Anti-neuroinflammatory Activity Research Articles

Piperhancosides A−C, new lignan glycosides from the stems of Piper hancei Maxim

Three new lignan glycosides, piperhancosides A−C (1−3), and two known compounds (4−5) were isolated from the n-BuOH extract of the stems of Piper hancei Maxim. The planar structures of the new compounds were elucidated by extensive spectroscopic analyses. Their relative and absolute configurations were determined by coupling constants, chemical shift differences, acid hydrolysis, enzymatic hydrolysis, and experimental ECD spectra. All the isolates were evaluated for their antineuroinflammatory and antioxidant activities, and compounds 4 and 5 showed significant DPPH.+ radical scavenging ability with EC50 value of 14.07 and 16.48 μM, respectively.

Chemical Constituents from the Aerial Parts of Artemisia iwayomogi and Their Anti-Neuroinflammatory Activities.

Neuroinflammation, predominantly mediated by microglial activation, is a key immunological response in the pathogenesis of neurodegenerative disorders. In our preliminary study, the aerial part of Artemisia iwayomogi inhibits LPS-induced microglial activation. The present study aims to identify chemical constituents with anti-neuroinflammatory properties in the aerial parts of A. iwayomogi. Two new guaianolide sesquiterpenes, iwayomogins A and B (1 and 2), along with thirteen known sesquiterpene lactones (3–15), one diterpene glycoside (16), and nine phenolic compounds (17–25) were isolated from the aerial parts of A. iwayomogi by repeated chromatography. The structures of the isolates were elucidated by their spectroscopic data. All isolates were evaluated for their inhibitory activities on nitric oxide (NO) production in LPS-induced BV-2 microglial cells. 2,3-Dehydro-1-epi-asperilin (11) exhibited the strongest inhibitory effect on NO production (IC50 value of 1.78 μM). In the molecular docking study, three compounds (1, 2, and 11) showed good binding affinities with iNOS. Additionally, compounds 1, 2, and 11 inhibit pro-inflammatory cytokines (TNF-α and IL-6) in dose-dependent manners. The present study demonstrates that the chemical constituents from A. iwayomogi inhibit NO production and pro-inflammatory cytokine release in BV-2 cells. However, further evaluation with biological experiments utilizing in vivo models is necessary.

Pramipexole inhibits astrocytic NLRP3 inflammasome activation via Drd3-dependent autophagy in a mouse model of Parkinson’s disease

Inflammation is one of the pathogenic processes in Parkinson’s disease (PD). Dopamine receptor agonist pramipexole (PPX) is extensively used for PD treatment in clinics. A number of studies show that PPX exerts neuroprotection on dopaminergic (DA) neurons, but the molecular mechanisms underlying the protective effects of PPX on DA neurons are not fully elucidated. In the present study, we investigated whether PPX modulated PD-related neuroinflammation and underlying mechanisms. PD model was established in mice by bilateral striatum injection of lipopolyssaccharide (LPS). The mice were administered PPX (0.5 mg·kg−1·d−1, i.p.) 3 days before LPS injection, and for 3 or 21 days after surgery, respectively, for biochemical and histological analyses. We showed that PPX administration significantly alleviated the loss of DA neurons, and suppressed the astrocyte activation and levels of proinflammatory cytokine IL-1β in the substantia nigra of LPS-injected mice. Furthermore, PPX administration significantly decreased the expression of NLRP3 inflammasome-associated proteins, i.e., cleaved forms of caspase-1, IL-1β, and apoptosis-associated speck-like protein containing a caspase recruit domain (ASC) in the striatum. These results were validated in LPS+ATP-stimulated primary mouse astrocytes in vitro. Remarkably, we showed that PPX (100–400 μM) dose-dependently enhanced the autophagy activity in the astrocytes evidenced by the elevations in LC3-II and BECN1 protein expression, as well as the increase of GFP-LC3 puncta formation. The opposite effects of PPX on astrocytic NLRP3 inflammasome and autophagy were eliminated by Drd3 depletion. Moreover, we demonstrated that both pretreatment of astrocytes with autophagy inhibitor chloroquine (40 μM) in vitro and astrocyte-specific Atg5 knockdown in vivo blocked PPX-caused inhibition on NLRP3 inflammasome and protection against DA neuron damage. Altogether, this study demonstrates an anti-neuroinflammatory activity of PPX via a Drd3-dependent enhancement of autophagy activity in astrocytes, and reveals a new mechanism for the beneficial effect of PPX in PD therapy.

Design and synthesis of novel indole and indazole-piperazine pyrimidine derivatives with anti-inflammatory and neuroprotective activities for ischemic stroke treatment

Microglia-mediated neuroinflammation plays an important role in ischemic stroke (IS). In this work, a series of novel indole and indazole-piperazine pyrimidine derivatives with anti-neuroinflammatory and neuroprotective activities were designed and synthesized for treatment of IS. Among these compounds, 5j displayed the most attractive cytoprotective effect against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced damage in BV2 cells. Meanwhile, it significantly ameliorated the release of inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, nitric oxide (NO) and prostaglandin E2 (PGE2), from lipopolysaccharide (LPS)-induced BV2 cells. Moreover, 5j can decrease the release of TNF-α and IL-1β form LPS-induced mouse brain neuroinflammation model. As a potent inhibitor against both cyclooxygenase-2 (COX-2, IC50 = 92.54 nM) and 5-lipoxygenase (5-LOX, IC50 = 41.86 nM), 5j inhibited the M1 phenotype polarization of microglia and promoted the M2 phenotype polarization of microglia. Additionally, 5j exhibited remarkable neuroprotection in middle cerebral artery occlusion (MCAO) rats by reducing their infarct volumes and neurological deficit scores. In conclusion, 5j has the potential for the treatment of stroke as an anti-inflammatory and neuroprotective agent.

Chalcones as Potential Ligands for the Treatment of Parkinson's Disease.

Along with the increase in life expectancy, a significant increase of people suffering from neurodegenerative diseases (ND) has been noticed. The second most common ND, after Alzheimer’s disease, is Parkinson’s disease (PD), which manifests itself with a number of motor and non-motor symptoms that hinder the patient’s life. Current therapies can only alleviate those symptoms and slow down the progression of the disease, but not effectively cure it. So now, in addition to understanding the mechanism and causes of PD, it is also important to find a powerful way of treatment. It has been proved that in the etiology and course of PD, the essential roles are played by dopamine (DA) (an important neurotransmitter), enzymes regulating its level (e.g., COMT, MAO), and oxidative stress leading to neuroinflammation. Chalcones, due to their “simple” structure and valuable biological properties are considered as promising candidates for treatment of ND, also including PD. Here, we provide a comprehensive review of chalcones and related structures as potential new therapeutics for cure and prevention of PD. For this purpose, three databases (Pubmed, Scopus and Web of Science) were searched to collect articles published during the last 5 years (January 2018–February 2022). Chalcones have been described as promising enzyme inhibitors (MAO B, COMT, AChE), α-synuclein imaging probes, showing anti-neuroinflammatory activity (inhibition of iNOS or activation of Nrf2 signaling), as well as antagonists of adenosine A1 and/or A2A receptors. This review focused on the structure–activity relationships of these compounds to determine how a particular substituent or its position in the chalcone ring(s) (ring A and/or B) affects biological activity.

Anti-neuroinflammatory 3-hydroxycoumaronochromones and isoflavanones enantiomers from the fruits of Ficus altissima Blume

A phytochemical study on the fruits of Ficus altissima Blume (lofty fig) led to the isolation and structural elucidation of three pairs of enantiomeric 3-hydroxycoumaronochromones and two pairs of enantiomeric isoflavanones, including eight undescribed compounds. Their structures were determined based on a comprehensive analysis of NMR and HR-ESI-MS spectroscopic data, calculated 13C NMR-DP4 plus analysis and the comparisons of experimental measurements of ECD with calculated ECD spectra by TDDFT or ECD plots in reported protocols. The inhibitory effects of the isolated enantiomers on NO production stimulated by LPS in microglial BV-2 cells were evaluated. Among them, ficusaltin D exhibited the most potent anti-neuroinflammatory activity, which inhibited the production of NO and the expression of iNOS, IL-6 and IL-1β and suppressed the NF-κB nuclear translocation in LPS-induced BV-2 cells, while its enantiomer displayed cytotoxicity.

Diverse polycyclic polyprenylated acylphloroglucinols with anti-neuroinflammatory activity from Hypericum beanii

A phytochemical investigation on the roots of Hypericum beanii resulted in the isolation of six new polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperberlones A-F, along with fourteen known analogues. The structural characterization of these compounds was carried out by analyzing the HRESIMS data, 1D and 2D NMR spectroscopic data, electronic circular dichroism (ECD) calculations, and gauge-independent atomic orbital (GIAO) NMR calculations. Hyperberlone A (1) was a caged PPAP with a rare tricyclo[4.3.1.03,8]decane carbon skeleton. It was deduced to be biosynthetically generated from hyperbeanol C (8) through key Paternò-Büchi reaction, radical cascade cyclizations, and retro-aldol reaction. Compounds 4, 6, 7, 9, 14, and 16 exhibited significant nitric oxide (NO) production inhibitory effects in lipopolysaccharide (LPS)-induced BV-2 microglial cells with IC50 values of 6.11–25.28 μM. Moreover, compound 4 significantly decreased the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in LPS-induced BV-2 microglia, as well as the phosphorylation of JNK.

Effects of Compounds Isolated from Lindera erythrocarpa on Anti-Inflammatory and Anti-Neuroinflammatory Action in BV2 Microglia and RAW264.7 Macrophage.

Lindera erythrocarpa contains various constituents such as cyclopentenedione-, flavonoid-, and chalcone-type components. In this study, a novel bi-linderone derivative and 17 known compounds were isolated from the leaves of L. erythrocarpa by using various chromatographic methods. The structures of the components were determined from nuclear magnetic resonance and mass spectrometry data. All isolated compounds were tested for anti-inflammatory and anti-neuroinflammatory activities in lipopolysaccharide (LPS)-induced BV2 and RAW264.7 cells. Some of these compounds showed anti-inflammatory effects by inhibiting the nitric oxide (NO) produced by LPS. In particular, linderaspirone A (16), bi-linderone (17) and novel compound demethoxy-bi-linderone (18) showed significant inhibitory effects on the production of prostaglandin E2 (PGE2), tumor necrosis factor-α, and interleukin-6. The three compounds also inhibited the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), which are pro-inflammatory proteins, and the activation of nuclear factor κB (NF-κB). Therefore, linderaspirone A (16), bi-linderone (17), and demethoxy-bi-linderone (18) isolated from the leaves of L. erythrocarpa have therapeutic potential in neuroinflammatory diseases.

Pyrone Derivatives from a Mangrove Endophytic Fungus Phomopsis asparagi LSLYZ-87.

Chemical investigation of the endophytic fungus Phomopsis asparagi LSLYZ-87 cultured on PDB medium led to the isolation of two new pyrone derivatives, phomasparapyrone A (1), and phomasparapyrone B (2), together with the known kojic acid (3). Their planar structures were connected through 1D and 2D NMR spectroscopic data. And the stereo structures of 1 and 2 were defined by comparison of the experimental ECD spectra to calculated one. All isolates were evaluated for their anti-neuroinflammatory activities. Among them, compound 2 showed moderate inhibition on NO accumulation induced by LPS on BV-2 cells in a dose dependent manner at 30, 40 and 50 μM, and without cytotoxicity in a concentration of 50.0 μM.

Hemp Seed Fermented by Aspergillus oryzae Attenuates Lipopolysaccharide-Stimulated Inflammatory Responses in N9 Microglial Cells.

The objective of our present work was to explore the possible enhanced anti-neuroinflammatory ability of Aspergillus oryzae fermented hemp seed in lipopolysaccharide (LPS)-stimulated N9 microglial cells and elucidate its underlying mechanism. The water extract of hemp seed was fermented by Aspergillus oryzae. LPS-stimulated N9 microglial cells were employed for the inflammatory cell model. The release of nitric oxide (NO) was determined by Griess assay. The cytokines and inflammatory mediator expression were measured by qPCR and ELISA. The phosphorylated key signaling proteins, including nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPKs), and phosphatidylinositol 3-kinase (PI3K/Akt), were quantified by western blot analysis. The production of intracellular reactive oxygen species (ROS) was measured by DCFH oxidation. Fermented hemp seed (FHS) reduced NO production by downregulating inducible nitric oxide synthase (iNOS) expression in LPS-stimulated N9 microglial cells. FHS treatment decreased LPS-stimulated expression of inflammatory cytokines either on mRNA or protein levels. Moreover, FHS inhibited LPS-stimulated phosphorylation of NF-κB, MAPKs, and PI3K/Akt signaling pathways. Furthermore, FHS significantly reduced the ROS production in the cells. It was concluded that FHS exerted its anti-neuroinflammatory activities by suppressing ROS production, thus inhibiting NF-κB, MAPKs, and PI3K/Akt activation, consequently decreasing the expression levels of inflammatory mediators and cytokines.

Phikud Navakot extract attenuates lipopolysaccharide-induced inflammatory responses through inhibition of ERK1/2 phosphorylation in a coculture system of microglia and neuronal cells

Ethnopharmacological relevancePhikud Navakot (PN), a mixture of nine herbal plants, is an ancient Thai traditional medicine used for relieving circulatory disorders and dizziness. PN has also shown anti-inflammatory effects in rats with acute myocardial infarction. Moreover, phytochemical-inhibiting neuroinflammation, including gallic acid, vanillic acid, ferulic acid, and rutin were detected in PN extract; however, the anti-neuroinflammatory activity of PN extract and its components in a coculture system of microglia and neuronal cells is limited. ObjectiveTo investigate the anti-neuroinflammatory activities of PN on lipopolysaccharide (LPS)-induced inflammation in a coculture system of microglia and neuronal cells. MethodsELISA and qRT-PCR were used to assess cytokine expression. The phosphorylation of mitogen-activated protein kinases (MAPKs) was determined by Western blotting. Microglia-mediated neuroinflammation was evaluated using a BV-2 microglia-N2a neuron transwell co-culture. ResultsPN extract and its component, gallic acid, decreased LPS-induced the mRNA expression of interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS), as well as IL-6 protein levels in both microglial monoculture and coculture systems. This was accompanied by a reduction in neurodegeneration triggered by microglia in N2a neurons with increased neuronal integrity markers (βIII tubulin and tyrosine hydroxylase (TH)). These effects were caused by the ability of PN extract to inhibit extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) activation. ConclusionThis is the first study to show that PN extract inhibits neurodegeneration in LPS-activated BV-2 microglia by targeting ERK signaling activity.

Two new clerodane diterpenoids and a new pyran-2-one derivative with anti-neuroinflammatory activities from Croton crassifolius.

Two new clerodane diterpenoids (1 and2), a new pyran-2-one derivative (3), along with five known compounds (4‒8), were isolated from Croton crassifolius. Notably, crassifolin X (1) is a novel clerodane diterpenoid, characterized with a peculiar δ-lactone core being formed between C-1 and C-4. Their structures, including absolute configurations, were established on the basis of spectroscopic methods (UV, IR, HRESIMS and NMR), and circular dichroism experiments. In addition, all compounds were evaluated for their anti-neuroinflammatory activities based on the expression of TNF-α and IL-6 levels on LPS-induced BV2 cells, and compounds 1‒3 and 5 showed potential anti-neuroinflammatory activity.

Astragalin and Isoquercitrin Isolated from Aster scaber Suppress LPS-Induced Neuroinflammatory Responses in Microglia and Mice

The current study investigated the anti-neuroinflammatory effects and mechanisms of astragalin (Ast) and isoquercitrin (Que) isolated from chamchwi (Aster scaber Thunb.) in the lipopolysaccharide (LPS)-activated microglia and hippocampus of LPS induced mice. LPS induced increased cytotoxicity, nitric oxide (NO) production, antioxidant activity, reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS) expression, the release of pro-inflammatory cytokines, protein kinase B phosphorylation, and mitogen-activated protein kinases (MAPK) phosphorylation in LPS-treated microglial cells. Intraperitoneal injection of LPS also induced neuroinflammatory effects in the murine hippocampus. Ast and Que significantly reduced LPS-induced production of NO, iNOS, and pro-inflammatory cytokines in the microglia and hippocampus of mice. Therefore, anti-inflammatory effects on MAPK signaling pathways mediate microglial cell and hippocampus inflammation. In LPS-activated microglia and hippocampus of LPS-induced mice, Ast or Que inhibited MAPK kinase phosphorylation by extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 signaling proteins. Ast and Que inhibited LPS-induced ROS generation in microglia and increased 1,1-diphenyl-2-picrylhydrazyl radical scavenging. In addition, LPS treatment increased the heme oxygenase-1 level, which was further elevated after Ast or Que treatments. Ast and Que exert anti-neuroinflammatory activity by down-regulation of MAPKs signaling pathways in LPS-activated microglia and hippocampus of mice.

Terpenoids from Glechoma hederacea var. longituba and their biological activities.

Glechoma hederacea var. longituba (common name: ground ivy) has been used for the treatment of asthma, bronchitis, cholelithiasis, colds, and inflammation. In the present study, three new sesquiterpene glycosides (1–3), two new diterpene glycosides (4 and 5), and four known compounds (6–9) were isolated from its MeOH extract. A structure elucidation was performed for the five new compounds (1–5) using 1D and 2D NMR, HRESIMS, DP4+ and ECD calculations, and chemical methods. All the isolates (1–9) were assessed for their antineuroinflammatory activities on nitric oxide (NO) production in lipopolysaccharide (LPS)-activated BV-2 cells, nerve growth factor (NGF) secretion stimulation activities in C6 glioma cells, and cytotoxic activities against four human cancer cell lines (A549, SK-OV-3, SK-MEL-2, and HCT15). Compounds 2 and 5–7 exhibited inhibitory effects on the NO production with IC50 values of 52.21, 47.90, 61.61, and 25.35 μM, respectively. Compound 5 also exhibited a significant stimulating effect on NGF secretion (122.77 ± 8.10%). Compound 9 showed potent cytotoxic activity against SK-OV-3 (IC50 = 3.76 μM) and SK-MEL-2 (IC50 = 1.48 μM) cell lines, while 7 displayed a strong cytotoxic activity against the SK-MEL-2 (IC50 = 9.81 μM) cell line.

Two previously undescribed phthalides from Talaromyces amestolkiae, a symbiotic fungus of Syngnathus acus

Amestolkins A (1) and B (2), two previously undescribed phthalides sharing the same planar structure of (1, 5-dihydroxyhexyl)-7-hydroxyisobenzofuran-1(3H)-one were isolated from Talaromyces amestolkiae. Their absolute configurations were elucidated by comprehensive analyses of spectroscopic evidences in high-resolution electrospray mass spectra (HRESIMS) and nuclear magnetic resonance (NMR) combined with electronic circular dichroism (ECD) and NMR calculations. 1 and 2 showed anti-neuroinflammatory activity by inhibiting the gene expressions of proinflammatory factors including C-C motif chemokine ligand 2 (CCL-2), tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6), as well as attenuating the excretion of inducible nitric oxide synthase (iNOS) in BV-2 microglial cells at the concentration of 30 μM.

Remifentanil inhibits the inflammatory response of BV2 microglia and protects PC12 cells from damage caused by microglia activation

ABSTRACT Microglia acts as a critical player in neuroinflammation and neuronal injury. Remifentanil (Rem) has been reported to exert anti-inflammatory activity in several types of diseases. However, the role of Rem in microglia-mediated neuroinflammation is unclear. The present study was designed to investigate the effects of Rem against lipopolysaccharide (LPS)-activated BV2 microglial and PC12 cell induced by activated BV2 microglia. Cell proliferative ability was assessed with cell counting kit-8 assay and cellular morphology was observed. ELISA assay was used to measure the expressions of PGE2 and inflammatory factors. The contents of p-NF-KB p65, p-IKKα/β, and COX2 were evaluated with the aid of western blot. The levels of NO and iNOS were assessed with Griess assay, qRT-PCR, and western blot. In addition, Tunel assay and western blot were performed to assess cell apoptosis. The data revealed that Rem alleviated BV2 microglial morphological injury induced by LPS. Furthermore, Rem suppressed inflammatory releases, iNOS, NO and PGE2 stimulated by LPS in activated BV2 cells. Moreover, Rem suppressed PC12 cell injury, the generations of inflammatory factors and cell apoptosis triggered by inflammatory mediators secreted from activated BV2 cells. These results suggest that Rem exhibited anti-neuroinflammatory activity in protecting PC12 cells against injury derived from LPS-stimulated BV2 microglia.

Comparative studies on the anti-neuroinflammatory and antioxidant activities of black and red goji berries

• This is the first study reporting the neuroinflammatory activity of black goji. • Black goji berries extract have higher anti-neuroinflammatory activity than red goji. • Black goji display higher phenolic content and antioxidant activity than red goji. • In vitro digestion decrease the anti-oxidant/inflammatory activities of both goji. Goji berries have several bioactivities and are consumed as food or used in folk medicine. In this study, the methanolic extracts from red and black goji berries were compared regarding their anti-inflammatory and antioxidant activities. Black goji berries extract has revealed significantly higher anti-inflammatory activity, in either biochemical assays or via decreasing the release of nitric oxide and inhibiting the gene expression of pro-inflammatory cytokines in LPS-stimulated BV2 microglial cells, in comparison with the red goji berries extract. Black goji berries’ extract has also revealed a significantly higher antioxidant activity, in comparison with the red goji one. Inflammation and related oxidative stress have been brought to light as underlying mechanisms in several chronic diseases, e.g. neurodegenerative diseases. Our results show that these goji berries, particularly the black ones, can have the potential to be a source of pharmacologically active compounds in diseases with an inflammatory and oxidative background.

Meroterpenoids and sesquiterpene dimers from Sarcandra glabra with anti-neuroinflammatory activity

Sarcandra glabra (Thunb.) Nakai is abundantly artificially cultivated for industrial use as an essential pharmaceutical and chemical raw material in China. In this work, five new meroterpenoids (1–5), along with one analog (6) and six known sesquiterpene dimers (7–12) were isolated from Sarcandra glabra. The chemical structures, including absolute configurations, were deduced by extensive spectroscopic methods combined with quantum mechanical electronic circular dichroism (ECD) and nuclear magnetic resonance (NMR) calculations, Mo2(OAc)4-induced ECD experiments, and customizable DP4 + probability analysis. Compounds 1–6 are biogenetically assembled by the cyclization of gentisicacid and monoterpene, featuring a novel 6/6/6 -fused ring system. Compounds 4 and 5 possess significant inhibitory effects on nitric oxide (NO) production against lipopolysaccharide (LPS)-induced microglia (BV2) cells, while compounds 8 and 9 displayed an approximately equal effect to Dexamethasone. The analysis of the protein-protein interaction (PPI) network and molecular docking showed 4 and 5 could play an anti-neuroinflammatory role by regulating heat shock proteins 90AA1 (Hsp90AA1). This study provided evidence for further research and utilization of S. glabra in anti-neuroinflammatory medicinal products.

Astragalin attenuates depression-like behaviors and memory deficits and promotes M2 microglia polarization by regulating IL-4R/JAK1/STAT6 signaling pathway in a murine model of perimenopausal depression

Neuroinflammation can be alleviated via M2 microglia polarization, which could promote the recovery of perimenopausal depression. Astragalin (AST) possesses anti-neuroinflammatory activity. However, the effects of AST on perimenopausal depression and the molecular mechanism in regulating microglia polarization remained unknown. The purpose was to investigate the effects of AST on mice with simulated perimenopausal depression through regulating microglia polarization. It was aimed to clarify the molecular mechanism related to the interleukin-4 receptor (IL-4R)/janus kinase (JAK) 1/signal transducer and activator of transcription (STAT) 6 signaling pathway. The ovariectomy (OVX)/chronic unpredictable mild stress (CUMS)-induced murine model of perimenopausal depression was established and treated with AST. Then the depression-like behaviors and cognitive ability of mice were examined. After that, we detected the markers of microglia polarization and its regulatory signals. In addition, lipopolysaccharides (LPS)/adenosine triphosphate (ATP)-induced inflammatory BV2 model were used to verify the potential molecular mechanism. AST alleviated perimenopausal depression-like behaviors and memory deficits. AST alleviated microglia activation and increased Ki67-positive cells in dentate gyrus (DG). The viability of BV2 decreased by LPS/ATP was raised by AST. Moreover, both in vivo and in vitro, AST switched microglia from M1 phenotype caused by OVX/CUMS or LPS/ATP to M2 phenotype. The IL-4R/JAK1/STAT6 signaling was restored, and the levels of inducible nitric oxide synthase (iNOS), nuclear NF-KappaB-p65 were reduced by AST. Importantly, AST showed prevention against the ubiquitination modification and degradation of STAT6. Our results revealed new insights into molecular mechanism associated with microglia polarization in the effect of AST on the mouse model of perimenopausal depression.

Therapeutic Potential and Clinical Evidence of Hesperidin as Neuroprotective Agent.

Neuroprotection is preserving neural function in various neurodegenerative diseases like Alzheimer's, Huntington's, Parkinson's, and multiple sclerosis. Hesperidin, a flavanone glycoside in citrus fruits such as sweet oranges and lemons, possesses many biological effects, including neuroprotection. The study aims to explore the neuropharmacological mechanisms and therapeutic potential of hesperidin in the management of neurodegenerative disorders. It emphasizes comparative and clinical trial studies with a number of targets reviewed from the data available on PubMed, Science Direct, Clinicaltrails.gov, and from many reputed foundations. Escalating clinical evidence has established the inhibitory effect of hesperidin in the management of neurodegenerative disorders. Neuroprotective potential of hesperidin is characterized by endogenous antioxidant defence functions, improvement of neural growth factors, antineuroinflammatory activity, and apoptotic pathways. The present study highlights the beneficial neuropharmacological potential of hesperidin, including anticonvulsant, antidepressant, antioxidant, anti-inflammatory, memory, and locomotor enhancing activities.