Neuroprotective effects of Shenghui decoction via inhibition of the JNK/p38 MAPK signaling pathway in an AlCl3-induced zebrafish (Danio rerio) model of Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) is a multi-factorial degenerative disease, and multi-targeted therapies targeting multiple pathogenic mechanisms should be explored. Shenghui decoction (SHD) is an ancient traditional Chinese medicine (TCM) formula used clinically to alleviate AD. However, the precise mechanism of action of SHD as a therapeutic agent for AD remains unclear. AIM OF THE STUDY: This study investigated the neuroprotective properties and potential mechanisms of action of SHD in mitigating AD-like symptoms induced by AlCl3 in a zebrafish model. MATERIALS AND METHODS: Active components of SHD were detected using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Zebrafish were exposed to AlCl3 (200 µg/L) for 30 days to establish an AD zebrafish model. AlCl3-exposed zebrafish were treated with SHD or donepezil. Behavioral tests were used to assess learning and memory, locomotor activity, and AD-related anxiety and aggression in AlCl3-exposed zebrafish. Nissl staining and transmission electron microscopy were used to evaluate histological alterations in brain neurons. The concentrations of pro-inflammatory cytokines (tumor necrosis factor-α, TNF-α; interleukin-1ß, IL-1ß) were quantified using Enzyme-linked immunosorbent assay (ELISA). Markers of oxidative stress and cholinergic activity (acetylcholinesterase, AChE) were detected using biochemical assays. Western blotting and immunofluorescence were used to detect the protein expression levels of Aß, p-tau, PSD-95, synaptophysin, TLR4, phosphorylation of NF-κB p65, p38, and JNK. RESULTS: Fifteen SHD compounds were identified by UPLC-MS/MS analysis. SHD improved AlCl3-induced dyskinesia, learning and memory impairment, anxiety-like behavior, and aggressive behavior in zebrafish. AlCl3-exposed zebrafish showed AD-like pathology, overexpression of Aß, hyperphosphorylated tau protein, marked neuronal damage, decreased expression of synaptic proteins, synaptophysin, and PSD-95, and impairment of synaptic structural plasticity. These effects were reversed by the SHD treatment. We also observed that SHD ameliorated oxidative stress and decreased AChE activity and inflammatory cytokine levels. These effects are similar to those observed for donepezil. Meanwhile, SHD could decrease the protein expression of TLR4 and inhibit phosphorylation of NF-κB, JNK, and p38 MAPK. These results demonstrate that SHD has the potential to exert neuroprotective effects, which may be partly mediated via inhibition of the JNK/p38 MAPK signaling pathway. CONCLUSIONS: Our findings revealed the therapeutic mechanism of SHD in mitigating AD progression and suggested that SHD is a potent neuroprotectant that contributes to the future development of TCM modernization and broader clinical applications.

Ginsenoside Rg1 alleviates sleep deprivation-induced learning and memory impairment by inhibiting excessive neuronal apoptosis in zebrafish.

Sleep deprivation impairs learning and memory. The neuroprotective function of ginsenoside Rg1 (Rg1) has been reported. This study aimed to investigate the alleviative effect and underlying mechanism of action of Rg1 on learning and memory deficits induced by sleep deprivation. Using 72 h of LED light to establish sleep deprivation model and treatment with Rg1-L (0.5 mg/ml), Rg1-H (1 mg/ml), and melatonin (positive control, 0.25 mg/ml), we investigated the behavioral performance of sleep deprivation zebrafish through 24 h autonomous movement tracking, a novel tank diving test, and a T-maze test. Brain injuries and ultrastructural changes were observed, brain water content was measured, and apoptotic events were analyzed using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining. The oxidation-associated biomarkers superoxide dismutase, catalase, and glutathione peroxidase activity and lipid peroxidation product malondialdehyde content were detected. Real-time PCR and western blotting were performed to detect the levels of apoptotic molecules (Bax, caspase-3, and Bcl-2). Rg1-treatment was observed to improve the behavioral performance of sleep-deprivation fish, alleviate brain impairment, and increase oxidative stress-related enzyme activity. Rg1 can effectively exhibit neuroprotective functions and improve learning and memory impairments caused by sleep deprivation, which could be mediated by the Bcl-2/Bax/caspase-3 apoptotic signaling pathway (see Supplementary Video Abstract, Supplemental digital content, http://links.lww.com/WNR/A702 which demonstrates our research objectives, introduction overview of Rg1, and main direction of future research).

A systematic review of the efficacy of donepezil hydrochloride combined with nimodipine on treating vascular dementia.

BACKGROUND: Vascular dementia (VaD) is a comprehensive syndrome related to the damage of cognitive function and various cerebral vascular illnesses. VaD is also generally recognized as the second most common type of dementia after Alzheimer disease, contributing to 30% of the dementia population in Asia and developing countries. The ability of donepezil hydrochloride and nimodipine had been respectively proven in improving cognitive function in vascular dementia. However, whether the combined application of both drugs contribute to better efficacy remains as a research hotspot. Studies had shown definite satisfactory result with such combination, however evidence-based evaluation of the efficacy is still lacking. Therefore, meta-analysis is employed in this study to evaluate the efficacy and safety of using donepezil hydrochloride combined with nimodipine in treating VaD to provide references for clinical treatments. The efficacy of donepezil hydrochloride combined with nimodipine on treating vascular dementia is systematically reviewed to provide evidence-based references for clinical applications. METHODS: Both Chinese and English databases were searched from the start till August, 2020 for any RCT regarding the combined use of the 2 drugs in treating vascular dementia. Two investigators would later evaluate and screened out research and data based on an improved Jaded scale. Software Rev Man 5.3.0 was employed to carry out meta-analysis on clinical effificacy, mini-mental state examination (MMSE) ratings, activity of daily living (ADL) ratings, and clinical dementia scale (CDR) ratings. RESULTS: Donepezil hydrochloride combined with nimodipine had demonstrated satisfactory efficacy on the treatment of vascular dementia. Improvements were namely spotted on MMSE scale, ADL scale, and CDR scale, with the utmost efficacy by 12 weeks after intervention. CONCLUSIONS: Donepezil hydrochloride combined with nimodipine had good efficacy in the treatment of patients with vascular dementia, mainly in terms of improving the Simple MMSE scores, the ability to use daily living scale (ADL) scores and the CDR, and the best results were obtained after 12 weeks of intervention. Such conclusion should be cautiously evaluated.