The salidroside content contributes significantly to Rhodiola's properties and is the main active bioactive component in Rhodiola Rosea. A number of studies have revealed that salidroside exhibits neuroprotective activities including anti-Alzheimer's disease, anti-Parkinson's disease, anti-Huntington's disease, anti-stroke, anti-depressive effects, and anti-traumatic brain injury; it is also useful for improving cognitive function, treating addiction, and preventing epilepsy. The underlying mechanisms of these potential protective effects associated with salidroside are the regulation of oxidative stress response, inflammation, apoptosis, the hypothalamus-pituitary-adrenal axis, neurotransmission, neural regeneration, and cholinergic systems. Being free from side effects makes salidroside potentially attractive as a candidate drug for the treatment of neurological diseases. The existing published literature demonstrates that salidroside has potential use as a beneficial therapeutic drug with high efficacy and low toxicity to the central nervous system. An in vitro study in Aβ1–42-induced AD PC12 cell lines determined that salidroside reduced cytotoxicity, decreased reactive oxygen species (ROS) accumulation, and reduced intracellular malondialdehyde by activating antioxidant enzymes in a dose-dependent manner after 3 hours of salidroside pre-incubation (1, 5, 10, and 50 mg/mL). Furthermore, pretreatment with salidroside (10, 50, and 100 μM) was shown to significantly inhibit oxidative stress and apoptosis in Aβ25-35-induced SH-SY5Y cells in a concentration-dependent manner by increasing antioxidant enzyme activities, regulating apoptosis-related protein expression, and repairing abnormalities in mitochondrial membrane potential (MMP) and ROS production in vitro. In addition, salidroside (5, 100, and 200 μM) was found to reduce Aβ levels in primary neurons incubated with Aβ1–42 via the PI3K/Akt/mTOR signaling pathway. Salidroside (2, 6, and 20 μM) improved both the longevity and locomotor activity of Tao transgenic Drosophila in a dose-dependent manner. These studies revealed that the protective effects of salidroside resulted from the upregulation of total p-GSK3β and the downregulation of p-tau.

In a recent study, Gao et al. demonstrated that salidroside (20 and 40 mg/kg) administered once daily for 28 days improved d-galactose-induced cognitive deficits in rats. The mechanism involved in this effect has been reported to be closely related to anti-neuroinflammation and apoptosis factors via the SIRT1/NF-κB pathway, although mediated by inflammatory cytokine levels and apoptosis. Furthermore, salidroside at doses of 10−7, 10−6, and 10−5 mol/L inhibited excessive Ca2+ increase and calcium store release in PC12 cells caused by glutamate excitotoxic damage. A further study reported that salidroside (120 and 240 µM) protected primary hippocampal neurons against glutamate-induced apoptosis in vitro by inducing p-Akt. Another study reported that salidroside (1-100 μM) regulated MMP, suppressed the release of mitochondrial cytosolic cytoplasm (CCP), and attenuated caspase activation via an apoptosis pathway in H2O2-induced PC12 cells. Specifically, salidroside (200 μM) effectively suppressed BACE1 expression, Aβ production, and β-secretase activity, and triggered the release of soluble amyloid precursor protein in hypoxia-induced SH-SY5Y cells, suggesting that salidroside may be useful in the prevention and treatment of AD.

PUBLICATIONS ON THE SUBJECT:

**Aging Dis. 2019 Feb 1;10(1):134-146.doi:10.14336/AD.2018.0511.eCollection 2019 Feb.

Rosenroot (Rhodiola): Potential Applications in Aging-related Diseases

** PLoS One. 2012;7(1):e29641.doi: 10.1371/journal.pone.0029641. Epub 2012 Jan 3.

Protective effects of a Rhodiola crenulata extract and salidroside on hippocampal neurogenesis against streptozotocin-induced neural injury in the rat

**Front Pharmacol. 2021 Nov 5;12:736198.doi: 10.3389/fphar.2021.736198. eCollection 2021.

Preclinical Evidence and Possible Mechanisms of Rhodiola rosea L. and Its Components for Ischemic Stroke: A Systematic Review and Meta-Analysis

** Drug Des Devel Ther. 2018 May 24;12:1479-1489.doi: 10.2147/DDDT.S160776.

Pharmacological activities, mechanisms of action, and safety of salidroside in the central nervous system

** Front Aging Neurosci. 2022 Jan 21;13:809433.doi: 10.3389/fnagi.2021.809433. eCollection 2021.

Salidroside Ameliorates Alzheimer's Disease by Targeting NLRP3 Inflammasome-Mediated Pyroptosis

** Chin Med. 2022 Jul 4;17(1):82.doi: 10.1186/s13020-022-00634-3.

Salidroside attenuates neuronal ferroptosis by activating the Nrf2/HO1 signaling pathway in Aβ1-42-induced Alzheimer's disease mice and glutamate-injured HT22 cells

**Cell Biosci. 2022 Nov 4;12(1):180.doi: 10.1186/s13578-022-00918-z.

Salidroside reduces neuropathology in Alzheimer's disease models by targeting NRF2/SIRT3 pathway