Lactoferrin modification of berberine nanoliposomes enhances the neuroprotective effects in a mouse model of Alzheimer’s disease

Previous studies have shown that berberine has neuroprotective effects against Alzheimer’s disease,including antagonizing tau phosphorylation,and inhibiting acetylcholinesterase activity and neural cell apoptosis.However,its low bioavailability and adverse reactions with conventional administration limit its clinical application.In this study,we prepared berberine nanoliposomes using liposomes characterized by low toxicity,high entrapment efficiency,and biodegradability,and modified them with lactoferrin.Lactoferrin-modified berberine nanoliposomes had uniform particle size and high entrapment efficiency.We used the lactoferrin-modified berberine nanoliposomes to treat a mouse model of Alzheimer’s disease established by injection of amyloid-beta 1-42 into the lateral ventricle.Lactoferrin-modified berberine nanoliposomes inhibited acetylcholinesterase activity and apoptosis in the hippocampus,reduced tau over-phosphorylation in the cerebral cortex,and improved mouse behavior.These findings suggest that modification with lactoferrin can enhance the neuroprotective effects of berberine nanoliposomes in Alzheimer’s disease.

Neuroprotective Effects of Bushen Decoction Against Glutamate-Induced Neurotoxicity in PC12 Cells

Aim The enhanced effect of Bushen (Kidney-tonifying) decoction (BS) oncultured PC12 cell proliferation and its antagonistic action on neurotoxicity induced by glutamatewere investigated by serum pharmacological method of the Chinese material medica (CMM) in vitro.Methods The effect of BS on cultured PC12 cell activity and its antagonistic action on neurotoxicityinduced by glutamate was observed by MTT method. Flow cytometry and fluorescence microscopetechniques were employed to observe the antagonistic effect of BS on early period apoptosis of PC12cells induced by glutamate. Results The serum with BS was able to enhance activity of PC12 cells andexert antagonistic effect on glutamate-induced neurotoxicity. Meanwhile, these beneficial effectsproduced by BS were found to be the strongest in 20% concentration of in serum BS. Moreover, it caninhibit apoptosis of PC12 cells induced by glutamate , which occurs in the early period. ConclusionBS may exert a potential neuroprotective effect.

Neuroprotective effects of statins against amyloid β-induced neurotoxicity

A growing body of evidence suggests that disruption of the homeostasis of lipid metabolism affects the pathogenesis of Alzheimer＇s disease （AD）. In particular, dysregulation of cholesterol homeostasis in the brain has been reported to considerably increase the risk of developing AD. Thus, dysregulation of lipid homeostasis may increase the amyloid β （Aβ） levels by affecting amyloid precursor protein （APP） cleavage, which is the most important risk factor involved in the pathogenesis of AD. Previous research demonstrated that Aβ can trigger neuronal insulin resistance, which plays an important role in response to Aβ-induced neurotoxicity in AD. Epidemiological studies also suggested that statin use is associated with a decreased incidence of AD. Therefore, statins are believed to be a good candidate for conferring neuropro- tective effects against AD. Statins may play a beneficial role in reducing A^-induced neurotoxicity. Their effect involves a putative mechanism beyond its cholesterol-lowering effects in preventing A[3-induced neurotoxicity. However, the underlying molecular mechanisms of the protective effect of statins have not been clearly determined in Aβ-induced neurotoxicity. Given that statins may provide benefits beyond the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A （HMG-CoA） reductase, these drugs may also improve the brain. Thus, statins may have beneficial effects on impaired insulin signaling by activating AMP-activated protein kinase （AMPK） in neuronal cells. They play a potential therapeutic role in targeting Aβ-mediated neurotoxicity.

Kongsheng Zhenzhong pill's effect on the learning and memory ability and its neuroprotective effects in vascular dementia rats

Clinical reports have demonstrated that the Kongsheng Zhenzhong pill （KSZZP）, a classical prescription deriving from Valuable Prescription for Emergencies, has good therapeutic effects on vascular dementia. However, the mechanisms that mediate its effects remain unclear. In this study, the expression of N-methyI-D-aspartate receptor 1 mRNA, the content of nitric oxide, and the concentration of calcium in neurons was determined with in situ hybridization, spectrophotometry and flow cytometry, respectively. In addition, the expressions of N-methyI-D-aspartate receptor 1, nerve growth factor protein, and glial cell line-derived neurotrophic factor protein were detected with immunohistochemistry. We found that KSZZP could significantly decrease the expression of N-methyI-D-aspartate receptor 1 mRNA and protein, the content of nitric oxide, and the concentration of calcium in neurons. KSZZP also increased the expression of nerve growth factor and glial cell line-derived neurotrophic factor protein in the hippocampus CA1 region and in the cerebral cortex. Morris water maze and passive avoidance tests verified that KSZZP ameliorated the cognitive impairments of vascular dementia rats. Moreover, the KSZZP-induced improvements in the cognitive functions of vascular dementia rats were correlated with both inhibition of N-methyl-D-aspartate-induced excitable neurotoxicity and elevation of neurotrophic factor expression.

The neuroprotective effects of the anti-diabetic drug linagliptin against Aβ-induced neurotoxicity

Impaired insulin signaling in Alzheimer’s disease（AD）brains：The insulin signaling pathway is a fundamental physiological mechanism that presents in nearly all vertebrate cells.However,sometimes cells stop responding properly to insulin stimulation.This condition is known as insulin resistance,which is a hallmark of two very common conditions,metabolic syndrome and type 2 diabetes（T2D）.

Interferon beta(IFN-β) treatment exerts potential neuroprotective effects through neurotrophic factors and novel neurotensin/neurotensin high affinity receptor 1 pathway

Multiple sclerosis（MS）is a chronic autoimmune disease of the central nervous system（CNS）characterized by coexisting processes of inflammation,demyelination,axonal neurodegeneration,and gliosis.It is the most common disabling neurological disease in young adulthood.

Mercury-induced neurotoxicity and neuroprotective effects of berberine

Exposure to mercury can cause immune, sensory, neurological, motor and behavioral dysfunctions similar to traits associated with autism spectrum disorders （ASDs）, and these similarities extend to neuroanatomy, neurotransmitters and biochemistry. It also affects antioxidant system in the cell, resulting in loss of membrane integrity and finally cellular necrosis （Abdel Moneim, 2015）.

Pretreatment with Rhodiola Rosea Extract Reduces Cognitive Impairment Induced by Intracerebroventricular Streptozotocin in Rats: Implication of Anti-oxidative and Neuroprotective Effects

Objective To investigate the pretreatment effects of Rhodiola rosea （R. rosea） extract on cognitive dysfunction, oxidative stress in hippocampus and hippocampal neuron injury in a rat model of Alzheimer＇s disease （AD）. Methods Male Sprague-Dawley rats were pretreated with R. rosea extract at doses of 1.5, 3.0, and 6.0 g/kg for 3 weeks, followed by bilateral intracerebroventricular injection with streptozotocin （1.5 mg/kg） on days 1 and 3. Behavioral alterations were monitored after 2 weeks from the lesion using Morris water maze task. Three weeks after the lesion, the rats were sacrificed for measuring the malondialdehyde （MDA）, glutathione reductase （GR） and reduced glutathione （GSH） levels in hippocampus and histopathology of hippocampal neurons. Results The MDA level was significantly increased while the GR and GSH levels were significantly decreased with striking impairments in spatial learning and memory and severe damage to hippocampal neurons in the model rat induced by intracerebroventricular injection of streptozotocin. These abnormalities were significantly improved by pretreatment with R. rosea extract （3.0 g/kg）. Conclusion R. rosea extract can protect rats against cognitive deficits, neuronal injury and oxidative stress induced by intracerebroventricular injection of streptozotocin, and may be used as a potential agent in treatment of neurodegenerative diseases such as AD.

Chemical constituents isolated from the aerial parts of Swertia pseudochinensis and their potential neuroprotective effects

Objective:Swertia pseudochinensis,an annual herb of the genus Swertia in the family Gentianaceae.Some constituents and extracts from the Swertia genus have been recently reported to possess neuroprotective effects,suggesting their potential utility in the prevention and treatment of Parkinson disease(PD).The aim of this work is to identify the chemical constituents and evaluate the potential biological activists of Swertia pseudochinensis.Methods:The phytochemicals from the aerial parts of S.pseudochinensis were isolated and purified by silica gel,Sephadex LH-20 gel,semi-preparative high-performance liquid chromatography,and identified by the spectroscopic methods.All compounds were evaluated for their potential neuroprotective effects against 1-methyl-4-phenylpyridinium-induced apoptosis in the SH-SY5Y human neuroblastoma cell line using the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay.Then,we performed an enrichment analysis using the Database for Annotation,Visualization,and Integrated Discovery and investigated the mechanisms by which bellidifolin regulates neurodegenerative disease.Results:Two new anthraquinone,1,5,6-trimethoxy-2-hydroxy-3-methy-anthraquinone(1)and 1,5,6,8-tetramethoxy-2-hydroxy-3-methyanthraquinone(2),together with nine known including 7-O-b-d-glucopyranosyl-1,8-dihydroxy-3-methoxyxanthone(3),gentisin(4),swertianolin(5),bellidifolin(6),gentiacaulein(7),norswertianolin(8),5-O-b-d-glucopyranosyl-1,3,8-trihydroxyapatone(9),1-hydroxy-3,5,8-trimethoxyxanthone(10),and aurantio-obtusin(11),were isolated and compounds 6–8 and 10 exhibited neuroprotective effects at a concentration of 50mmol/L.Among them,bellidifolin showed significant protective activity,and might have potential as a neuroprotective agent for the treatment of PD,possibly by acting on oxidative damage and reactive oxygen species.Conclusions:These findings indicate that further research on the genus Swertia and its bioactive constituents toward neurodegenerative disorders could be extremely rewarding.

GPCR-Gs mediates the protective effects of ginsenoside Rb1 against oxygen-glucose deprivation/re-oxygenation-induced astrocyte injury

Objectives:To investigate whether the protective actions of ginsenoside Rb1(Rb1)on astrocytes are mediated through the G_(s)-type G-protein-coupled receptor(GPCR-G_(s)).Methods:Primary astrocyte cultures derived from neonatal mouse brain were used.Astrocyte injury was induced via oxygen-glucose deprivation/re-oxygenation(OGD/R).Cell morphology,viability,lactate dehydrogenase(LDH)leakage,apoptosis,glutamate uptake,and brain-derived neurotrophic factor(BDNF)secretion were assessed to gauge cell survival and functionality.Western blot was used to investigate the cyclic adenosine monophosphate(cAMP)and protein kinase B(Akt)signaling pathways.GPCR-G_(s)-specific inhibitors and molecular docking were used to identify target receptors.Results:Rb1 at concentrations ranging from 0.8 to 5μM did not significantly affect the viability,glutamate uptake,or BDNF secretion in normal astrocytes.OGD/R reduced astrocyte viability,increasing their LDH leakage and apoptosis rate.It also decreased glutamate uptake and BDNF secretion by these cells.Rb1 had protective effects of astrocytes challenged by OGD/R,by improving viability,reducing apoptosis,and enhancing glutamate uptake and BDNF secretion.Additionally,Rb1 activated the cAMP and Akt pathways in these cells.When the GPCR-G_(s) inhibitor NF449 was introduced,the protective effects of Rb1 completely disappeared,and its activation of cAMP and Akt signaling pathways was significantly inhibited.Conclusion:Rb1 protects against astrocytes from OGD/R-induced injury through GPCR-G_(s) mediation.

Qualitative and quantitative analysis of four different polarity fractions from Huang-Lian-Jie-Du-Decoction by HPLC-DAD-ESI-MS/MS and their related neuroprotective effects

Huang-Lian-Jie-Du-Decoction （HLJDD） has been widely used for the treatment of Alzheimer＇s disease （AD） in clinic. However, the relationship between its chemical profile and neuroprotective bioactivity was not clearly clarified yet. In present study, the water extract of HLJDD and subsequent three polarity fractions divided by different reagents were investigated. A total of 17 chromatographic peaks were confirmed by comparison with standards and their UV, MS spectra. Among them, 11 major compounds were determined by HPLC-DAD method with good linear regression relationship （r2, 0.9994-0.9999）, precisions （inter-day precision RSD, 0.79%-1.07%; intra-day precision RSD, 1.59%-2.10%）, repeatability （RSD, 1.66%-3.67%）, stability （RSD, 1.26%-4.77%） and recovery （95.24%-105.41%, RSD, 0.29%-2.69%）. Furthermore, PC12 cells and primary neurons cells were used for the neuroprotective effective assessment of aforementioned four samples from HLJDD. 3＂he total aqueous extract and n-butanol extract of HLJDD presented more significant effects than the other two parts. According to their quality and quantity determination results, iridoids and alkaloids have a positive correlation with the neuroprotective effectiveness of HLJDD.

Characteristic Dihydroagarofuran Sesquiterpenoids with Neuroprotective Effects from the Celastraceae Plant Tripterygium wilfordii

Ten new characteristic dihydroagarofuran sesquiterpenoids and three known ones were acquired from the Celastraceae plant Tripterygium wilfordii.Their structure characterizations were done through spectroscopic data,while compounds 10-12 were further con firmed by single crystal diffractions.Several dihydroagarofurans protected PC12 cells against H2O2-i nduced cytotoxicity as detected by CCK8 assay.Compounds 5-7 and 13 sign ificantly in creased the levels of reactive oxyge n species(ROS)and superoxide dismutase(SOD),and decreased malondialdehyde(MDA)levels.In addition,compounds 5-7 and 13 activated the Nrf2 signaling pathway and increased Nrf2,NQO1,and HO1 expression levels in PC12 cells after H_(2)O_(2) treatment.

Diverse sesquiterpenoids from Litsea lancilimba Merr.with potential neuroprotective effects against H_(2)O_(2)-induced SH-SY5Y cell injury

Five undescribed sesquiterpenoids(1–5),and nine known sesquiterpenoids(6–14)were obtained from the fruits of Litsea lancilimba Merr.by LC-MS/MS molecular networking strategies.Litsemene A(1)possessed a unique 8-member ring through unexpected cyclization of the methyl group on C-10 of guaiane.Their structures were elucidated by spectroscopic techniques including IR,UV,NMR,HR-ESI-MS,and their absolute configurations were assigned by ECD calculations.All isolated sesquiterpenoids were analyzed by bioinformatics and evaluated for their neuroprotective effects against H_(2)O_(2)-induced injury in human neuroblastoma SH-SY5Y cells.

Bioactive chemical constituents from the marine-derived fungus Cladosporium sp.DLT-5

A new isochromanone,cladosporinisochromanone(1),accompanied by 15 known compounds(2–16)were obtained from secondary metabolites produced by marine-derived fungus Cladosporium sp.DLT-5.NMR and HRESIMS spectra elucidation determined the planar structure of 1.Subsequent electronic circular dichroism(ECD)experiment assigned the absolute configuration of 1.Compounds 1,2,4–6,and 10 displayed different degrees of neuroprotective activities on human neuroblastoma cells SH-SY5Y.Five compounds(1,3–5,and 13)emerged resistance to protein tyrosine phosphatase 1B(PTP1B),further kinetic analysis and molecular docking study indicated that the most potent compound 13(IC50value of 10.74±0.61μmol/L)was found as a noncompetitive inhibitor for PTP1B.Surface plasmon resonance(SPR)and molecular docking studies also demonstrated the interaction between compound 12 and Niemann-Pick C1 Like 1(NPC1L1),which has been identified as significant therapeutic target for hypercholesteremia.In addition,compounds 3,6,and 14 showed attractive inhibitory activity against the phytopathogenic fungi:Colletotrichum capsici.Therefore,library of Cladosporium metabolites is enriched and new active uses of known compounds are explored.

Syringaldehyde exerts neuroprotective effect on cerebral ischemia injury in rats through anti-oxidative and anti-apoptotic properties

There are few studies on the neuroprotective effects of syringaldehyde in a rat model of cerebral ischemia. The study aimed to elucidate the mechanisms underlying the neuroprotective effects of syringaldehyde on ischemic brain cells. Rat models of cerebral ischemia were intraperitoneally administered syringaldehyde. At 6 and 24 hours after syringaldehyde administration, cell damage in the brain of cerebral ischemia rats was obviously reduced, superoxide dismutase activity and nuclear respiratory factor 1 expression in the brain tissue were markedly increased, malondi-adehyde level was obviously decreased, apoptosis-related cysteine peptidase caspase-3 and -9 immunoreactivity was obviously decreased, and neurological function was markedly improved. These ifndings suggest that syringaldehyde exerts neuroprotective effects on cerebral ischemia injury through anti-oxidation and anti-apoptosis.

Synthesis and Neuroprotective Activity of Novel C4, C7 Derivatives in Tetracycline Series

Since the discovery of the tetracycline in 1953, numerous natural andsemisynthelic tetracyclines have been reported with broad spectrum antibacterial activity .Doxycycline 1 and minocycline 2 are semisyn-thetic second-generation tetracyclines that exertanti-inflammatory effects. These effects appear completely separate and distinct fromtheirantimicrobial actio. Minocycline and doxycycline are absorbed rapidly and show higher brainpenetrability than other tetracyclines. During recent years, doxycycline and minocycline have shownto have neuroprotective effects in models of global and focal ischemia . The neuroprotective effectsare assumed to result from the inhibition of microglia activation. Furthermore, from an in vitrostudy, it was reported that minocycline induces neuroprotection against NMDA-induced neurotoxicityby inhibiting p38 MAP ki-nase activity in microglia . However, neuroprotective mechanisms andstructure-activity relationships of these compounds in neurons are unclear.

(＋)-Borneol is neuroprotective against permanent cerebral ischemia in rats by suppressing production of proinflammatory cytokines

Stroke is one of the leading causes of disability and death globally.It occurs when a major artery is occluded in the brain and leads to death of cells within the injured tissue.（＋）-Borneol,a simple bicyclic monoterpene extracted from traditional Chinese medicine,is widely used in various types of diseases.However,no study has proved the effects of（＋）-borneol on functional recovery from permanent ischemic stroke and the mechanism is still unknown.Here,we report that in the rat model of permanent cerebral ischemia,we found that（＋）-borneol（1.0 mg/kg） significantly ameliorated infarct size and neurological scores via reducing the expression of inducible nitric oxide synthase（iNOS）and tumor necrosis factor-alpha（TNF-α） in a dose dependent manner.Notably,（＋）-borneol showed long-term effects on the improvement of sensorimotor functions in the photothrombotic model of stroke,which decreased the number of foot faults in the grid-walking task and forelimb asymmetry scores in the cylinder task,at least in part through reducing loss of dendritic spines in the length,brunch number and density.These findings suggest that（＋）-borneol could serve as a therapeutic target for ischemic stroke.

Neuroprotective effect of the Chinese medicine Tiantai No.1 and its molecular mechanism in the senescence-accelerated mouse prone 8

Tiantai No.1, a Chinese medicine predominantly composed of powdered Rhizoma Gastrodiae, Radix Ginseng, and Ginkgo leaf at a ratio of 2：1：2 and dissolved in pure water, is neuroprotective in animal models of various cognitive disorders, but its molecular mechanism remains unclear. We administered Tiantai No.1 intragastrically to senescence-accelerated mouse prone 8（SAMP8） mice（a model of Alzheimer＇s disease） at doses of 50, 100 or 150 mg/kg per day for 8 weeks and evaluated their behavior in the Morris water maze and expression of Alzheimer＇s disease-related proteins in the brain. Tiantai No.1 shortened the escape latency in the water maze training trials, and increased swimming time in the target quadrant during the spatial probe test, indicating that Tiantai No.1 improved learning and memory in SAMP8 mice. Immunohistochemistry revealed that Tiantai No.1 restored the proliferation potential of Ki67-positive cells in the hippocampus. In addition, mice that had received Tiantai No.1 had fewer astrocytes, and less accumulation of amyloid-beta and phosphorylated tau. These results suggest that Tiantai No.1 is neuroprotective in the SAMP8 mouse model of Alzheimer＇s disease and acts by restoring neuronal number and proliferation potential in the hippocampus, decreasing astrocyte infiltration, and reducing the accumulation of amyloid-beta and phosphorylated tau.

The neuroprotective effect of walnut-derived peptides against glutamate-induced damage in PC12 cells: mechanism and bioavailability

In our previous study, defatted walnut meal hydrolysate(DWMH) could attenuate D-galactose-induced acute memory deficits in vivo, and six potent active peptides including WSREEQ, WSREEQE, WSREEQEREE, ADIYTE, ADIYTEEAG and ADIYTEEAGR were identified. The aim of this study was to investigate the possible mechanism underlying their neuroprotective effects on glutamate-induced apoptosis in PC12 cells and their digestive stability. Results showed that all these peptides could attenuate the reduction of cell viability caused by glutamate in PC12 cells, especially WSREEQEREE and ADIYTEEAGR. The addition of Arg residue in WSREEQEREE and ADIYTEEAGR might be the potential reason for their stronger protective effects. Additionally, these two peptides possibly protected PC12 cells against glutamate-induced apoptosis via activating intracellular antioxidant defence(superoxide dismutase(SOD) and glutathione peroxidase(GSH-Px)) through Kelch-like ECH-associated protein 1(Keap1) inhibition, inhibiting ROS production, Ca;influx and mitochondrial membrane potential(MMP) collapse as well as regulating the expression of apoptosis-related proteins(Bax and Bcl-2). This might be due to the presence of Trp, Tyr and Arg in these two peptides. However, encapsulation of WSREEQEREE and ADIYTEEAGR should be considered based on their digestive sensibility during in vitro gastrointestinal digestion.

Interleukin-4 promotes microglial polarization toward a neuroprotective phenotype after retinal ischemia/reperfusion injury

Glaucoma results from irreversible loss of retinal ganglion cells(RGCs)through an unclear mechanism.Microglial polarization and neuroinflammation play an important role in retinal degeneration.Our study aimed to explore the function of microglial polarization during glaucoma progression and identify a strategy to alleviate retinal neuroinflammation.Retinal ischemia/reperfusion injury was induced in C57BL/6 mice.In a separate cohort of animals,interleukin(IL)-4(50 ng/mL,2μL per injection)or vehicle was intravitreally injected after retinal ischemia/reperfusion injury.RGC loss was assessed by counting cells that were positive for the RGC marker RNA binding protein,mRNA processing factor in retinal flat mounts.The expression of classically activated(M1)and alternatively activated(M2)microglial markers were assessed by quantitative reverse transcription-polymerase chain reaction,immunofluorescence,and western blotting.The results showed that progressive RGC loss was accompanied by a continuous decrease in M2 microglia during the late phase of the 28-day period after retinal ischemia/reperfusion injury.IL-4 was undetectable in the retina at all time points,and intravitreal IL-4 administration markedly improved M2 microglial marker expression and ameliorated RGC loss in the late phase post-retinal ischemia/reperfusion injury.In summary,we observed that IL-4 treatment maintained a high number of M2 microglia after RIR and promoted RGC survival.