,47,54,55]. Moreover, preclinical and
clinical studies have conrmed that salidroside and the natural plant
R. rosea are safer and have better efcacy than conventional antide-
pressants [53,56,57].
Anxiety and depression are strongly associated with disturbances in
serotonergic, noradrenergic, and dopaminergic (DAergic)
Fig. 1. Chemical structure of salidroside.
T. Zhu et al.
Biomedicine & Pharmacotherapy 170 (2024) 115999
3
neurotransmission [58–60], and these monoaminergic systems are
thought to be vital targets for the treatment of depression or anxiety
[61–63]. Salidroside has been shown to increase serotonin (5-HT) levels,
improve neurotransmitter homeostasis, and promote the proliferation
and differentiation of neural stem cells in the hippocampus in a rat
model of stress-induced depression [49,64]. Moreover, compared with
control treatment, oral administration of salidroside and R. rosea
signicantly increases the concentrations of noradrenaline (NE), 5-HT
and DA in the rat brainstem [65]. Salidroside can improve neurotrans-
mitter homeostasis in the brain by increasing the ability of precursors of
dopamine (DA) and 5-HT to cross the blood–brain barrier (BBB) [49,64].
Furthermore, pretreatment with salidroside and R. rosea products
effectively increases the levels of 5-HT and NE in the prefrontal cortex in
an LPS-treated model [55], and salidroside and R. rosea play a vital role
in preserving injured neurons in the hippocampus [49,64]. Clearly,
salidroside can regulate brain neurotransmitter homeostasis and
improve brain network function and thus may be benecial in allevi-
ating anxiety and depression-like symptoms or behaviours caused by
stress stemming from the COVID-19 pandemic (Fig. 2).
2.2. Salidroside normalises hypothalamic
–
pituitary
–
adrenal (HPA)
axis activity
Under normal physiological conditions, HPA axis activity can be
normalised via endogenous glucocorticoid-mediated negative feedback
inhibition, which is largely dependent on the function of glucocorticoid
receptors (GRs) in several brain regions [66]. The HPA axis is a major
component of the stress response, and abnormal activation of this axis by
chronic exposure to severe stress plays an important role in the patho-
genesis of depression [67]. In CMS models, salidroside has been shown
to decrease corticosterone (CORT) levels and increase the expression of
stress-responsive genes, especially in the hippocampus and prefrontal
cortex [49,68]. Salidroside also attenuates corticotropin-releasing hor-
mone (CRH) expression in the hypothalamus [49] and signicantly re-
duces the serum levels of CORT in an OBX rat model [49]. Salidroside
can alleviate the changes in CORT and adrenocorticotropic hormone
(ACTH) levels caused by prolonged exposure to severe stress in rats, thus
maintaining HPA axis homeostasis [69].
In addition, stress-induced CRH expression causes the release of
ACTH from the pituitary gland, and ACTH stimulates the release of
adrenal hormones and NPY to mobilise energy and help the body cope
with stress; in turn, NPY induces the release of CRH and has a mood- and
cognition-enhancing effect [46], and salidroside appears to stimulate
the expression and release of NPY in neuroglial cells [46]. Moreover,
salidroside markedly upregulates the expression of brain-derived neu-
rotrophic factor (BDNF) and TrkB in the prefrontal cortex and hippo-
campus [47,49,55], decreases CRH and corticotropin expression in the
hypothalamus via the HPA axis [49], and increases GR levels, thereby
Fig. 2. Neuroprotective effects of salidroside against the relevant depression and anxiety symptoms caused by stress stemming from the COVID-19 pandemic. First of
all, salidroside enhances the balance of neurotransmitters (NE, 5-HT, and DA), maintains the homeostasis of HPA axis (CORT and ACTH) and regulates the CRH and
glucocorticoid receptor (GR) functions, contributing to a decrease in the brain network disturbance caused by the stress or COVID-19 pandemic. Then, salidroside
exerts anti-inammatory regulation via the ERK1/2, P38 MAPK, P2×7-NLRP3-Caspase1, and NF-kB pathways, decreases the proinammatory cytokine levels (IL-1β,
IL-6 and TNF-
α
), and attenuates the neural cell injuries and pyroptosis, which is helpful to alleviate inammation injuries related to chronical stress or the COVID-19
sequela. Moreover, salidroside notably enhances the synaptic plasticity via the BNDF-TrkB pathway. All of these powerfully support the potential of salidroside
against depression and anxiety as well as the relevant sequela symptoms in the COVID-19 pandemic. ProCAS, Pro-Caspase 1.
T. Zhu et al.
Biomedicine & Pharmacotherapy 170 (2024) 115999
4
improving synaptic plasticity [47,49,55]. These effects are helpful in
alleviating neuroendocrine disorders and emotional dysfunction trig-
gered by social stress.
2.3. Salidroside ameliorates neuroinammation and pyroptosis
Depression and anxiety are strongly associated with chronic stress
exposure and social stimulation [70]; the key pathogenic mechanisms of
these disorders are chronic inammation and microglial activation in
the brain [71–73]. Salidroside has been demonstrated to exert anti-
neuroinammatory effects and to prevent depression and anxiety [47,
49,50,54,55,74,75]. In CMS-, OBX-, or LPS-induced inammation
models, salidroside notably alleviates stress-induced hyperactivity and
anxiety-like behaviours [49,74,75], decreases immobility time and
depression-like behaviours [49,74], increases sucrose preference and
locomotor activity [74], and decreases escape latency. Additionally, it
has been found that salidroside exerts anti-inammatory effects via the
NF-kB pathway [55,74]; the levels of interleukin (IL)−1β, IL-6, IL-18
and tumour necrosis factor (TNF)-
α
in both the serum and brain were
found to be decreased in salidroside-treated CMS and LPS-induced
anxiety and depression model animals compared to control model ani-
mals [47,49,54,74].
Chronic inammation and microglial activation in the brain are
often associated with the emergence of depression symptoms [72,73,76]
and play an important role in the regulation of neuronal cell death,
neurogenesis, and synaptic interactions [76–78]. Salidroside signi-
cantly reduces the activation of microglia in the brain, inhibits the po-
larization of microglia towards the deleterious M1 phenotype in the
hippocampus [54], and thus decreases the expression and release of
neuroinammatory cytokines (IL-1β, IL-6, IL-18 and TNF-
α
) [54].
Furthermore, salidroside notably hinders microglial activation [54,55]
and ameliorates microglial morphology alterations and microglial
dysfunction caused by CMS and LPS [54,79] via suppression of the
extracellular signal-regulated kinase (ERK) 1/2 and P38
mitogen-activated protein kinase (MAPK) pathways [54] and inhibition
of p65 NF-κB activation and inducible nitric oxide synthase (iNOS)
expression [54,55,74].
Furthermore, the effects of salidroside are associated with NLRP3-
mediated pyroptosis and the P2×7 and NLRP3 signalling pathways
[47,49,74]. Salidroside markedly upregulates the expression of NLRP3,
cleaved Caspase-1, and cleaved GSDMD protein [47]. Interestingly, a
recent study revealed that salidroside attenuates cell pyroptosis by
interacting with the P2×7 and NLRP3 signalling pathways [47], and this
phenomenon was further veried using related siRNAs and inhibitors.
2.4. Summary
Taken together, the current ndings (Table 1 and Fig. 2) demonstrate
that salidroside plays a crucial role in anxiety and depression; salidro-
side not only inhibits microglia-mediated neuroinammation in the
brain and reduces the levels of inammatory cytokines but also sup-
presses oxidative stress- and inammation-mediated neural cell
apoptosis and pyroptosis. These effects are benecial for the prevention
of behavioural alterations and chronic stress- or pandemic-induced in-
creases in cytokine levels in the brain. Moreover, salidroside regulates
the P2×7-NLRP3 pathway and the ERK1/2-p38 MAPK pathway, pre-
vents p65 NF-κB activation, enhances BDNF and TrkB activation to
improve synaptic plasticity, and ameliorates anxiety and depression
symptoms (Fig. 2).
In addition, salidroside regulates neurotransmitter homeostasis by
affecting the release, degradation and reuptake of neurotransmitters
such as NE, DA and 5-HT; attenuates disturbances in brain network
function caused by stress stemming from the COVID-19 pandemic; and
reverses the disruption of the balance between CRH and corticotropin
levels via the HPA axis. Considering these neuroprotective effects
(Table 1 and Fig. 2), salidroside has great application potential for the
prevention and treatment of depression and anxiety; salidroside may be
developed as a promising agent for the prevention and treatment of
mental sequelae caused by stress stemming from the COVID-19
pandemic in the general population and COVID-19 patients.
3. Effects of salidroside on cognitive impairment and AD
AD is the most prevalent form of dementia [80,81]. To date, there are
no efcient and safe therapies for preventing and curing AD due to an
incomplete understanding of the pathogenesis [81–83]. As both
COVID-19 and the unhealthy lifestyles associated with governmental
controls during the pandemic [84] as well as resultant social stresses
[84,85] cause severe oxidative damage and activation of inammatory
cascades, they increase the risk of AD progression [3]. Therefore,
cost-effective and convenient novel approaches for preventing cognitive
impairment and halting the progression of AD are urgently needed. The
discovery of new natural ingredients with bioactive properties is of great
importance for the development of novel drugs to alleviate cognitive
impairment and prevent and treat AD [86–93]. Recent studies have
demonstrated that salidroside exerts neuroprotective effects by modu-
lating oxidative stress responses, inammation and apoptosis [50,94,
95]. This work summarises the therapeutic value and clinical prospects
of salidroside in the prevention and treatment of cognitive impairment
as well as its ability to prevent AD progression and discusses the po-
tential of salidroside as a widely applicable psychoactive substance for
preventing cognitive impairment caused by stress stemming from the
COVID-19 pandemic (Fig. 3).
3.1. Salidroside inhibits oxidative injury and cell apoptosis in the nervous
system
In addition to genetic risk factors (APOE4) [81,96], cognitive
dysfunction and decline are associated with oxidative stress and
inammation in the brain resulting from consumption of a high-fatty
acid diet or western diet [97], ageing [98], and chronic exposure to
social stress [99,100], which promote oxidative stress, reactive oxygen
species (ROS) production, chronic low-grade inammatory stress and
microglial activation and neurodegeneration in the brain. Through its
robust pharmacological activities, salidroside exerts potent anti-
oxidative and neuroprotective effects in different models of cognitive
impairment and AD, making it a potential candidate drug for the
treatment of AD and other neurodegenerative diseases [40,50,95].
Oxygen deciency, isourane exposure and cerebral hypoperfusion
can induce cognitive impairment, robustly inhibit long-term potentia-
tion (LTP) and increase hippocampal neuron loss [101–103], and sali-
droside signicantly improves memory function [103,104], ameliorates
isourane-induced cognitive dysfunction [101], and improves hippo-
campal LTP [103] in hypoxemia/hypoperfusion-exposed rats. Further-
more, salidroside improves learning and spatial memory, increases the
number of dendritic intersections and enhances arborization in rats
exposed to hypoxia [102]. Furthermore, excessive ROS production leads
to severe oxidative damage within the cellular membrane, including
damage to membrane lipids, proteins, and intranuclear DNA; impairs
mitochondrial and synaptic function; and leads to cognitive impairment.
Conversely, salidroside can signicantly inhibit oxidative damage, in-
crease the activity of superoxide dismutase (SOD) and glutathione
peroxidase (GPx) and the concentration of glutathione (GSH) in the
hippocampus [104], increase the activity of choline acetyltransferase
and the content of acetylcholine, decrease the concentrations of
malondialdehyde (MDA) and nitrate [38,104,105], and increase the
activity of acetylcholine esterase in the hippocampus [101]. These ef-
fects further suppress Caspase-3 activation and increase the Bax/Bcl-2
ratio [103,104,106], contributing to a decrease in hippocampal
neuron loss [103,104] and the inhibition of oxidative damage and
neural cell apoptosis [103,104].
In addition, salidroside exerts antioxidative effects, thereby
T. Zhu et al.
Biomedicine & Pharmacotherapy 170 (2024) 115999
5
Table 1
The therapeutic effects and potential target pathways of salidroside in the prevention and treatment of mental disorders and psychiatric sequelae in in vivo or in vivo
studies.
Psychiatric Animal/Model Type Administration Effects/Conclusion Refs.
Anxiety and
depression
LPS- and LPS+CMS-induced rat and
mouse models
In
vivo
In
vitro
i.p.: 10 mg/kg
i.g.: 12 and 24 mg/
kg
i.p.: 20 and 40 mg/
kg
Orally: 5 mg/kg
↑ NE, 5-HT, and BDNF/TrkB levels
↓ P2×7/NLRP3 levels and microglia number
↑ BDNF levels and synaptic plasticity
↓ IL-1β, IL-18, TNF-
α
, and IL-6 levels
↓ ERK1/2, P38 MAPK, and NF-κB levels
↓ Neuroinammation and pyroptosis
↓ Depressive or anxiety-like behaviour
[47,54,55,74,191–193]
CMS, OBX, and STZ rat /mouse models In
vivo
i.g.:
20 and 40 mg/kg
10, 15, and 20 mg/
kg
10 and 25 mg/kg
↑ BDNF and GR levels and HPA axis
↑ Anti-inammatory effects
↓ CORT, CRH, TNF-
α
, and IL-1β levels
↓ MAPK and p65 NF-κB activation
↓ Depressive or anxiety-like behaviour
[39,49,54,74,75,191,193,
194]
CORT-treated PC12 cells;
H2O2-treated NSCs;
LPS-treated primary microglia
In
vitro
Coculture:
2, 10, 50 µm
50, 100, 200 µm
1–50 mg/ml
↓ ROS levels and NSC death
↑ Proliferation and differentiation
↓ Oxidative and inammatory stress
↓ P2×7/NF-κB/NLRP3, acetylcholinesterase
[39,47,54,193,195]
AD
Cognitive
impairment
Hypoxia–ischaemia rat model;
Isourane-induced rat model
CIA or LPS-induced inammation;
Cadmium‑induced toxicity
In
vivo
Orally:
25 mg/kg
200 mg/kg
60–120 mg/kg
2, 20, 40 mg/kg
i.p.: 20 mg/kg
↓ Memory impairment
↑ Learning and spatial memory
↓ Cognitive decits and neuronal loss
TNF-
α
, IL-1β, MDA, and Aβ levels
↑ SOD, GPx, and acetylcholine levels
↓ ROCK/SIRT1/NF-κB pathway
↑ IRA-AMPK, SIRT1 and CYP2E1 pathway
↑ Nrf-2/HO-1; ↓ Rho/ROCK/NF-κB pathway
↓ Inammatory and oxidative stress
[39,101–103,107,126,
194,196]
Aβ
1–42
-treated rats/ mice
APP/PS1 mice;
Mouse prone 8
(SAMP8) mice;
Drosophila
In
vivo
Orally: 20, 40 mg/
kg
25, 50, and 75 mg/
kg
i.g.: 20, 40, and
80 mg/kg
Free access:
0.3 mg/ml
↓ Inammation and pyroptosis
↓ COX-2, iNOS and RAGE levels
↑ SOD, GPx, and nicotinamide adenine
↓ ROS, MDA and oxidative stress
↓ IL-1β, IL-1
α
, IL-6, IL-17A, IL-18 and IL-12
↓ Aβ, p-Tau levels Aβ aggregation and
neurotoxicity
↑ SIRT1, PSD95, NMDAR1, p-GSK-3β and PI3K-
AKT pathway
↓ NF-κB and NLRP3 inammasome;
Inammation of the Gut-Brain Axis
[38,111,113,115,116,119,
123–125,133,197]
Aβ-treated PC12 and SH-SY5 cells;
LPS, D-galactose and nigericin-treated
PC12 cells and
primary neuronal cells or animal
In
vitro
In
vivo
Coculture:
2–20 µM
0.3–100 µM
12.5–100 µM
50–100 µM
1–50 mg/ml
Orally:
20, 40 mg/kg
↓ TNF-
α
, IL-6 and pyroptosis
↑ NAD
+
, NAMPT-NAD
+
axis activity
↑ ERK1/2, PI3K/AKT and HO-1 levels
↓ NLRP3, Caspase-1/3, pyroptosis
↓ TLR4, NF-κB, JNK/p38 MAPK
↓ Caspase-3 activity, JNK/p38 MAPK
↓ ROS, LDH, MDA and oxidative stress
↓ BACE1, β-secretase activity, Aβ neurotoxicity
and neuronal apoptosis
[102,113,115,116,
120–123,127,132,196,
198]
Stroke
Brain Injuries
MCAO/R and pMCAO rat and mouse
models
In
vivo
i.p.:
25–100 and
5–20 mg/kg
50 and 100 mg/kg;
Orally: 12 and
48 mg/kg
i.v.: 2.5–20 mg/kg
↓ Inammation and oxidative stress
↑ Dendritic spine number; synaptic plasticity
↓ NLRP3 inammasome levels and apoptosis
↓ ROS levels and mitochondria damage
↑ M2 macrophage number, polarization
↓ Cerebral infarction; ↑ Motor function
↓ Imbalance of mitochondrial ssion and fusion
↑ Mitochondrial biogenesis by attenuating the
AMPK activity
↑ The number of NeuN-positive cells, and ↓ the
number of GFAP-positive cells
↓The expression of CD11b and pro-inammatory
cytokines
↑ The levels of DA, HVA, and DOPAC
[159,160,163,164,166,
173,178,180,182,187,
199]
OGD/R-treated PC12 cells, HT22 cells,
HUVECs, and primary neurons;
neuron-microglia cocultures
In
vitro
5–20
μ
M
1–100
μ
M
25–100
μ
M
12.5–400
μ
M
100, 200 and
400 µM
↓ Inammation and apoptosis
↑ Oligodendrocyte differentiation
↓ LDH release and excessive mitophagy
↑ Bcl-2/Bax ratio and neuronal survival
↓ Mitochondrial calcium uorescence intensity
by down-regulating GRP75 expression
↑ Proliferation, migration and↓apoptosis of
MSCs
[43,159,160,166,167,173,
182,183,199]
PD
Movement
damages
MPP
+
-treated SH-SY5Y, PC12,
SN4741 and MN9D cells;
WT/A30P-
α
-syn-treated SH-SY5Y cells;
LPS-treated BV2 cells and MSCs;
6-hydroxydopamine-treated SN4741 cells
In
vitro
20 µM
25–100
μ
M
10–80
μ
M
10–100
μ
M
10–30
μ
M
10–50
μ
M
↓ TLR4/MyD88/NF-κB
↑ rMSC differentiation
↓ ROS, NO, NOX2, and
α
-syn levels
↓ TXNIP/NLRP3/Caspase-1
↓ Inammation and oxidative stress
↑ SOD, glutathione, and NK1/Parkin
[138,140,142–145,
147–149,151,200–203]
(continued on next page)
T. Zhu et al.
Biomedicine & Pharmacotherapy 170 (2024) 115999
6
improving metabolism in the brain, promoting antioxidative pathways
and alleviating neuroinammation. Salidroside can promote insulin
receptor (IR) signalling [102,107], activate AMP-activated protein ki-
nase (AMPK) [107,108] by regulating the expression levels of AMPK
α
1
and AMPK
α
2 [102], and elevate the phosphorylation of cAMP response
element-binding protein (CREB) in the hippocampus [107,108], result-
ing in mitochondrial biogenesis and enhancement of metabolism in the
nervous system. Furthermore, salidroside increases silent information
regulator 1 (SIRT1) activity through a cytochrome P4502E1
(CYP2E1)-regulated mechanism [102]; increases the expression of
SIRT1, nuclear factor E2-related factor 2 (Nrf-2), and HO-1 [102,107,
108]; and reduces the expression of the apoptotic proteins Bax, Bcl-2,
Caspase-3, and Caspase-9 [103,108]. Overall, these results (Fig. 3)
reveal that salidroside exerts antioxidative and antiapoptotic effects to
Table 1 (continued )
Psychiatric Animal/Model Type Administration Effects/Conclusion Refs.
2–50
μ
M
100 µg/ml
↓ Caspase-3, ER stress, and apoptosis
↑ PI3K/Akt, DJ-1/Nrf2, and MEF2D-ND6
pathway activity
MPTP mouse models In
vivo
i.p.:
5 and 45 mg/kg
15 and 50 mg/kg
45 and 50 mg/kg
40 and 80 mg/kg
↓ ROS, NO, and Caspase-1 levels
↑ MEF2D-ND6 pathway activity
↑ PINK1/Parkin-mediated mitophagy
↓TXNIP/NLRP3 pathway and pyroptosis
↑ DJ-1/Nrf2 and antioxidant pathway activity
[141,147,149,201,202,
204]
Notes: CIA, collagen-induced arthritis; MAPK, mitogen-activated protein kinases; AKT, protein kinase B; MDA, malondialdehyde; IRA, Insulin receptor subunit A; GPx,
glutathione peroxidase; p-Tau, phosphorylation of Tau; CI, cognitive impairment; PI3K, phosphatidylinositide 3-kinase; CaMKII, calmodulin-dependent protein kinase
II; NE, norepinephrine; 5-HT, 5-hydroxytryptamine; BDNF, brain-derived neurotrophic factor; LPS, lipopolysaccharide; IL, interleukin, NF-κB, nuclear factor-κB; TrkB,
tropomyosin-related kinase B; TNF-
α
, tumor necrosis factor-
α
; CORT, corticosterone; NSC, neural stem cells; OBX, olfactory bulbectomized; GR, glucocorticoid re-
ceptor; CRH, corticotropin-releasing hormone; SOD, superoxide dismutase; LC3, microtubule-associated proteins 1 A/1B light chain 3; NOX2, NADPH oxidase 2; MSCs,
Bone marrow-derived cells; MCAO, middle cerebral artery occlusion; pMCAO, permanent MCAO; OGD, oxygen/glucose deprivation; HUVECs, human umbilical
endothelial cells; MQC, mitochondrial quality control; MPP+, N-methyl-4-phenylpyridinium; MPTP, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine; ROS, reactive
oxygen species; NADPH, nicotinamide adenine dinucleotide phosphate; Nrf2, nuclear factor- (erythroid-derived 2-) like 2; PINK1, PTEN-induced kinase-1; NLRP3, NLR
Family Pyrin Domain Containing 3; MEF2D; mitochondrial myocyte enhancer factor 2D; ND6, NADH dehydrogenase 6; DA, dopamine; HVA, homovanillic acid;
DOPAC, 3,4-dihydroxyphenylacetic acid; i.p., intraperitoneal; i.g. intragastric; i.v., intravenous injection. References (Refs) are cited from the main text.
Fig. 3. Neuroprotective effects of salidroside in treating cognitive impairment and AD caused by stress stemming from the COVID-19 pandemic. COVID-19 may
result in cognitive decline and increase the risk of cognitive impairment and AD. Salidroside mitigates oxidative damage, such as ROS- and MDA-induced injury and
mitochondrial damage; improves neuroinammation, such as by decreasing the levels of proinammatory cytokines (IL-6, IL-1β and TNF-
α
); reduces Aβ production
and aggregation; and attenuates Aβ-induced neurotoxicity and cell death. Thus, salidroside contributes to improving learning, memory and cognition, possibly
preventing AD progression. The underlying mechanisms may involve the IR-AMPK-AKT/CREB, MAPK, PI3K-AKT, Nrf-2/HO-1, NAMPT-NAD+-SIRT1, TLR4/AKT,
NLRP3-ASC-Caspase-1, SIRT1-NF-κB, BACE1 and Caspase-3/Caspase-9 signalling pathways. Salidroside may contributing to decreasing cognitive decits caused by
stress stemming from the COVID-19 pandemic. CI, cognitive impairment. AD, Alzheimer’s disease.
T. Zhu et al.
Biomedicine & Pharmacotherapy 170 (2024) 115999
7
alleviate cognitive impairment and AD pathology and that the under-
lying mechanisms involve the IR, SIRT1, Nrf-2/HO-1/NF-κB, and AMPK
pathways, indicating that salidroside may be developed as a novel
therapeutic drug for AD.
3.2. Salidroside ameliorates neuroinammation and cell damage
Activation of microglia and brain inammation are prominent
pathological features of AD [96,109] and promote disease progression.
Natural products and compounds that target these immune mechanisms
are potential therapies or preventive agents for AD [82,109,110]. Sali-
droside has been shown to exert neuroprotective effects, prevent
cognitive impairment and halt AD progression by ameliorating inam-
matory damage, reducing oxidative stress, and inhibiting apoptosis and
thus may be a promising agent for the treatment of AD.
LPS injection into the central nervous system, chicken type II
collagen and Freund’s adjuvant can induce neuroinammation and
cause learning and memory decits in animal models of cognitive
impairment [108,111,112] and AD [95,104,113]. In contrast, salidro-
side treatment effectively ameliorates LPS-induced decits in learning,
memory and cognition [108,111,112] and signicantly reduces the
levels of proinammatory cytokines (TNF-
α
, IL-1β and IL-6) in the
serum, hippocampus, and cell supernatant in vivo and in vitro [108,112,
114]. Furthermore, it markedly decreases the levels of IL-1
α
, IL-6, IL-17
and IL-12 in the peripheral circulation [111], reduces the release of
TNF-
α
and IL-1β in isourane-exposed rats [101], and downregulates
the expression of IL‑6 and TNF‑
α
in APPswe/PS1ΔE9 mice [104].
Notably, salidroside signicantly suppresses the expression of NF-κB
p65 and IκB
α
[108] in a SIRT1-dependent manner, thus increasing
SIRT1 activity and expression [108,113] and inhibiting the NF-κB [107,
108,113] and SIRT1-NF-κB pathways [113]. Salidroside treatment also
markedly inhibits the RhoA-ROCK1/2 pathway and decreases the levels
of p-NF-κB (p65), p-IκB
α
, p-IKK
α
and p-IKKβ, boosting neuroimmunity
[112,114]. Further studies have shown that salidroside effectively at-
tenuates microglial activation [94,111] in SAMP8 mice and reduces the
levels of proinammatory factors in both the brain and the peripheral
circulation [94,111]; these peripheral effects are associated with im-
provements in gut barrier integrity, maintenance of the gut microbiota
balance, reversal of the change in the ratio of Bacteroidetes to Firmicutes,
and elimination of Clostridiales and Streptococcaceae [94,111]. It has
been demonstrated that salidroside exerts a protective effect against
inammation-induced cognitive dysfunction and AD.
In addition, D-galactose and cadmium have neurotoxic effects and
aggravate cognitive impairment and AD progression. Salidroside in-
hibits cadmium toxicity in GL261 cells [105]; reverses the abnormal
changes in the levels of inammatory cytokines, such as TNF-
α
, IL-1β,
IL-18, and IL-6, oxidative stress and glial cell activation [113,115,116];
and attenuates cognitive impairment and neuroinammation caused by
D-galactose and amyloid-β (Aβ) [113,115,116]. Further studies have
demonstrated that salidroside can ameliorate inammation and
neuronal damage by suppressing RIP1-driven inammatory signalling
and the Notch/HES-1 signalling axis in the brain, regulating
TLR4/NF-κB and NLRP3/Caspase-1 signalling, and reducing
inammation-mediated pyroptosis in the brain. Salidroside can reverse
the increase in the levels of TLR4-NF-κB/p-NF-κB pathway-related pro-
teins, NLRP3-ASC-Caspase-1 pathway-related proteins and cleaved
GSDMD [113,115,116]; downregulate the expression of Bax, Bcl-2,
Caspase-3 and Caspase-9; and inhibit neural cell pyroptosis and cell
death [113,115,116]. These results (Fig. 3) suggest that salidroside has
important neuroimmunity-related effects in preventing and treating
cognitive impairment and highlight its value as a potential agent for
cognitive impairment and AD.
3.3. Salidroside reduces Aβ generation and aggregation
Aβ plaque formation is a key histopathological hallmark of AD, and
Aβ accumulation is a crucial early feature of AD pathogenesis [117].
Inhibiting β-secretase (BACE1) activity and reducing Aβ levels in the
brain are efcacious strategies for preventing and treating AD [83,118].
As discussed above, salidroside not only alleviates cognitive impairment
and hinders AD progression [109,119–122] but also protects against Aβ
accumulation and Aβ-induced neurotoxicity [102,123–127] by exerting
anti-inammatory and antioxidative effects, thus contributing to the
amelioration of AD pathology.
Both BACE1 and γ-secretase are required for the production of Aβ
[83,117,128]. Hypoxia can regulate secretase activity and expression
and induce abnormal processing of amyloid precursor protein (APP)
[102]. Conversely, salidroside pretreatment signicantly decreases the
mRNA expression of BACE1, reduces the protein levels of BACE1 and
HIF-1
α
, and promotes the secretion of sAPP
α
in hypoxia-exposed
SH-SY5Y cells but has no effect on the APP level [102]; salidroside
also decreases Aβ levels and Aβ deposition in the brain [102,123]. Sal-
idroside can attenuate hypoxia-induced abnormal processing of APP,
inhibit BACE1 activity and Aβ generation [102], and alleviate Aβ40/42
aggregation and cytotoxicity [119,129] through the HIF1
α
-BACE1
pathway without affecting γ-secretase activity [102,123], allowing it to
reduce Aβ levels.
Furthermore, salidroside can improve locomotor activity in a trans-
genic Drosophila model of AD, ameliorate Aβ-treated toxicity and
reduce neuronal loss in the brain [123,124] by promoting phosphati-
dylinositide 3-kinase (PI3K)/Akt signalling [124]. Salidroside increases
the levels of phosphorylated glycogen synthase kinase 3β (p-GSK-3β),
decreases the level of p-Tau [123,124], and regulates the APP and
GSK-3β pathways [124,125] to protect against Aβ-induced neurotoxicity
and alleviate AD and other neurodegenerative diseases (Fig. 3).
3.4. Salidroside alleviates Aβ-induced neurotoxicity and cell death
Aβ oligomers, which are the principal toxic forms of Aβ, can cause
cytotoxicity, mitochondrial damage, neurite degeneration and cell death
in the brain [120–122], resulting in memory and learning impairment,
cognitive decline and progression of AD [130,131]. Due to its potent
pharmacological activities, salidroside can protect against Aβ-induced
neurotoxicity and cell apoptosis or death in AD models and Aβ-treated
cells [102,123–127].
First, salidroside signicantly decreases Aβ-mediated intracellular
ROS accumulation and MDA production [121,127,132]; inhibits lactate
dehydrogenase (LDH) release, morphological alterations, and neuronal
DNA condensation [127]; dose-dependently reverses the
Aβ
25–35
-induced decrease in cell viability; prevents Aβ
25–35
-induced
apoptosis [127]; and improves the mitochondrial membrane potential
and energy metabolism [120,127]. Thus, salidroside contributes to
preventing Aβ-induced toxicity and decreasing antioxidant enzyme ac-
tivity. Salidroside also exerts protective effects against Aβ-induced
oxidative stress by inhibiting Aβ
25–35
-induced phosphorylation of c-Jun
NH2-terminal kinase (JNK) and p38 MAPK [127] and alleviates
Aβ-induced cell damage by increasing the expression of nicotinamide
phosphoribosyltransferase (NAMPT) and the synthesis of NAD
+
[120],
boosting SIRT1 activity and protecting against AD progression [107,
108,113].
Further studies have demonstrated that salidroside signicantly re-
pairs damaged synapses in APP/PS1 mice [133], enhances the survival
and proliferation of PC-12 cells [122], reduces both Aβ levels and Aβ
deposition [123,133], and increases longevity and improves locomotor
activity in Drosophila [123] and that the mechanisms underlying these
effects are associated with promotion of the PI3K-Akt-mTOR signalling
pathways [123,133] and activation of the ERK1/2 and AKT pathways
[122,123]. Moreover, salidroside increases the expression of PSD-95,
NMDAR1, and calmodulin-dependent protein kinase II [133], resulting
in signicant improvements in synthesis and mitochondrial function
[126,127].
In addition, salidroside notably reverses NF-κB activation in Aβ
1–40
-
T. Zhu et al.
Biomedicine & Pharmacotherapy 170 (2024) 115999
8
injected rats; downregulates COX-2, iNOS and RAGE expression [38];
and reduces the release of the inammatory cytokines TNF-
α
, IL-1β, and
IL-18 [108,111,116]. Salidroside can reduce both Aβ accumulation and
hyperphosphorylation of Tau, inhibit neuroinammation caused by Aβ,
and alleviate inammasome-mediated pyroptosis [38,108,111,116],
and the mechanisms involve the TLR4/AKT, SIRT1-NFκB, and
NLRP3/Caspase-1 inammasome signalling pathways (Fig. 3).
3.5. Summary
Overall, the current evidence (Table 1 and Fig. 3) demonstrates that
salidroside exerts powerful neuroprotective effects to prevent cognitive
impairment and AD progression and plays an important role in regu-
lating oxidative stress and neuroinammation; inhibiting neuronal cell
apoptosis; improving mitochondrial metabolism, synaptic function, and
neurotransmission; inhibiting Aβ synthesis and deposition; and reducing
neurotoxicity. In addition, salidroside not only inhibits oxidative dam-
age in the brain and alleviates neuroinammation but also reduces Aβ
production and aggregation and attenuates Aβ-induced neurotoxicity
and cell death, thus ameliorating learning, memory and cognitive de-
cits. The underlying mechanisms may involve the IR-AMPK-AKT/CREB,
MAPK, PI3K-AKT, Nrf2/HO-1, NAMPT-NAD
+
-SIRT1, TLR4/AKT,
NLRP3-ASC-Caspase-1, SIRT1-NF-κB, BACE1 and Caspase-3/Caspase-9
signalling pathways.
Salidroside has shown great promise as an adjunctive agent for the
treatment of AD and cognitive impairment, and thus, it may be a po-
tential therapeutic agent for treating or preventing neurodegenerative
diseases. In contrast to interventions targeting Aβ and Tau, salidroside
may be more suitable for daily management of AD and prevention of the
disease in the general public. The primary effects of salidroside in pre-
venting AD include antioxidant and anti-inammatory effects and the
ability to mitigate neurological damage. It is particularly suitable for
alleviating cognitive impairment and delaying AD progression caused by
social stresses and unhealthy lifestyles [115,134] during the COVID-19
pandemic [3,85,135].
4. Effects of salidroside on Parkinson’s disease (PD)
PD is a movement disorder and neurodegenerative disease charac-
terised by a range of recognisable clinical syndromes [136]. Identifying
effective therapeutic strategies for PD pathogenesis is an enormous
challenge. Six months after recovery from COVID-19, survivors mainly
experience fatigue, muscle weakness and changes in the brain [16,22],
indicating that COVID-19 might increase the vulnerability of DAergic
neurons in the substantia nigra pars compacta (SNpc) [16,22,137].
Therefore, the COVID-19 pandemic has increased the need to
develop strategies for preventing and alleviating PD. Considering that
salidroside exerts neuroprotective effects, we wondered whether sali-
droside can alleviate PD- and pandemic-related pathology underlying
motor dysfunction. Herein, we discuss and analyse the specic effects of
salidroside in PD and its potential application for treating movement
disorders caused by stress stemming from the COVID-19 pandemic
(Fig. 4).
Fig. 4. Neuroprotective effects of salidroside against PD or motor impairment under the COVID-19 pandemic. As the COVID-19 may increase the risk of PD, sali-
droside exhibits the multiple effects, such as anti-inammation, anti-oxidation, anti-apoptosis, anti-pyroptosis, regulation of autophagy, and improvement of the
mitochondrion pathway, which may prevent the PD progression. The underlying mechanisms may be through the PI3K/AKT, mitochondrial apoptosis, PINK1-Parkin,
MAPK, mTOR/p-70S6K, GSK3, TXNIP-NLRP3-Caspase-1, and DJ-1/Nrf2 signalling pathways, contributing to a decrease of PD declines exposed to the COVID-19
pandemic. ND6, NADH dehydrogenase 6; PTK, protein tyrosine kinase.
T. Zhu et al.
Biomedicine & Pharmacotherapy 170 (2024) 115999
9
4.1. Effects of salidroside against oxidative stress injury and apoptosis
1-Methyl-4-phenylpyridinium (MPP) has been used to generate
models to study the protective mechanism of salidroside against PD.
Oxidative stress, which mainly results from excessive production of ROS,
contributes to PD pathology [138], and mitogen-dependent oncogene-1
(DJ-1) and SIRT1 act as key modulators of oxidative stress through the
ERK1/2–Elk1, Cu/Zn-SOD1, and Nrf2 pathways [138,139].
Sirt1 has deacetylase activity and regulates many biological pro-
cesses (oxidative stress, apoptosis, and metabolism). Salidroside sup-
presses ROS production and NADPH oxidase 2 (NOX2) expression while
upregulating SOD activity and GSH levels by enhancing SIRT1 activa-
tion [138]. Salidroside inhibits the phosphorylation of p38, ERK and
JNK, which are involved in the MAPK pathways, in MPP-treated
SH-SY5Y cells [138]. Furthermore, salidroside signicantly increases
the mRNA and protein levels of Nrf2, glutamate-cysteine ligase catalytic
(GCLc), SOD1, and SOD2, while silencing of DJ-1 has the opposite effect
[140], suggesting that the DJ-1 and SOD antioxidant pathway is another
potential mechanism by which salidroside ameliorates PD. Additionally,
salidroside increases the number of tyrosine hydroxylase (TH)-positive
neurons in the SNpc and the levels of DA, DOPAC, and HVA in the
striatum by increasing the phosphorylation of Akt and GSK3β; elevating
the Bcl-2/Bax ratio; and inhibiting the activation of caspase-3, cas-
pase-6, and caspase-9 [141]. These ndings demonstrate that the
PI3K/AKT/GSK3β signalling pathway may mediate the protective effect
of salidroside against PD (Fig. 4).
Salidroside ameliorates PC12 cell apoptosis by inhibiting NO-related
pathways, including by decreasing NO, iNOS, and neuronal nitric oxide
synthase (nNOS) levels, and suppressing the accumulation of ROS and
intracellular free Ca
2+
[142]. Moreover, pretreatment with salidroside
signicantly decreases MPP(+)-induced chromatin condensation and
LDH content and enhances Akt phosphorylation [143]. This indicates
that salidroside protects against PD by activating the PI3K-Akt pathway.
Furthermore, salidroside exerts multiple pharmacological effects, as
it signicantly inhibits ROS production and MDA activity, increases GSH
levels, decreases inammatory cytokine (TNF-
α
and IL-1β) expression
and regulates the expression of apoptosis-related proteins (caspase-9,
caspase-3, Bax, and Bcl-2) [144]. Overall, the ndings indicate that
salidroside can exert signicant antioxidative effects and decrease the
risk of PD during the COVID-19 pandemic, giving it good therapeutic
value.
4.2. Salidroside regulates autophagy and pyroptosis
The formation of Lewy bodies (LBs) in surviving neurons in the SNpc
results from the accumulation of
α
-synuclein (
α
-syn) or
α
-syn phos-
phorylated at serine 129 (pSer129-
α
-syn) during PD pathogenesis [145].
Salidroside exerts neuroprotective effects against PD by decreasing the
pSer129-
α
-syn level, promoting the clearance of
α
-syn, and restoring
20 S proteasome activity [145].
Salidroside decreases pSer129-
α
-syn levels as well as the ratio of
microtubule-associated protein 1 A/1B light chain 3 (LC3) I to LC3 II,
suggesting that it reduces the phosphorylation of
α
syn via autophagy
and affects mTOR/p70S6K to protect against PD [158]. Salidroside in-
creases the number of TH-positive neurons in the substantia nigra, DAT
expression, and DA and metabolite levels in the striatum by enhancing
PINK1/Parkin-mediated mitophagy [159]. Furthermore, pyroptosis is a
newly discovered form of programmed cell death that plays a key role in
PD [162]. Salidroside can ameliorate MPTP-induced PD symptoms by
inhibiting NLRP3-dependent pyroptosis [163].
Salidroside can maintain autophagy homeostasis via the PINK1-
Parkin pathway and inhibit inammatory damage and pyroptosis via
the NLRP3-ACS-Caspase-1, PI3K-Akt, and MAPK pathways, demon-
strating that it has great potential for preventing PD (Fig. 4).
4.3. Salidroside attenuates mitochondrial apoptosis-related pathways
Dysfunction of mitochondria, the powerhouses of nerve cells, con-
tributes to the occurrence and development of PD [146]. Salidroside
pretreatment protects DAergic neurons via mitochondrial pathways.
Salidroside reduces ROS and NO production, decreases cytochrome-c
and Smac release, and inhibits
α
-synuclein aggregation, thus allevi-
ating mitochondrial damage. Furthermore, salidroside regulates the
Bcl-2/Bax ratio; inhibits caspase-3, caspase-6, and caspase-9 activation;
and thus regulates mitochondrial apoptosis-related pathways [147].
Complex I has been reported to be involved in the development of
PD. Salidroside exerts robust neuroprotective effects by activating
complex I via the DJ-1/Nrf2-mediated antioxidant pathway [148]. Sal-
idroside can increase neuronal cell viability and restore mitochondrial
complex I activity in vivo and in vitro via the mitochondrial myocyte
enhancer factor 2D (MEF2D)-NADH dehydrogenase 6 (ND6) pathway
[149]. Thus, salidroside attenuates PD pathology via mitochondrial
apoptosis pathways, indicating that it may have potential therapeutic
efcacy for motor disorders caused by stress stemming from the
COVID-19 pandemic.
4.4. Salidroside induces mesenchymal stem cell (MSC) differentiation
Loss of DAergic neurons in the substantia nigra is a key process in PD
[150]. Salidroside induces MSCs to differentiate into neuron-like cells by
upregulating the expression of neuronal markers (gamma neuronal
enolase 2 (Eno2/NSE), microtubule-associated protein 2 (MAP2), and
beta 3 class III tubulin (Tubb3/β-tubulin III)) and increasing BDNF,
neurotrophin-3 (NT-3) and nerve growth factor (NGF) mRNA expression
and secretion [150]. Importantly, salidroside signicantly upregulates
the expression of dopamine-beta-hydroxy (DBH), dopa decarboxylase
(DDC) and TH, which are DAergic neuron markers [150]. This result
suggests that salidroside can induce rat MSCs (rMSCs) to differentiate
into DAergic neurons.
In addition, endoplasmic reticulum (ER) stress has been reported to
be involved in DAergic neuron death [151]. Salidroside prevents cyto-
toxicity in a DAergic neuron cell line (SN4741) and primary cortical
neurons by regulating the levels of ROS, calcium, and cleaved
caspase-12, which are associated with ER stress [151].
4.5. Summary
Multiple lines of evidence indicate that salidroside exerts multiple
pharmacological effects, including anti-inammatory, antioxidative,
anti-apoptotic, anti-pyroptotic, autophagy-regulating, and mitochon-
drial pathway-promoting effects, in the treatment of PD. The PI3K/AKT,
mitochondrial apoptosis, PINK1-Parkin, MAPK, Wnt/β-Catenin, mTOR/
p-70S6K, GSK3, TXNIP-NLRP3-Caspase-1, DJ-1/Nrf2, and MEF2D-ND6
pathways are involved in these effects. Furthermore, salidroside not
only induces MSCs to differentiate into neuron-like cells and DAergic
neurons but also attenuates ER stress (Fig. 4). Overall, these ndings
indicate that salidroside can increase the number and improve the
function of DAergic neurons, thereby suppressing the development and
progression of PD. Importantly, salidroside has anti-inammatory and
α
-syn-regulating effects and may play crucial roles in treating PD during
the COVID-19 crisis. These ndings provide evidence for interesting and
thought-provoking strategies for preventing and treating PD and COVID-
19-induced motor dysfunction (Table 1 and Fig. 4).
5. Effects of salidroside on ischaemic stroke and brain injury
The pathogenesis of ischaemic stroke is complex, and up to 85% of
stroke cases are caused by cerebral ischaemia due to thrombotic
obstruction of the arteries. Given the large number of people who have
contracted COVID-19 globally and the high mortality rate of COVID-19-
related stroke, the potential societal impact of COVID-19-related stroke
T. Zhu et al.
Biomedicine & Pharmacotherapy 170 (2024) 115999
10
is enormous [152]. The aetiology of stroke in patients with COVID-19 is
multifactorial and includes coagulopathy, inammation, platelet acti-
vation, and vascular endothelial changes [152]. Traditional Chinese
medicine (TCM) prescriptions can play a role in preventing and treating
stroke by exerting specic biological effects to maintain physiological
functions [153–157]. Thus, new natural compounds for preventing and
treating COVID-19-related stroke are urgently needed.
Based on the current evidence, salidroside has anti-inammatory,
antioxidant stress, and anti-apoptotic effects. In addition, it can reduce
the imbalance between mitochondrial ssion and fusion, enhance
mitophagy [158], promote dendritic synaptic plasticity [159], and
improve MSC survival [160] to protect against ischaemia-induced brain
injury. Thus, it has good potential for treating brain injury in COVID-19
patients and preventing exacerbation of ischaemic injury (Fig. 5).
5.1. Effects of salidroside on oxidative stress and inammation
Although the pathological mechanisms of ischaemic stroke are
complex, they are closely related to oxidative stress and inammation
[154,161]. In a rat model of middle cerebral artery occlusion
(MCAO)-induced cerebral ischaemia–reperfusion injury (CIRI), there is
an imbalance between Th17 and Treg cells in the peripheral blood.
Salidroside can signicantly ameliorate neurological decits and reduce
the infarct size in MCAO rats and reverse oxidative stress by targeting
STAT-3 [162]. In addition, intraperitoneal injection of 50 mg/kg sali-
droside after 24 h of reperfusion following MCAO increases the number
of NeuN-positive cells and reduces the number of CD11b-positive cells in
the peri-infarct area of the rat brain. These effects are accompanied by
decreased expression of inammatory factors, such as IL-6, IL-1β, TNF-
α
,
CD14, CD44, and iNOS [163]. Intraperitoneal injections of salidroside
(100 mg/kg) for 1 day after permanent MCAO (pMCAO) decrease the
cerebral infarct volume and neurological decit score in rats, and this
effect involves regulation of the PI3K/PKB and Nrf2/NF-κB signalling
pathways [164]. In an oxygen/glucose deprivation (OGD)-induced cell
model mimicking CIRI in rodents [165], salidroside was proven to
inhibit RIP140-mediated inammation and apoptosis [166]. Further-
more, salidroside signicantly increases the levels of CD46 and CD59
and decreases the levels of VCAM-1, ICAM-1, P-selectin and E-selectin in
human umbilical endothelial cells (HUVECs) after OGD and reperfusion
(OGD/R) [167].
Microglia are the main mediators of immune defence against cere-
bral ischaemic injury[168]. Activated microglia are mainly polarized
towards one of two phenotypes, i.e., the M1 and M2 phenotypes. M1 and
M2 microglia play different roles; M1 microglia trigger an inammatory
cascade by releasing inammatory factors, such as TNF-
α
, IL-1β, and
iNOS, and aggravate brain tissue damage [169], and M2 microglia
release anti-inammatory factors such as TGF-β, IL-10 and Arg-1 to
promote brain tissue repair [170–172]. Therefore, promoting the tran-
sition of activated microglia from the proinammatory M1 phenotype to
the anti-inammatory M2 phenotype is a potential strategy for the
treatment of ischaemic stroke. Evidence has shown that salidroside can
enhance microglial phagocytosis and suppress microglia-derived
Fig. 5. Neuroprotective effects of salidroside in the context of ischaemic stroke caused by stress stemming from the COVID-19 pandemic. COVID-19 may increase the
risk of ischaemic stroke. Salidroside exerts neuroprotective effects by inhibiting oxidative stress, inammation and apoptosis; maintaining mitochondrial function;
inhibiting mitochondrial alterations; and promoting dendritic and synaptic plasticity. The underlying mechanisms may involve the STAT-3, PI3K/NF-κB, PI3K/Akt,
cAMP/PKA/CREB, and Akt/GSK-3β signalling pathways. Thus, salidroside is a candidate agent for preventing brain injury caused by stress stemming from the
COVID-19 pandemic.
T. Zhu et al.
Biomedicine & Pharmacotherapy 170 (2024) 115999
11
inammatory cytokine release. Additionally, coculture of oligodendro-
cytes and salidroside-treated M1 microglia increases oligodendrocyte
differentiation. Moreover, salidroside protects neurons against OGD by
promoting M2 microglial polarization [173].
Inhibition of the NLRP3 inammasome can signicantly reduce the
degree of neurological decits and alleviate CIRI under ischaemic con-
ditions in vivo and in vitro [174]. The NLRP3 inammasome is acti-
vated, and the protein levels of ASC, Caspase-1, IL-1β, and IL-18 are
increased in BV2 cells subjected to OGD/R. However, treatment with
salidroside was shown to inhibit NLRP3 inammasome activation. Sal-
idroside also decreases the levels of proteins related to the TRL4 sig-
nalling pathway, such as TLR4, MyD88, and p-NF-κB p65/NF-κB p65
[43].
In summary, salidroside can ameliorate neurological decits, reduce
the infarct size and reverse oxidative stress and inammation, and these
effects are related to regulation of the STAT3 and PI3K/PKB/Nrf2/NF-κB
signalling pathways. Salidroside can also alleviate cerebral ischaemia by
promoting microglial polarization and inhibiting the NLRP3 inamma-
some (Fig. 5). Therefore, natural products targeting oxidative stress and
inammation are potential therapeutic agents for stroke.
5.2. Effect of salidroside on apoptosis
Bcl-2 family members and Caspase family members play a central
role in receiving, transmitting, and propagating apoptotic signals inside
and outside cells, as well as the execution of cell apoptosis [175–177].
Increasing evidence indicates that salidroside protects against CIRI in
vivo and in vitro. For instance, in rats, salidroside treatment reduces the
apoptosis rate of neurons in the hippocampal CA1 region. In addition,
salidroside increases the Bcl-2/Bax ratio and reduces the p53 protein
level [178].
Recent in vitro studies have shown that salidroside can increase cell
viability, ameliorate neuronal cell injury, and decrease the cell apoptosis
rate, possibly by regulating the BDNF-mediated PI3K/Akt apoptotic
pathway in a DNA-binding-dependent and DNA-binding-independent
manner [179]. Salidroside also increases cellular viability and de-
creases Caspase-3 levels and the rate of human brain vascular smooth
muscle cell (HBVSMC) apoptosis. Furthermore, salidroside elevates
SIRT1 and phosphorylated FOXO3
α
protein levels in HBVSMCs after
hypoxia/reoxygenation, suggesting that salidroside exerts neuro-
protective effects via the SIRT1/FOXO3
α
pathway [180].
In summary, salidroside exerts neuroprotective effects after CIRI by
alleviating neuronal apoptosis and inhibiting apoptotic signalling. These
studies offer insight into the mechanisms by which salidroside protects
against CIRI and identify salidroside as a potential candidate for treating
ischaemic stroke.
5.3. Effect of salidroside on mitochondrial quality control (MQC)
The MQC system is an endogenous self-regulation system in cells that
mainly involves mitochondrial biosynthesis, dynamics, autophagy, and
vesicles. The MQC system is an important endogenous mechanism for
maintaining mitochondrial homeostasis. Studies have shown that stra-
tegies targeting the MQC system can alleviate secondary injury and
promote rehabilitation after ischaemic stroke [181]. Salidroside allevi-
ates the OGD- or ischaemia-induced imbalance between mitochondrial
ssion and fusion, enhances mitophagy, promotes mitochondrial
biogenesis in neurons, and inhibits AMPK activity.
Furthermore, salidroside can maintain calcium homeostasis in neu-
rons, demonstrating that salidroside can effectively restore MQC
through the attenuation of AMPK signalling [158]. Salidroside also in-
hibits oxidative stress by reducing mitochondrial permeability and
mitochondrial damage, and it can promote the PINK1-Parkin signalling
pathway and mitophagy to eliminate damaged mitochondria [182].
Salidroside has also been reported to preserve mitochondrial
morphology and mitochondrial function. An in vitro study revealed that
salidroside plays a role in reducing neuronal death after OGD exposure
by maintaining mitochondrial function, providing evidence that sali-
droside can treat ischaemic stroke by inhibiting mitochondrial alter-
ations [183].
In summary, salidroside can maintain mitochondrial ssion and
fusion and mitophagy, promote mitochondrial biogenesis, reduce
apoptosis, and inhibit mitochondrial alterations by reducing mitophagy
and preserving mitochondrial morphology. These effects are related to
the attenuation of AMPK signalling.
5.4. Effect of salidroside on synaptic plasticity
Overproliferation of glial cells, especially the formation of the glial
scar, can affect the growth of neuronal axons and the reconstruction of
synapses and may even lead to the development of epilepsy-related
pathology [184]. Salidroside has been shown to improve long-term re-
covery, inhibit reactive astrocyte proliferation and ameliorate glial scar
formation, probably by restoring Akt/GSK-3β pathway activity [173].
Glial cells provide energy to neurons in a variety of ways, provide
raw materials for the synthesis of neurotransmitters, and prevent exci-
totoxicity caused by excessive glutamate diffusion, thus playing an
important role in maintaining the normal transmission of signals be-
tween synapses [185]. A previous study illustrated that salidroside
signicantly promotes dendritic and synaptic plasticity in PC12 cells
after OGD/R and in rats subjected to MCAO/R. The effects of salidroside
in promoting synaptic plasticity involve the FGF2-mediated cAMP/P-
KA/CREB pathway [159]. DA, a neurotransmitter, is only present in
DAergic nerve endings in the striatum. The content of DA in the brain
reects changes in the structure and function of DAergic neurons and is
widely used as a parameter in studies of brain injury [186]. Salidroside
has been found to ameliorate neurobehavioural impairment and in-
crease TH immunoreactivity in the SNpc, which may indicate improved
DAergic system function [187].
5.5. Summary
Salidroside has signicant antioxidant stress and anti-inammatory
effects. In addition, it can reduce the cerebral infarct volume in rats,
inhibit inammatory cytokine secretion, improve neurological function,
and exert neuroprotective effects (Table 1 and Fig. 5). Given the simi-
larities between the pathogenesis of COVID-19 and that of cerebral
ischaemia, research on the protective effects of salidroside against CIRI
and the related mechanism can provide a theoretical basis for the use of
salidroside in the treatment of stroke caused by stress stemming from the
COVID-19 pandemic.
6. Conclusions and remarks
In this work, we thoroughly reviewed the current evidence for the
neuroprotective effects of the natural product salidroside in the context
of different mental disorders, including anxiety, depression, AD, PD, and
brain injuries such as ischaemic stroke, and discuss the roles of sali-
droside in the prevention and treatment of psychiatric sequelae caused
by stress. Taken together, the results indicate that salidroside exerts
signicant effects in the regulation of the oxidative stress, neuro-
inammation, neural regeneration and cell apoptosis in the brain, the
network homeostasis of neurotransmission, HPA axis and the cholin-
ergic system, and the improvement of synaptic plasticity; and conrm
that this natural product can robustly prevent and alleviate mental
disorders and symptoms (Table 1). This demonstrates that salidroside
has great potential to mitigate psychiatric sequelae and brain injuries
resulting from multiple stressors, implying its potential applications in
the prevention and treatment of mental psychological distress and mood
symptoms that may stem from stress during the COVID-19 pandemic,
such as anxiety-depressive behaviours, cognitive decline, motor
impairment (fatigue and muscle weakness) and brain injury after
T. Zhu et al.
Biomedicine & Pharmacotherapy 170 (2024) 115999
12
recovery from COVID-19. The current evidence (Table 1) provides an
alternative to psychoactive substances for alleviating mental disorders,
and natural preventive compounds or functional foods may be benecial
for preventing psychiatric symptoms in the general population during
the COVID-19 pandemic.
While COVID-19 itself can lead to psychiatric sequelae and neuro-
logical damage, including PTSD, anxiety, depression, motor dysfunction
[1,12,18,19,22,188,189], cognitive impairment [10,134] and ischaemic
brain injury [16,135,152], related socioeconomic stressors and un-
healthy lifestyles may increase the risk of mental disorders [6,16,20,
188], such as anxiety, depression, PD, AD, and ischaemic stroke, in the
general population [3,22]. The current evidence suggests that salidro-
side can ameliorate the exacerbation of psychiatric sequelae and brain
injuries via multiple pathways and combat the negative effects of
stressors (Table 1 and Figs. 2–5); therefore, it may be developed as a
novel alternative agent for treating psychological distress and mood
symptoms associated with stress or sequalae stemmed for the COVID-19
pandemic. Furthermore, many mechanisms, including inammation,
oxidative stress, apoptosis, and glial scar formation, have been impli-
cated in stroke caused by stress stemming from the COVID-19 pandemic.
While the introduction of the COVID-19 vaccine has made people opti-
mistic about the treatment of psychiatric sequelae or potential brain
injuries related to COVID-19, the burden of COVID-19 is evident in daily
clinical practice. In the aspects of pharmacological activities and
mechanisms of molecular signalling pathway, these current evidences
show the excellent potential of salidroside in the addressing psychiatric
symptoms or brain injuries stemmed from stress; and it implies sali-
droside as a preventive or adjunctive treatment for the psychiatric
sequelae or symptoms that arose by multiple stress.
Compared to currently available psychotropic drugs [190], salidro-
side and other natural medical products have remarkable advantages.
Salidroside exhibits multiple pharmacological activities and exerts
synergistic effects on multiple molecular processes and signalling
pathways, thus contributing to preventing and treating diseases with
multifactorial and complex pathologies. Considering the prevalence of
psychiatric sequelae and mental disorders during the COVID-19
pandemic, the synergistic regulatory effects of salidroside via multiple
pathways provide an advantage in simultaneously alleviating multiple
symptoms of mental disorders with no side effects. In addition, given its
synergistic effects, salidroside is more suitable for widespread use in the
general population, signicantly reducing the health care burden and
decreasing the risk of mental health issues in the general population.
The present work provides sufcient experimental evidence and an
experimental basis for the application of salidroside as a novel adjunc-
tive psychoactive agent for the prevention and treatment of psychiatric
sequelae and brain injuries caused by stress stemming from the COVID-
19 pandemic. This work implies that it may be more suitable as a natural
compound for the adjunctive prevention and treatment of psychiatric
symptoms or sequalae stemmed from social stress than single-target
antipsychotic drugs. However, there have been few clinical trials on
the benecial effect of salidroside in the general population, and no
direct scientic data have been obtained for COVID-19 patients; there-
fore, the most effective clinical dose is unclear. Furthermore, while
salidroside-related oral formulations should be easily accessible, widely
available, and economical during the COVID-19 pandemic, there is
currently a lack of such formulations on the market. Future work is
urgently needed to conrm the effectiveness of salidroside in animal and
human trials and to develop salidroside-related oral formulations to
address the mental health crisis during the COVID-19 pandemic.
Funding
This work was funded by the National Natural Science Foundation of
China (No. 82101622, W. X.), the China Postdoctoral Science Founda-
tion (No. 2021M692118, W. X.), the Shanghai Super Postdoctoral
Incentive Program (No. 2020327, W. X.) and the Outstanding Clinical
Discipline Project of Shanghai Pudong (Grant No.: PWYgy2021–02). We
express our sincere gratitude to these foundations.
CRediT authorship contribution statement
Chen Shuai: Investigation, Writing – review & editing. Gao Shiman:
Data curation, Formal analysis. Jiang Ning: Conceptualization, Writing
– original draft. Xie Weijie: Conceptualization, Funding acquisition,
Writing – review & editing. Liu Hui: Writing – original draft. Zhu Ting:
Writing – original draft.
Declaration of Competing Interest
The authors declare that they have no known competing nancial
interests or personal relationships that could have appeared to inuence
the work reported in this paper.
Data availability
The data that supports the ndings of this study are available on
request from the corresponding author.
Acknowledgements
Not applicable.
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