Two new compounds isolated from the aerial parts of gastrodia elata blume.

Two new aromatic compounds, namely gastupdin A (1), and gastupdin B (2), together with three known compounds, arundin(3), phomosines B (4) and monocillin IV (5), were isolated from the aerial parts of Gastrodia elata Blume. The structures of the new compounds were confirmed through spectral analyses including NMR, HR-ESI-MS, ECD, UV, and IR. All isolated compounds were evaluated for their neuroprotective effects against 6-hydroxydopamine-induced cell death in Human Neuroblastoma Cells, with curcumin as the positive control, however, the activity of all compounds was weaker than the positive control, showing no significant activity.

New alkylamides from the pericarps of Zanthoxylum schinifolium.

The pericarps of Zanthoxylum schinifolium Sieb. et Zucc were called "green huajiao", which were used as traditional folk medicine and popular seasoning in China. In this study, twenty-seven alkylamides, including a rare alkylamide containing two amide groups (1), an alkylamide with a furan ring (5), six new alkylamide analogues (2-4, 6-8), together with nineteen known alkylamides (9-27) were isolated from green huajiao. Their structures were elucidated by extensive spectroscopic analysis, including 1D, 2D NMR, HRESIMS, and UV spectra. Furthermore, compounds 5, 18, 21, and 22 exhibited weak protective activity for corticosterone-induced PC12 cells damage.

Tailored Melatonin- and Donepezil-Based Hybrids Targeting Pathognomonic Changes in Alzheimer's Disease: An In Vitro and In Vivo Investigation.

A plethora of pathophysiological events have been shown to play a synergistic role in neurodegeneration, revealing multiple potential targets for the pharmacological modulation of Alzheimer's disease (AD). In continuation to our previous work on new indole- and/or donepezil-based hybrids as neuroprotective agents, the present study reports on the beneficial effects of lead compounds of the series on key pathognomonic features of AD in both cellular and in vivo models. An enzyme-linked immunosorbent assay (ELISA) was used to evaluate the anti-fibrillogenic properties of 15 selected derivatives and identify quantitative changes in the formation of neurotoxic ß-amyloid (Aß42) species in human neuronal cells in response to treatment. Among the most promising compounds were 3a and 3c, which have recently shown excellent antioxidant and anticholinesterase activities, and, therefore, have been subjected to further in vivo investigation in mice. An acute toxicity study was performed after intraperitoneal (i.p.) administration of both compounds, and 1/10 of the LD50 (35 mg/kg) was selected for subacute treatment (14 days) with scopolamine in mice. Donepezil (DNPZ) and/or galantamine (GAL) were used as reference drugs, aiming to establish any pharmacological superiority of the multifaceted approach in battling hallmark features of neurodegeneration. Our promising results give first insights into emerging disease-modifying strategies to combine multiple synergistic activities in a single molecule.

Design, synthesis and biological evaluation of 1-aryldonepezil analogues as anti-Alzheimer's disease agents.

Aim: To design and synthesize a novel series of 1-aryldonepezil analogues. Materials & methods: The 1-aryldonepezil analogues were synthesized through palladium/PCy3-catalyzed Suzuki reaction and were evaluated for cholinesterase inhibitory activities and neuroprotective effects. In silico docking of the most effective compound was conducted. Results: The 4-tert-butylphenyl analogue exhibited good inhibitory potency against acetylcholinesterase and butyrylcholinesterase and had a favorable neuroprotective effect on H2O2-induced SH-SY5Y cell injury. Conclusion: The 4-tert-butylphenyl derivative is a promising lead compound for anti-Alzheimer's disease drug development.

[Box: see text].

From Epimedium to Neuroprotection: Exploring the Potential of Wushanicaritin.

Epimedium has been used for functional foods with many beneficial functions to human health. Wushanicaritin is one of the most important chemicals int Epimedium. This study investigated the neuroprotective effects of wushanicaritin and potential underlying mechanisms. The results demonstrated that wushanicaritin possessed superior intercellular antioxidant activity compared to icaritin. Wushanicaritin, with an EC50 value of 3.87 µM, showed better neuroprotective effect than quercetin, a promising neuroprotection agent. Wushanicaritin significantly reversed lactate dehydrogenase release, reactive oxygen species generation, cell apoptosis, and mRNA expression related to cell apoptosis and oxidative defense, in glutamate-induced PC-12 cells. Wushanicaritin could also maintain the enzymatic antioxidant defense system and mitochondrial function. The suppression of caspase-3 activation and amelioration of mitochondrial membrane potential loss and nucleus morphology changes were involved in the antiapoptotic effect of wushanicaritin. These findings suggested that wushanicaritin possesses excellent intercellular antioxidant and neuroprotective activities, showing potential promise in functional foods.

Profiling and optimized extraction of bioactive polyphenolic compounds from young, red-fleshed apple using eco-friendly deep eutectic solvents.

Red-fleshed apple cultivars with an enhanced content of polyphenolic compounds have attracted increasing interest due to their promising health benefits. Here, we have analysed the polyphenolic content of young, red-fleshed apples (RFA) and optimised extraction conditions of phenolics by utilising natural deep eutectic solvents (NDES). We also compare the antioxidant, neuroprotective and antimicrobial activities of NDES- and methanol-extracted phenolics from young RFA. High-performance liquid chromatography coupled to high-resolution mass spectrometry (HPLC-HRMS) was used for phenolics identification and quantification. Besides young RFA, ripe red-fleshed, young and ripe white-fleshed apples were analysed, revealing that young RFA possess the highest phenolic content (2078.4 ± 4.0 mg gallic acid equivalent/100 g), and that ripe white-fleshed apples contain the least amount of phenolics (545.0 ± 32.0 mg gallic acid equivalent/100 g). The NDES choline chloride-glycerol containing 40 % w/w H2O gave similar yields at 40 °C as methanol. In addition, the polyphenolics profile, and bioactivities of the NDES extract from young RFA were comparable that of methanol extracts. Altogether, our data show that NDES extracts of young RFA are a promising source of bioactive polyphenolics with potential applications in diverse sectors, e.g., for functional food production, smart material engineering and natural therapies.

Highly oxidized guaiane 12(8),15(6)-dilactones with neuroprotective activities from the roots of Lindera aggregata (Sims) Kosterm.

In our search for neuroprotective agents, six previously undescribed highly oxidized guaiane sesquiterpenes, linderaggrols A-F (1-6), together with three known sesquiterpenes, were isolated from the roots of Lindera aggregata (Sims) Kosterm. Their structures including absolute configurations were established by a combination of NMR spectroscopic techniques and single crystal X-ray diffraction experiments. Compounds 1-6 represented the first instances of guaiane 12(8),15(6)-dilactones. Additionally, compound 6 possessed a rare 1,8-O-bridge. Neuroprotective effects against erastin-induced ferroptosis on HT-22 cells showed that some compounds demonstrated neuroprotective effects at 20.0 µM.

Chemical Constituents of the Fruits of Cornus Officinalis and Evaluation of their Neuroprotective Activity.

The phytochemical investigation of the fruits of Cornus officinalis yielded a new phenolic acid derivative, neophenolic acid A (1), and a novel flavonoid glycoside, (2R)-naringenin-7-O-ß-(6''-galloyl-glucopyranoside) (2 a), along with six known flavonoid glycosides (2 b-7). Their structures were determined by 1D, 2D NMR and HRESIMS data. The absolute configuration of 1 was established by ECD analysis. Compounds 1- 7 were evaluated for their neuroprotective activities against corticosterone (CORT)-induced injury in PC-12 cells. Compounds 1, 2 a, 2 b, 5, and 6 exhibited neuroprotective activities against CORT-induced neurotoxicity in PC-12 cells. The underlying mechanism study suggested that compounds 1, 2 a, 2 b, 5, and 6 were able to attenuate CORT-induced apoptosis and damage, increase the levels of MMP and decrease Ca2+ inward flow in PC-12 cells.

UHPLC-MS/MS analysis and protective effects on neurodegenerative diseases of phenolic compounds in different parts of Diospyros kaki L. cv. Mopan.

Persimmon (Diospyros kaki L. cv. Mopan.), an important commercial crop belonging to the genus of Diospyros in the Ebenaceae family, is rich in bioactive phenolic compounds. In this study, the phenolic compounds from fruits, leaves, and calyces of persimmon were qualitatively and quantitatively determined by UPLC-Q-Exactive-Orbitrap/MS and UPLC-QqQ-MS/MS, respectively. Furthermore, the role of phenolic extract from different parts of persimmon on neuroprotective activity in vitro, through against oxidative stress and anti-neuroinflammation effect was firstly evaluated. The results showed that 75 phenolic compounds, and 3 other kinds of compounds were identified, among which 44 of phenolic compounds were quantified from different parts of persimmon. It is the first time that epicatechin-epigallocatechin, catechin-epigallocatechin, catechin-epigallocatechin (A-type), and glycoside derivatives of laricitrin were identified in persimmon extract. The dominated phenolic compounds in three parts of persimmon were significantly different. All phenolic extracts from each part of persimmon showed strong neuroprotective activities against H2O2-induced oxidative stress in PC-12 cells and LPS-induced BV2 cells. The fruit extract presented the strongest activity, followed by calyx and leaf extract. The systematic knowledge on the phytochemical composition along with activity evaluation of different parts of persimmon could contribute to their targeted selection and development.

Flavonoid-Rich Trianthema decandra Ameliorates Cognitive Dysfunction in the Hyperglycemic Rats.

The present study was aimed at the evaluation of neuroprotective ability of methanolic extract of Trianthema decandra (METD) against hyperglycemia-related cognitive impairment in rats. The extract of T. decandra was standardized by TLC and HPTLC methods. To verify the identity and purity of isolated compounds, they were segregated and characterized using various techniques, including UV-visible spectrophotometry, FT-IR, H-NMR, and Mass spectroscopy. α-Amylase and α-glucosidase inhibition property of the extracts were assessed in-vitro. The screening of the neuroprotective effects of METD in hyperglycemic rats was done utilizing Morri's water (MWM) and elevated plus maze (EPM) model, as well as acetylcholinesterase (AChE) activity. The extracts of Trianthema decandra and its chemical constituents, namely quercetin and phytol, demonstrated a significant protective effect on enzymes like α-amylase and α-glucosidase. Methanol and hydroalcoholic extracts have shown the strongest inhibitory activity followed by chloroform extract. Quercetin and phytol were associated with the methanolic and chloroform extracts which were identified using TLC and HPTLC techniques. During the thirty days of the study, the induction of diabetes in the rats exhibited persistent hyperglycemia, hyperlipidemia, higher escape latency during training trials and reduced time spent in target quadrant in probe trial in Morris water maze test, and increased escape latency in EPM task. Regimen of METD (200 and 400 mg/kg) in the diabetic rats reduced the glucose levels in blood, lipid, and liver profile and showed positive results on Morri's water and elevated plus maze tasks. During the investigation, it was determined that Trianthema decandra extracts and the chemical constituent's quercetin and phytol in it had anti-diabetic and neuroprotective activities.

Lathyrane and premyrsinane Euphorbia diterpenes against Alzheimer's disease: Bioinspired synthesis, anti-cholinesterase and neuroprotection bioactivity.

The first systematic acylated diversification of naturally scarce premyrsinane diterpenes, together with their biosynthetic precursors lathyrane diterpene were carried out. Two new series of premyrsinane derivates (1a-32a) and lathyrane derivates (1-32) were synthesized from the naturally abundant lathyrane diterpene Euphorbia factor L3 through a bioinspired approach. The cholinesterase inhibitory and neuroprotective activities of these diterpenes were investigated to explore potential anti-Alzheimer's disease (AD) bioactive lead compounds. In general, the lathyrane diterpenes showed the better acetylcholinesterase (AChE) inhibitory activity than that of premyrsinanes. The lathyrane derivative 17 bearing a 3-dimethylaminobenzoyl moiety showed the best AChE inhibition effect with the IC50 value of 7.1 µM. Molecular docking demonstrated that 17 could bond with AChE well (-8 kal/mol). On the other hand, premyrsinanes showed a better neuroprotection profile against H2O2-induced injury in SH-SY5Y cells. Among them, the premyrsinane diterpene 16a had significant neuroprotective effect with the cell viability rate of 113.5 % at 12.5 µM (the model group with 51.2 %). The immunofluorescence, western blot and reactive oxygen species (ROS) analysis were conducted to demonstrate the mechanism of 16a. Furthermore, a preliminary SAR analysis of the two categories of diterpenes was performed to provide the insights for anti-AD drug development.

Polyphenols from Maackia amurensis Heartwood Protect Neuronal Cells from Oxidative Stress and Prevent Herpetic Infection.

Here, we continued the investigation of anti-HSV-1 activity and neuroprotective potential of 14 polyphenolic compounds isolated from Maackia amurensis heartwood. We determined the absolute configurations of asymmetric centers in scirpusin A (13) and maackiazin (10) as 7R,8R and 1″S,2″S, respectively. We showed that dimeric stilbens maackin (9) and scirpusin A (13) possessed the highest anti-HSV-1 activity among polyphenols 1-14. We also studied the effect of polyphenols 9 and 13 on the early stages of HSV-1 infection. Direct interaction with the virus (virucidal activity) was the main mechanism of the antiviral activity of these compounds. The neuroprotective potential of polyphenolic compounds from M. amurensis was studied using models of 6-hydroxydopamine (6-OHDA)-and paraquat (PQ)-induced neurotoxicity. A dimeric stilbene scirpusin A (13) and a flavonoid liquiritigenin (6) were shown to be the most active compounds among the tested polyphenols. These compounds significantly increased the viability of 6-OHDA-and PQ-treated Neuro-2a cells, elevated mitochondrial membrane potential and reduced the intracellular ROS level. We also found that scirpusin A (13), liquiritigenin (6) and retusin (3) considerably increased the percentage of live Neuro-2a cells and decreased the number of early apoptotic cells. Scirpusin A (13) was the most promising compound possessing both anti-HSV-1 activity and neuroprotective potential.

Highly oxidized rearranged derivatives of quinochalcone C-glycosides from Carthamus tinctorius.

Safflopentsides A-C (1-3), three highly oxidized rearranged derivatives of quinochalcone C-glycosides, were isolated from the safflower yellow pigments. Their structures were determined based on a detailed spectroscopic analysis (UV, IR, HR-ESI-MS, 1D and 2D NMR), and the absolute configurations were confirmed by the comparison of experimental ECD spectra with calculated ECD spectra. Compounds 1-3 have an unprecedented cyclopentenone or cyclobutenolide ring A containing C-glucosyl group, respectively. The plausible biosynthetic pathways of compounds have been presented. At 10 µM, 2 showed strong inhibitory activity against rat cerebral cortical neurons damage induced by glutamate and oxygen sugar deprivation.

Design, Synthesis, and Biological Evaluation of Novel Cinnamide Derivatives as Neuroprotective Agents for the Treatment of Cerebral Ischemia.

BACKGROUND: Ischemic stroke, the most common type of cerebrovascular accident, is a major cause of severe disability among adults worldwide. Although there has been progress in interventions for ischemic stroke in the past decades, there is no effective treatment to prevent brain damage in acute ischemic stroke. Therefore, it is urgent to develop novel neuroprotective agents with a wide therapeutic time window to provide a better prognosis for ischemic stroke patients. OBJECTIVE: The current study aimed to synthesize novel derivatives with substituent cinnamide scaffolds, evaluate biological activity, and obtain neuroprotective agents. METHODS: The target compounds were synthesized using classical methods of medicinal chemistry. The neuroprotective effects in vitro against Glu-induced neurotoxicity injury were evaluated in PC12 cells by MTT assay. The cell apoptosis was analyzed by flow cytometer. The proteins were detected by western blotting. The neuroprotective activities in vivo were determined in two in vivo models of global and focal cerebral ischemia. RESULTS: Among the title compounds, 9t, 9u, 9y, and 9z exhibited good neuroprotection in vivo and in vitro, which were selected and further studied to determine their mechanism of action. 9t, 9u, 9y and 9z protected PC12 cells against glutamate-induced apoptosis in a dose-dependent manner via caspase-3 pathway. Moreover, the four compounds significantly reduced brain infarct area and exhibited excellent neuroprotective activities in the in vivo MCAO model. CONCLUSION: Compounds 9t, 9u, 9y, and 9z, as potent neuroprotective agents with anti- neurotoxicity activity in vitro and anticerebral infarction efficacy in vivo, might serve as a useful molecular tool for further physiology and pathophysiology function studies, leading to potential clinical therapeutic agents for ischemic injury.

Two new terpenoids from the branches and leaves of Rhododendron dauricum L. with neuroprotective activity.

Two new terpenoids were isolated from the branches and leaves of Rhododendron dauricum L., named as rhodayritions A (1) and B (2), together with five known compounds which were identified litseachromolaevane A (3), 11-αH-dihydrodehydrocostus lactone (4), (+)-9ß-hydroxyeudesma-4,11(13)-dien-12-al (5), macrostachyoside B (6) and aglaiabbreviatin E (7), respectively. The structures of isolated compounds were determined by UV, HR-ESI-MS, NMR analysis and X-Ray. Their neuroprotective activity was studied on serum deprivation-induced PC12 cells by the MTT method, compounds 1, 6, and 7 exhibited significant neuroprotective activity at 20 µΜ.

Isolation and Bioactivity Evaluation of Sesquiterpenes from an Alcyonarian of the Genus Lemnalia from the Saudi Arabian Red Sea.

Over the last decades, soft corals have been proven a rich source of biologically active compounds, featuring a wide range of chemical structures. Herein, we investigated the chemistry of an alcyonarian of the genus Lemnalia (Neptheidae), specimens of which were collected from the coral reefs near Al Lith, on the south-west coast of Saudi Arabia. A series of chromatographic separations led to the isolation of 31 sesquiterpenes, featuring mainly the nardosinane and neolemnane carbon skeletons, among which three (13, 14 and 28) are new natural products. The metabolites isolated in sufficient amounts were evaluated in vitro in human tumor and non-cancerous cell lines for a number of biological activities, including their cytotoxic, anti-inflammatory, anti-angiogenic, and neuroprotective activities, as well as for their effect on androgen receptor (AR)-regulated transcription. Among the tested metabolites, compound 12 showed comparable neuroprotective activity to the positive control N-acetylcysteine, albeit at a 10-fold lower concentration.

Chemical constituents of Wikstroemia alternifolia and their neuroprotective activities.

Phytochemical investigation on the plant of Wikstroemia alternifolia led to the isolation of 26 compounds including two new ones, wikstralternifols A and B (1 and 7). Their structures including the absolute configuration were elucidated by spectroscopic data together with analysis of experimental and calculated ECD data. All compounds were isolated from this plant for the first time, and their main structural types were lignans, sesquiterpenoids, and flavonoids. In the sodium nitroprusside-induced rat pheochromocytoma PC-12 cell model, the neuroprotective activities of the selected sesquiterpenoids (1 and 4) and lignans (7 - 14) were screened at the concentration of 10 µM, and 7 - 14 displayed better activities than the positive control edaravone.

Sesquiterpenoids and bibenzyl derivative from Dendrobium hercoglossum.

Three new sesquiterpenoids, dendrohercoglin A - C (1-3), and one new bibenzyl derivative, dendronbiline D (4), together with nine known sesquiterpenoids (5-13) were isolated from Dendrobium hercoglossum. The structures of the new compounds were elucidated by extensive spectroscopic analysis as well as NMR and ECD calculations. All the compounds were evaluated for their neuroprotective and anti-inflammatory activities. Compounds 2 and 3 increased the H2O2-damaged SH-SY5Y cell viabilities from 43.3% to 58.6% and 68.4%, respectively. Compound 4 exhibited pronounced anti-inflammatory activity with IC50 value of 9.5 ± 0.45 µM which was superior to the reference compound quercetin (IC50: 15.7 ± 0.89 µM).

New Lycopodium alkaloids with neuroprotective activities from Lycopodium japonicum Thunb.

One new lycopodine-type alkaloid (1), one new natural product (2), and eight known analogs (3-10) were isolated from the whole plants of Lycopodium japonicum Thunb. The structures of 1-10 were determined based on extensive comprehensive spectroscopic analyses, including UV, IR, NMR, and HRESIMS. Moreover, the isolated alkaloids were evaluated for their neuroprotective activity against Hemin-induced HT22 cell damage. Notably, compounds 1 and 10 exhibited potential neuroprotective activities, with 21.45% and 20.55% increase in cell survival at 20 µM, respectively. Moreover, compounds 1 and 10 revealed protective effects on Hemin-induced apoptosis in HT22 cells.

[Research progress on natural guaiane-type sesquiterpenoids and their biological activities].

Guaiane-type sesquiterpenoids are a class of terpenoids with [5,7] ring-fused system as the basic skeletal structure composed of three isoprene units, which are substituted by 4,10-dimethyl-7-isopropyl. According to the difference in functional groups and degree of polymerization, they can be divided into simple guaiane-type sesquiterpenoids, sesquiterpene lactones, sesquiterpene dimers, and sesquiterpene trimers. Natural guaiane-type sesquiterpenoids are widely distributed in plants, fungi, and marine organisms, especially in families such as Compositae, Zingiberaceae, Thymelaeaceae, Lamiaceae, and Alismataceae. Guaiane-type sesquiterpenoids have good antibacterial, anti-inflammatory, anticancer, and neuroprotective effects. In this paper, the novel guaiane-type sesquiterpenoids isolated and identified in recent 10 years(2013-2022) and their biological activities were reviewed in order to provide refe-rences for the research and development of guaiane-type sesquiterpenoids.