Table 1.
Summary of the neuropharmacological effects of salidroside
| Effect | Inducer | Functions | Dose | Animal/cell line | In vivo/in vitro | Regimen duration | Control |
|---|---|---|---|---|---|---|---|
| Anti-AD | Aβ1–42 | ↑: Antioxidant pathway | 1, 5, 10, and 50 μg/mL | PC12 cells | In vitro | 3 h | Vitamin E38 |
| Aβ25–35 | ↓: Oxidative stress, apoptosis | 10, 50, and 100 μM | SH-SY5Y cells | In vitro | 24 h | N/A39 | |
| Aβ | ↑: PI3K/Akt/mTOR signaling ↓: Aβ |
5, 100, and 200 μM | Primary neurons | In vitro | 24 h | Aricept40 | |
| Transgenes | ↑: Life span, locomotor activity, p-GSK-3β ↓: p-Tau |
2, 6, and 20 μM | Drosophila | In vivo | 40 days | Aricept40,41 | |
| STZ | ↑: Neurogenesis ↓: Oxidative stress, cellular activities |
1 mM | NSCs | In vitro | 12 h | Catalase42 | |
| d-galactose | ↓: Cognitive impairment, inflammation, SIRT1/NF-κB signaling | 20 and 40 mg/kg (PO) | SD rats | In vivo | 28 days | N/A43 | |
| Glutamate | ↓: Glutamate excitotoxic damage, Ca2+, calcium stores | 10−7, 10−6, and 10−5 mol/L | PC12 cells | In vitro | 24 h | N/A20 | |
| Glutamate | ↑: Akt pathway ↓: Apoptosis |
120 and 240 μM | Primary neurons | In vitro | 24 h | MADP44 | |
| H2O2 | ↑: Bcl-2 family ↓: Apoptosis, cyt c release |
1, 10, and 100 μM | PC12 cells | In vitro | 6, 9, or 12 h | N/A45 | |
| Hypoxia | ↓: Abnormal APP, BACE1 | 200 μM | SH-SY5Y cells | In vitro | 1 h | β-Secretase (inhibitor)46 | |
| Anti-PD | MPP+ | ↓: Apoptosis, ROS-NO-related mitochondrial pathway | 10, 50, and 100 μM | PC12 cells | In vitro | 24 h | L-NMMA29,50 |
| MPP+ | ↑: PI3K/Akt pathway ↓: Apoptosis |
1, 10, and 30 μM | PC12 cells | In vitro | 24 h | NGF, LY294002 (inhibitor)51 | |
| MPP+ | ↑: DJ-1-Nrf2-antioxidant pathway | 25, 50, and 100 μM | SH-SY5Y cells | In vitro | 24 h | N/A53 | |
| MPTP | ↑: PI3K/Akt/GSK3β signaling pathway ↓: Behavioral impairments, apoptosis, ROS-NO- related mitochondrial pathway |
15 and 45 mg/kg (IP) | C57BL/6 mice | In vivo | 7 days | N/A29,52 | |
| None | ↑: Dopaminergic neurons | 100 μg/mL | MSCs | In vitro | 1–12 days | Retinoic acid54 | |
| 6-OHDA | ↓: Endoplasmic reticulum stress | 25 μmol/L | SN4741 cells, primary neurons | In vitro | 10 h | 4-PBA55 | |
| Anti-stroke | 4VO | ↓: Cognitive impairment, cerebral edema degree, free radical abnormity | 12 mg/kg (IP) | SD rats | In vivo | 7 days | N/A60 |
| MCAO | ↓: Blood brain barrier, TNF-α | 24 mg/kg (IP) | SD rats | In vivo | 7 days | N/A61 | |
| MCAO | ↓: Infarct area, neurological deficit | 12 mg/kg (caudal vein) | SD rats | In vivo | 7 days | Tyrosol galactoside62 | |
| MCAO | ↑: Neuroplasticity-related genes ↓: Infarction, neurological deficit, Bax/Bcl-xl- related apoptosis, complement drives (Egrs) |
50 mg/kg (IP) | SD rats | In vivo | 1, 2, and 6 days | C3aRA (antagonist)28,64 | |
| MCAO | ↑: Nrf2 pathway ↓: Infarct area, neurological deficit, oxidative stress |
30 mg/kg (IP) | SD rats | In vivo | 1 day (twice) | N/A63 | |
| MCAO | ↓: Cerebral infarction, cerebral edema, inflammation, apoptosis | 20 and 40 mg/kg (PO) | SD rats | In vivo | 1 day | Clopidogrel65 | |
| I/R injury | ↓: Inflammation, apoptosis | 5, 10, and 20 μM | SH-SY5Y cells | In vitro | 6 h | Clopidogrel65 | |
| H2O2 | ↓: Apoptosis, oxidative stress | 100 μM | Primary neurons | In vitro | 24 h | Tyrosol galactoside62 | |
| CoCl | ↑: Neuroplasticity-related genes ↓: Bax/Bcl-xl-related apoptosis |
10 μM | PC12 cells | In vitro | 48 h | Egr4-targeted siRNA28 | |
| CoCl | ↓: Hypoxia damage, REDD1/mTOR/p70S6K signaling repression | 90 μM | PC12 cells | In vitro | 12 h | RAD001 (blocker)66 | |
| CoCl2 | ↑: HIF-1α ↓: Apoptosis, ROS, NF-κB |
120, 240, and 480 μM | Primary neurons | In vitro | 24 h | R59949 (inhibitor)67 | |
| LPS | ↓: Migration, NF-κB, and MAPK signaling | 75, 150, and 300 μM | BV2 cells | In vitro | 12 h | N/A68 | |
| Hypoglycemia, serum limitation | ↑: MMP ↓: Apoptosis, ROS |
2–320 μg/mL | PC12 cells | In vitro | 24 h | Adenosine, salidroside analogs69–71 | |
| Cognition enhancement | Hypoxia | ↑: Cognitive, mitochondrial biogenesis, pIRA and SIRT1 synergy | 25 mg/kg (PO) | SD rats | In vivo | 22 days | Disulfiram (antagonist)18 |
| Hypoxia, transgenes | ↑: Mitochondrial biogenesis, pIRA, and SIRTA synergy | 1.5 mM | Primary neurons | In vitro | 48 h | U0126 and GSK2110183 (antagonist) EX527 (inhibitor)18 |
|
| 2-VO | ↓: Cognitive impairment, apoptosis | 20 mg/kg (IP) | SD rats | In vivo | 34 days | N/A75 | |
| Old mice, transgenes | ↑: Learning and memory performance, plasticity, neurogenesis via CREB | 5 mg/kg (IV) | C57BL/6J mice | In vivo | 5 days | N/A76 | |
| None | ↑: Differentiation, proliferation | 1 μM | NSCs | In vitro | 1, 3, 4, and 8 days | N/A76 | |
| Collagen | ↓: Arthritic lesions, cognitive deficits, Rho/ROCK/NF-κB pathway | 20 and 40 mg/kg (PO) | SD rats | In vivo | 14 days | Leflunomide19 | |
| Isoflurane | ↓: Cognitive impairment, inflammatory response, oxidative stress, cholinergic system dysfunction | 60, 120, and 180 mg/kg (PO) | SD rats | In vivo | 6.5 h, 2 days | N/A77 | |
| Aβ1–40 | ↓: Cognitive deficits, oxidative stress, inflammatory mediators | 25, 50, and 75 mg/kg (PO) | SD rats | In vivo | 21 days | Huperzine A78 | |
| d-galactose | ↓: Cognitive impairment, neuroinflammation, apoptosis | 20 and 40 mg/kg (PO) | SD rats | In vivo | 28 days | N/A79 | |
| Antidepressive and anxiolytic effects | Olfactory bulbectomy | ↓: Anti-inflammatory action, glucocorticoid receptor ↓: Depressive-like behaviors, HPA axis activity |
20 and 40 mg/kg (PO) | SD rat | In vivo | 14 days | Amitriptyline26 |
| LPS | ↑: Neurotransmitters, BDNF/TrkB signaling pathway ↓: Depression-like behavior, inflammatory response |
12 and 24 mg/kg (IG) | ICR mice | In vivo | 5 days | Fluoxetine85 | |
| EPM test, OFT, TST | ↓: Anxiety-like and depression-like behavior | 25 mg/kg (IP) | C57B1/6J WT mice | In vivo | 1 day | N/A86 | |
| Ameliorating TBI | Contusion | ↑: Long-term functional recovery, histological outcomes, PI3K/Akt survival signaling ↓: Apoptosis, brain edema |
20 and 50 mg/kg (IP) | C57BL/6 mice | In vivo | 1, 3, and 28 days | LY294002 (inhibitor)22 |
| Stretch | ↑: Viability (%) | 0.1, 1, 10, 20, 50 μM | Primary neurons | In vitro | 24 h | N/A22 | |
| None | ↑: Differentiation, BMP signaling ↓: Proliferation, Notch1 signaling |
5, 25, 50, and 100 μg/mL | D1 cells | In vitro | 12–72 h | DAPT, Noggin (antagonist)87 | |
| Anti-HD | Transgenes, paraquat | ↓: Neuronal death, behavioral dysfunction, oxidative stress | 50, 100, and 200 μM | Caenorhabditis elegans | In vivo | 0–120 h | EGCG24 |
| Anti-addiction | Nicotine, CPP | ↓: Withdrawal syndrome, rewarding properties, relapse | 0.2 mg/kg (IG) | CD-1 mice | In vivo | 60 min before sessions | Rhodiola rosea L. extract23 |
| Anti-epileptic | Kainic acid | ↑: Latency, AMPK/SIRT1/FoxO1 pathway ↓: Incidence, oxidative stress |
25 and 50 mg/kg (IP) | C57BL/6 mice | In vivo | 75 min–2 days | Sirtinol (inhibitor)31 |
Notes: Upward arrows (↑) denote increase, upregulation, or activation; downward arrows (↓) denote decrease, downregulation, or suppression.
Abbreviations: 4-PBA, 4-phenylbutyrate; 4VO, 4-vessel occlusion; 6-OHDA, 6-hydroxydopamine; AD, Alzheimer’s disease; AMPK, AMP-activated protein kinase; APP, amyloid precursor protein; Aβ, beta-amyloid; BACE, β-site APP cleaving enzyme; BDNF, brain-derived neurotrophic factor; CREB, cAMP response element binding protein; CPP, conditioned place preference; cyt c, cytochrome c; DAPT, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester; EGCG, epigallocatechin gallate; EPM, elevated plus maze; HD, Huntington’s disease; HIF-1α, hypoxia-inducible factor-1α; HPA, hypothalamus-pituitary-adrenal; ICR, Institute of Cancer Research; IG, intragastrically; IP, intraperitoneally; I/R, ischemia–reperfusion; IV, intravenous; LPS, lipopolysaccharide; MADP, N-((2R,3R,4R,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2-(4-methoxyphenethoxy)tetrahydro-2H-pyran-3-yl)acetamide; MCAO, middle cerebral artery occlusion; MMP, mitochondrial membrane potential; MPTP, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine; MSCs, mesenchymal stem cells; mTOR, mammalian target of rapamycin; N/A, not available/applicable; NF-κB, nuclear factor kappa B; Nrf2, nuclear factor erythroid 2-related factor 2; NSCs, neural stem cells; OFT, open field test; PO, per os; PD, Parkinson’s disease; pIRA, phosphorylation of insulin receptor subunit A; REDD1, regulated in development and DNA damage response 1; ROS, reactive oxygen species; SD, Sprague-Dawley; STZ, streptozocin; TBI, traumatic brain injury; TH, tyrosine hydroxylase; TNF-α, tumor necrosis factor-α; TrκB, tropomyosin-related kinase B; TST, tail suspension test; WT, wild type.