AD is the most prevalent form of dementia (96, 97). To date, there are no efficient and safe therapies for preventing and curing AD due to an incomplete understanding of the pathogenesis (97–99). As both COVID-19 and the unhealthy lifestyles associated with governmental controls during the pandemic (100) as well as resultant social stresses (6, 100) cause severe oxidative damage and activation of inflammatory 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 (101–108). Recent studies have demonstrated that salidroside exerts neuroprotective effects by modulating oxidative stress responses, inflammation and apoptosis (55, 67, 109). 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 potential of salidroside as a widely applicable psychoactive substance for preventing cognitive impairment caused by stress stemming from the COVID-19 pandemic (Fig. 2).
Salidroside inhibits oxidative injury and cell apoptosis in the nervous system
In addition to genetic risk factors (APOE4) (97, 110), cognitive dysfunction and decline are associated with oxidative stress and inflammation in the brain resulting from consumption of a high-fatty acid diet or western diet (111), ageing (112), and chronic exposure to social stress (113, 114), which promote oxidative stress, reactive oxygen species (ROS) production, chronic low-grade inflammatory stress and microglial activation and neurodegeneration in the brain. Through its robust pharmacological activities (55, 67), salidroside exerts potent antioxidative 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 (53, 55, 67).
Oxygen deficiency, isoflurane exposure and cerebral hypoperfusion can induce cognitive impairment, robustly inhibit long-term potentiation (LTP) and increase hippocampal neuron loss (115–117), and salidroside significantly improves memory function (117, 118), ameliorates isoflurane-induced cognitive dysfunction (115), and improves hippocampal LTP (117) in hypoxemia/hypoperfusion-exposed rats. Furthermore, salidroside improves learning and spatial memory, increases the number of dendritic intersections and enhances arborization in rats exposed to hypoxia (116). Furthermore, excessive ROS production leads to severe oxidative damage within the cellular membrane, including damage to membrane lipids, proteins, and intranuclear DNA [7, 8]; impairs mitochondrial and synaptic function; and leads to cognitive impairment [4, 8]. Conversely, salidroside can significantly inhibit oxidative damage, increase the activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx) and the concentration of glutathione (GSH) in the hippocampus (118), increase the activity of choline acetyltransferase and the content of acetylcholine, decrease the concentrations of malondialdehyde (MDA) and nitrate (52, 118, 119), and increase the activity of acetylcholine esterase in the hippocampus (115). These effects further suppress Caspase-3 activation and increase the Bax/Bcl-2 ratio (117, 118, 120), contributing to a decrease in hippocampal neuron loss (117, 118) and the inhibition of oxidative damage and neural cell apoptosis (117, 118).
In addition, salidroside exerts antioxidative effects, thereby improving metabolism in the brain, promoting antioxidative pathways and alleviating neuroinflammation. Salidroside can promote insulin receptor (IR) signalling (116, 121), activate AMP-activated protein kinase (AMPK) (121, 122) by regulating the expression levels of AMPKα1 and AMPKα2 (116), and elevate the phosphorylation of cAMP response element-binding protein (CREB) in the hippocampus (121, 122), resulting 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 (116); increases the expression of SIRT1, nuclear factor E2-related factor 2 (Nrf-2), and HO-1 (116, 121, 122); and reduces the expression of the apoptotic proteins Bax, Bcl‐2, Caspase‐3, and Caspase‐9 (117, 122). Overall, these results (Fig. 2) reveal that salidroside exerts antioxidative and antiapoptotic effects to alleviate cognitive impairment and AD pathology and that the underlying 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.
Salidroside ameliorates neuroinflammation and cell damage
Activation of microglia and brain inflammation are prominent pathological features of AD (110, 123) and promote disease progression. Natural products and compounds (103, 106, 107, 124–126) that target these immune mechanisms are potential therapies or preventive agents for AD (98, 123, 127). Salidroside has been shown to exert neuroprotective effects, prevent cognitive impairment and halt AD progression by ameliorating inflammatory 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 neuroinflammation and cause learning and memory deficits in animal models of cognitive impairment (122, 128, 129) and AD (55, 118, 130). In contrast, salidroside treatment effectively ameliorates LPS-induced deficits in learning, memory and cognition (122, 128, 129) and significantly reduces the levels of proinflammatory cytokines (TNF-α, IL-1β and IL-6) in the serum, hippocampus, and cell supernatant in vivo and in vitro (122, 129, 131). Furthermore, it markedly decreases the levels of IL-1α, IL-6, IL-17 and IL-12 in the peripheral circulation (128), reduces the release of TNF-α and IL-1β in isoflurane-exposed rats (115), and downregulates the expression of IL‑6 and TNF‑α in APPswe/PS1ΔE9 mice (118).
Notably, salidroside significantly suppresses the expression of NF-κB p65 and IκBα (122) in a SIRT1-dependent manner, thus increasing SIRT1 activity and expression (122, 130) and inhibiting the NF‐κB (121, 122, 130) and SIRT1-NF‐κB pathways (130). Salidroside treatment also markedly inhibits the RhoA-ROCK1/2 pathway and decreases the levels of p-NF‐κB (p65), p-IκBα, p-IKKα and p-IKKβ, boosting neuroimmunity (129, 131). Further studies have shown that salidroside effectively attenuates microglial activation (109, 128) in SAMP8 mice and reduces the levels of proinflammatory factors in both the brain and the peripheral circulation (109, 128); these peripheral effects are associated with improvements 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 (109, 128). It has been demonstrated that salidroside exerts a protective effect against inflammation-induced cognitive dysfunction and AD.
In addition, D-galactose and cadmium have neurotoxic effects and aggravate cognitive impairment and AD progression. Salidroside inhibits cadmium toxicity in GL261 cells (119); reverses the abnormal changes in the levels of inflammatory cytokines, such as TNF-α, IL-1β, IL-18, and IL-6, oxidative stress and glial cell activation (130, 132, 133); and attenuates cognitive impairment and neuroinflammation caused by D-galactose and amyloid-β (Aβ) (130, 132, 133). Further studies have demonstrated that salidroside can ameliorate inflammation and neuronal damage by suppressing RIP1-driven inflammatory signalling and the Notch/HES-1 signalling axis in the brain, regulating TLR4/NF-κB and NLRP3/Caspase-1 signalling, and reducing inflammation-mediated pyroptosis in the brain. Salidroside can reverse the increase in the levels of TLR4-NF-κB/p-NF-κB pathway-related proteins, NLRP3-ASC-Caspase-1 pathway-related proteins and cleaved GSDMD (130, 132, 133); downregulate the expression of Bax, Bcl-2, Caspase-3 and Caspase-9; and inhibit neural cell pyroptosis and cell death (130, 132, 133). These results (Fig. 2) 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.
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 (134). Inhibiting β-secretase (BACE1) activity and reducing Aβ levels in the brain are efficacious strategies for preventing and treating AD (99, 135). As discussed above, salidroside not only alleviates cognitive impairment and hinders AD progression (123, 136–139) but also protects against Aβ accumulation and Aβ-induced neurotoxicity (116, 140–144) by exerting anti-inflammatory and antioxidative effects, thus contributing to the amelioration of AD pathology.
Both BACE1 and γ-secretase are required for the production of Aβ (99, 134, 145). Hypoxia can regulate secretase activity and expression and induce abnormal processing of amyloid precursor protein (APP) (116). Conversely, salidroside pretreatment significantly decreases the mRNA expression of BACE1, reduces the protein levels of BACE1 and HIF-1α, and promotes the secretion of sAPPα in hypoxia-exposed SH-SY5Y cells but has no effect on the APP level (116); salidroside also decreases Aβ levels and Aβ deposition in the brain (116, 140). Salidroside can attenuate hypoxia-induced abnormal processing of APP, inhibit BACE1 activity and Aβ generation (116), and alleviate Aβ40/42 aggregation and cytotoxicity (136, 146) through the HIF1α-BACE1 pathway without affecting γ-secretase activity (116, 140), allowing it to reduce Aβ levels.
Furthermore, salidroside can improve locomotor activity in a transgenic Drosophila model of AD, ameliorate Aβ-treated toxicity and reduce neuronal loss in the brain (140, 141) by promoting phosphatidylinositide 3-kinase (PI3K)/Akt signalling (141). Salidroside increases the levels of phosphorylated glycogen synthase kinase 3β (p-GSK-3β), decreases the level of p-Tau (140, 141), and regulates the APP and GSK-3β pathways (141, 142) to protect against Aβ-induced neurotoxicity and alleviate AD and other neurodegenerative diseases (Fig. 2).
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 (137–139), resulting in memory and learning impairment, cognitive decline and progression of AD (147, 148). 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 (116, 140–144).
First, salidroside significantly decreases Aβ-mediated intracellular ROS accumulation and MDA production (138, 144, 149); inhibits lactate dehydrogenase (LDH) release, morphological alterations, and neuronal DNA condensation (144); dose-dependently reverses the Aβ25–35-induced decrease in cell viability; prevents Aβ25–35-induced apoptosis (144); and improves the mitochondrial membrane potential and energy metabolism (137, 144). Thus, salidroside contributes to preventing Aβ-induced toxicity and decreasing antioxidant enzyme activity. Salidroside also exerts protective effects against Aβ-induced oxidative stress by inhibiting Aβ25–35-induced phosphorylation of c-Jun NH2-terminal kinase (JNK) and p38 MAPK (144) and alleviates Aβ-induced cell damage by increasing the expression of nicotinamide phosphoribosyltransferase (NAMPT) and the synthesis of NAD+ (137), boosting SIRT1 activity and protecting against AD progression (121, 122, 130).
Further studies have demonstrated that salidroside significantly repairs damaged synapses in APP/PS1 mice (51), enhances the survival and proliferation of PC-12 cells (139), reduces both Aβ levels and Aβ deposition (51, 140), and increases longevity and improves locomotor activity in Drosophila (140) and that the mechanisms underlying these effects are associated with promotion of the PI3K-Akt-mTOR signalling pathways (51, 140) and activation of the ERK1/2 and AKT pathways (139, 140). Moreover, salidroside increases the expression of PSD-95, NMDAR1, and calmodulin-dependent protein kinase II (51), resulting in significant improvements in synthesis and mitochondrial function (143, 144).
In addition, salidroside notably reverses NF-κB activation in Aβ1-40-injected rats; downregulates COX-2, iNOS and RAGE expression (52); and reduces the release of the inflammatory cytokines TNF-α, IL-1β, and IL-18 (122, 128, 133). Salidroside can reduce both Aβ accumulation and hyperphosphorylation of Tau, inhibit neuroinflammation caused by Aβ, and alleviate inflammasome-mediated pyroptosis (52, 122, 128, 133), and the mechanisms involve the TLR4/AKT, SIRT1-NFκB, and NLRP3/Caspase-1 inflammasome signalling pathways (Fig. 2).
Summary
Overall, the current evidence (Table 1 and Fig. 2) demonstrates that salidroside exerts powerful neuroprotective effects to prevent cognitive impairment and AD progression and plays an important role in regulating oxidative stress and neuroinflammation; 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 damage in the brain and alleviates neuroinflammation but also reduces Aβ production and aggregation and attenuates Aβ-induced neurotoxicity and cell death, thus ameliorating learning, memory and cognitive deficits. 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 potential 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 preventing AD include antioxidant and anti-inflammatory 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 (13, 132) during the COVID-19 pandemic (3, 6, 150).