Oxidative Stress-induced Neuronal Cell Research Articles

Insights on Quercetin Therapeutic Potential for Neurodegenerative Diseases and its Nano-technological Perspectives.

The neurodegeneration process begins in conjunction with the aging of the neurons. It manifests in different parts of the brain as Aβ plaques, neurofibrillary tangles, Lewy bodies, Pick bodies, and other structures, which leads to progressive loss or death of neurons. Quercetin (QC) is a flavonoid compound found in fruits, tea, and other edible plants have antioxidant effects that have been studied from subcellular compartments to tissue levels in the brain. Also, quercetin has been reported to possess a neuroprotective role by decreasing oxidative stress-induced neuronal cell damage.The use of QC for neurodegenerative therapy, the existence of the blood-brain barrier (BBB) remains a significant barrier to improving the clinical effectiveness of the drug, so finding an innovative solution to develop simultaneous BBB-crossing ability of drugs for treating neurodegenerative disorders and improving neurological outcomes is crucial. The nanoparticle formulation of QC is considered beneficial and useful for its delivery through this route for the treatment of neurodegenerative diseases seems necessary. Increased QC accumulation in the brain tissue and more significant improvements in tissue and cellular levels are among the benefits of QC-involved nanostructures.

Pathogenesis of DJ-1/PARK7-Mediated Parkinson's Disease.

Parkinson's disease (PD) is a common movement disorder associated with the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Mutations in the PD-associated gene PARK7 alter the structure and function of the encoded protein DJ-1, and the resulting autosomal recessively inherited disease increases the risk of developing PD. DJ-1 was first discovered in 1997 as an oncogene and was associated with early-onset PD in 2003. Mutations in DJ-1 account for approximately 1% of all recessively inherited early-onset PD occurrences, and the functions of the protein have been studied extensively. In healthy subjects, DJ-1 acts as an antioxidant and oxidative stress sensor in several neuroprotective mechanisms. It is also involved in mitochondrial homeostasis, regulation of apoptosis, chaperone-mediated autophagy (CMA), and dopamine homeostasis by regulating various signaling pathways, transcription factors, and molecular chaperone functions. While DJ-1 protects neurons against damaging reactive oxygen species, neurotoxins, and mutant α-synuclein, mutations in the protein may lead to inefficient neuroprotection and the progression of PD. As current therapies treat only the symptoms of PD, the development of therapies that directly inhibit oxidative stress-induced neuronal cell death is critical. DJ-1 has been proposed as a potential therapeutic target, while oxidized DJ-1 could operate as a biomarker for PD. In this paper, we review the role of DJ-1 in the pathogenesis of PD by highlighting some of its key neuroprotective functions and the consequences of its dysfunction.

Neuroprotective effect of short-chain fatty acids against oxidative stress-induced SH-SY5Y injury via GPR43-dependent pathway.

A neurodegenerative disorder is a condition that causes a degeneration of neurons in the central nervous system, leading to cognitive impairment and movement disorders. An accumulation of oxidative stress in neurons contributes to the pathogenesis of neurodegenerative disorders. Over the past few years, several studies have suggested that short-chain fatty acids, metabolites of the gut microbiota, might have a beneficial effect in neurodegenerative disorders. A G protein-coupled receptor 43 (GPR43) plays an important role in modulating oxidative stress and inflammatory processes in several tissues. Interestingly, the downstream signaling pathways activated by GPR43 to modulate oxidative stress differ among tissues. Moreover, the cellular mechanisms underlying GPR43 activation in neuronal cells to handle oxidative stress remain unclear. In this present study, we tested the role of GPR43, which is activated by short-chain fatty acids or a specific GPR43 agonist, in an oxidative stress-induced neuronal cell line (SH-SY5Y) injury. Our findings suggest that a combination of short-chain fatty acids with a physiological function could protect neurons from H2 O2 -induced cell damage. The effect of short-chain fatty acids mixture was abolished by pretreatment with a GPR43 antagonist, indicating this protective effect is a GPR43-dependent mechanism. In addition, a specific GPR43 agonist shows a similar result to that found in short-chain fatty acids mixture. Furthermore, our findings indicate that the downstream activation of GPR43 to protect against oxidative stress-induced neuronal injury is a biased Gq activation signaling of GPR43, which results in the prevention of H2 O2 -induced neuronal apoptosis. In conclusion, our results show new insight into the cellular mechanism of GPR43 and its neuroprotective effect. Taken together, this newly discovered finding suggests that activation of the biased Gq signaling pathway of GPR43 might be a potential therapeutic target for aging-related neurodegeneration.

Protective effect of GK2 fused BLVRA protein against oxidative stress-induced dopaminergic neuronal cell damage.

It is well known that oxidative stress is highly associated with Parkinson's disease (PD), and biliverdin reductase A (BLVRA) is known to have antioxidant properties against oxidative stress. In this study, we developed a novel N-acetylgalactosamine kinase (GK2) protein transduction domain (PTD) derived from adenosine A2A and fused with BLVRA to determine whether the GK2-BLVRA fusion protein could protect dopaminergic neuronal cells (SH-SY5Y) from oxidative stress in vitro and in vivo using a PD animal model. GK2-BLVRA was transduced into various cells, including SH-SY5Y cells, without cytotoxic effects, and this fusion protein protected SH-SY5Y cells and reduced reactive oxygen species production and DNA damage after 1-methyl-4-phenylpyridinium (MPP+ ) exposure. GK2-BLVRA suppressed mitogen-activated protein kinase (MAPK) activation and modulated apoptosis-related protein (Bcl-2, Bax, cleaved Caspase-3 and -9) expression levels. In the PD animal model, GK2-BLVRA transduced into the substantia nigra crossed the blood-brain barrier and markedly reduced dopaminergic neuronal cell death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animals. These results indicate that our novel PTD GK-2 is useful for the transduction of protein, and GK2-BLVRA exhibits a beneficial effect against dopaminergic neuronal cell death in vitro and in vivo, suggesting that BLVRA can be used as a therapeutic agent for PD.

Tau promotes oxidative stress-associated cycling neurons in S phase as a pro-survival mechanism: Possible implication for Alzheimer’s disease

Multiple lines of evidence have linked oxidative stress, tau pathology and neuronal cell cycle re-activation to Alzheimer’s disease (AD). While a prevailing idea is that oxidative stress-induced neuronal cell cycle reactivation acts as an upstream trigger for pathological tau phosphorylation, others have identified tau as an inducer of cell cycle abnormalities in both mitotic and postmitotic conditions. In addition, nuclear hypophosphorylated tau has been identified as a key player in the DNA damage response to oxidative stress. Whether and to what extent these observations are causally linked remains unclear. Using immunofluorescence, fluorescence-activated nucleus sorting and single-nucleus sequencing, we report an oxidative stress-associated accumulation of nuclear hypophosphorylated tau in a subpopulation of cycling neurons confined in S phase in AD brains, near amyloid plaques. Tau downregulation in murine neurons revealed an essential role for tau to promote cell cycle progression to S phase and prevent apoptosis in response to oxidative stress. Our results suggest that tau holds oxidative stress-associated cycling neurons in S phase to escape cell death. Together, this study proposes a tau-dependent protective effect of neuronal cell cycle reactivation in AD brains and challenges the current view that the neuronal cell cycle is an early mediator of tau pathology.

The Neuroprotective Effects of Arecae Pericarpium against Glutamate-Induced HT22 Cell Cytotoxicity.

Arecae Pericarpium has been found to exert anti-migraine, antidepressant, and antioxidative effects. However, the mechanisms involved are unclear. This study explored the possibility that Arecae Pericarpium ethanol extract (APE) exerts neuroprotective effects against oxidative stress-induced neuronal cell death. Since glutamate excitotoxicity has been implicated in the pathogenesis and development of several neurodegenerative disorders, we explored the mechanisms of action of APE on oxidative stress-induced by glutamate. Our results revealed that pretreatment with APE prevents glutamate-induced HT22 cell death. APE also reduced both the levels of intracellular reactive oxygen species and the apoptosis of cells, while maintaining glutamate-induced mitochondrial membrane potentials. Western blotting showed that pretreatment with APE facilitates the upregulation of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) phosphorylation; the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2); and the production of antioxidant enzymes, including catalase, glutamate-cysteine ligase catalytic subunits, NAD(P)H quinone oxidoreductase 1, and heme oxygenase (HO)-1. The administration of LY294002, a PI3K/Akt inhibitor, attenuated the neuroprotective effects of APE on oxidative stress-induced neuronal cell damage. This allowed us to infer that the protective effects of APE on oxidative damage to cells can be attributed to the PI3K/Akt-mediated Nrf-2/HO-1 signaling pathway.

Sargachromenol Isolated from Sargassum horneri Attenuates Glutamate-Induced Neuronal Cell Death and Oxidative Stress through Inhibition of MAPK/NF-κB and Activation of Nrf2/HO-1 Signaling Pathway.

Oxidative stress-induced neuronal cell loss is considered to be the major mechanism underlying the pathogenesis of neurodegenerative diseases, which could be induced by a high concentration of glutamate. In this study, sargachromenol (SC) was isolated from a marine brown seaweed Sargassum horneri (S. horneri) and its neuroprotective effects against glutamate-induced oxidative stress in HT22 cells were investigated. An MTT assay was applied to assess the cytotoxicity of the SC, and the efficacies of SC were determined by flow cytometry, an analysis of ROS production, quantitative Real-Time PCR, and the Western blot assay. Our results showed that the pretreatment of SC reduced glutamate-induced apoptosis in HT22 cells via inhibiting the sub-G1 population, DNA fragmentation, and nuclear condensation, as well as up-regulating anti-apoptotic protein (Bcl-2) and down-regulating apoptotic proteins (Bax, p53, cleaved-PARP, caspase-3, caspase-9, and cytochrome c). Additionally, SC attenuated glutamate-induced oxidative stress by suppressing mitogen-activated protein kinases (MAPKs;ERK, JNK, and p38) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling (IκBα and NF-κB p65), while activating nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling (Nrf2; HO-1, and NQO-1). Our results suggest that SC could be used as a pharmacological candidate for the prevention and treatment of neurodegenerative diseases.

Polydatin protects neuronal cells from hydrogen peroxide damage by activating CREB/Ngb signaling.

Oxidative stress-induced neuronal cell death contributes significantly to the physiological processes of a number of neurological disorders. Polydatin (PD) has been reported to protect against Alzheimer's disease (AD), ischemic stroke and traumatic brain injury. However, the underlying neuroprotective mechanisms remain to be elucidated. The current study suggested that PD activates AKT/cAMP response element-binding protein (CREB) signaling and induces neuroglobin (Ngb) to protect neuronal cells from hydrogen peroxide (H2O2) in vitro. PD inhibited the H2O2-induced neuronal cell death of primary mouse cortical neurons and N2a cells. Functional studies showed that PD attenuated H2O2-induced mitochondrial dysfunction and mitochondrial reactive oxygen species production. Mechanistically, PD was verified to induce the phosphorylation of AKT and CREB and increase the protein level of Ngb. The luciferase assay results showed that Ngb transcriptional activity was activated by CREB, especially after PD treatment. It was further indicated that PD increased the transcription of Ngb by enhancing the binding of CREB to the promoter region of Ngb. Finally, Ngb knockdown largely attenuated the neuroprotective role of PD against H2O2. The results indicated that PD protected neuronal cells from H2O2 by activating CREB/Ngb signaling in neuronal cells, indicating that PD has a neuroprotective effect against neurodegenerative diseases.

Antioxidant Properties and Protective Effects of Aerial Parts from Cnidium officinale Makino on Oxidative Stress-Induced Neuronal Cell Death.

The rhizomes of Cnidium officinale Makino have been used as a traditional medicine for many purposes, however, use of its aerial parts is very limited. We investigated the antioxidant properties and protective effects of the aerial parts (leaves and stems) from C. officinale on H2O2-induced toxicity in SH-SY5Y neuroblastoma. C. officinale methanol extracts (70%) were sequentially fractionated using hexane (non-polar fraction, NF), ethyl acetate (intermediate polar fraction, IF), and water (polar fraction, PF). Total phenolics and flavonoids contents were highest in IF, followed by PF. IF also showed the strongest radical scavenging activities against 2,2-diphenyl-2-picrylhydrazyl and 2,2’-azinobis(3-ethylbenzo-thiazoline-6-sulfonic acid), as well as superoxide, with the half maximal inhibitory concentrations of 13.2, 23.2, and 12.8 mg/mL, respectively. Furthermore, all fractions significantly inhibited linoleic acid peroxidation induced by the Fenton reaction or by UV irradiation. Both PF and IF protected against H2O2-induced SH-SY5Y neuronal cell death by increasing the cell survival by 22.1∼47.7 and 35.9∼50.3% at concentrations of 25∼100 and 25∼400 μg/mL, respectively, whereas NF was toxic to the cells at these concentrations. IF also significantly decreased intracellular levels of reactive oxygen species by 7.72∼47.47% at a concentration of 25∼200 μg/mL. Our results indicate that compounds from the aerial parts of C. officinale have potent antioxidant activities, which may help rescue neuronal cells from oxidative stress-induced injury. Therefore, the aerial parts, as well as the rhizomes, of C. officinale may have medicinal applications.

Transduced Tat-PRAS40 prevents dopaminergic neuronal cell death through ROS inhibition and interaction with 14-3-3σ protein

Proline rich Akt substrate (PRAS40) is a component of mammalian target of rapamycin complex 1 (mTORC1) and activated mTORC1 plays important roles for cellular survival in response to oxidative stress. However, the roles of PRAS40 in dopaminergic neuronal cell death have not yet been examined. Here, we examined the roles of Tat-PRAS40 in MPP+- and MPTP-induced dopaminergic neuronal cell death. Our results showed that Tat-PRAS40 effectively transduced into SH-SY5Y cells and inhibited DNA damage, ROS generation, and apoptotic signaling in MPP+-induced SH-SY5Y cells. Further, these protective mechanisms of Tat-PRAS40 protein display through phosphorylation of Tat-PRAS40, Akt and direct interaction with 14-3-3σ protein, but not via the mTOR-dependent signaling pathway. In a Parkinson’s disease animal model, Tat-PRAS40 transduced into dopaminergic neurons in mouse brain and significantly protected against dopaminergic cell death by phosphorylation of Tat-PRAS40, Akt and interaction with 14-3-3σ protein. In this study, we demonstrated for the first time that Tat-PRAS40 directly protects against dopaminergic neuronal cell death. These results indicate that Tat-PRAS40 may provide a useful therapeutic agent against oxidative stress-induced dopaminergic neuronal cell death, which causes diseases such as PD.

Mechanisms and Neuroprotective Activities of Stigmasterol Against Oxidative Stress-Induced Neuronal Cell Death via Sirtuin Family.

Background: Accumulating studies have confirmed that oxidative stress leads to the death of neuronal cells and is associated with the progression of neurodegenerative diseases, including Alzheimer's disease (AD). Despite the compelling evidence, there is a drawback to the use of the antioxidant approach for AD treatment, partly due to limited blood-brain barrier (BBB) permeability. Phytosterol is known to exhibit BBB penetration and exerts various bioactivities such as antioxidant and anticancer effects, and displays a potential treatment for dyslipidemia, cardiovascular disease, and dementia.Objective: In this study, the protective effects of stigmasterol, a phytosterol compound, on cell death induced by hydrogen peroxide (H2O2) were examined in vitro using human neuronal cells (SH-SY5Y cells).Methods: MTT assay, reactive oxygen species measurement, mitochondrial membrane potential assay, apoptotic cell measurement, and protein expression profiles were performed to determine the neuroprotective properties of stigmasterol.Results: H2O2 exposure significantly increased the levels of reactive oxygen species (ROS) within the cells thereby inducing apoptosis. On the contrary, pretreatment with stigmasterol maintained ROS levels inside the cells and prevented oxidative stress-induced cell death. It was found that pre-incubation with stigmasterol also facilitated the upregulation of forkhead box O (FoxO) 3a, catalase, and anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) in the neurons. In addition, the expression levels of sirtuin 1 (SIRT1) were also increased while acetylated lysine levels were decreased, indicating that SIRT1 activity was stimulated by stigmasterol, and the result was comparable with the known SIRT1 activator, resveratrol.Conclusion: Taken together, these results suggest that stigmasterol could be potentially useful to alleviate neurodegeneration induced by oxidative stress.

Kisspeptin-54 attenuates oxidative stress and neuronal apoptosis in early brain injury after subarachnoid hemorrhage in rats via GPR54/ARRB2/AKT/GSK3β signaling pathway

Oxidative stress-induced neuron apoptosis plays a crucial role in the early brain injury (EBI) after subarachnoid hemorrhage (SAH). Kisspeptin has been reported as antioxidant to reduce oxidative stress-induced neuronal cell death through G protein-coupled receptor 54 (GPR54). The goal of this study was to determine the neuroprotection of the Kisspeptin/GRP54 signaling pathway against EBI after SAH. Two hundred and ninety-two Sprague Dawley male rats were used and SAH was induced by the endovascular perforation. Exogenous Kisspeptin 54 (KP54) was delivered intranasally. Small interfering ribonucleic acid (siRNA) for endogenous KISS1, a selective GPR54 antagonist kisspeptin 234, or β-arrestin 2 siRNA for ARRB2 (a functional adaptor of GPR54) were administered intracerebroventricularly. Post-SAH evaluations included neurobehavioral tests, SAH grade, Western blot, immunofluorescence, Fluoro-Jade C, TUNEL, and Nissl staining. The results showed that endogenous KISS1 knockdown aggravated but exogenous KP54 (1.0 nmol/kg) treatment attenuated neurological deficits, brain oxidative stress, and neuronal apoptosis at 24 h after SAH. The benefits of KP54 persisted to 28 days after SAH, which significantly improved cognitive function in SAH rats. The GPR54 blockade or the ARRB2 knockout offset the neuroprotective effects of KP54 in SAH rats. In conclusion, our results suggested that administration of KP54 attenuated oxidative stress, neuronal apoptosis and neurobehavioral impairments through GPR54/ARRB2/AKT/GSK3β signaling pathway after SAH in rat. Thus, KP54 may provide an effective treatment strategy for SAH patients.

Alpha-lipoic acid protects human dopaminergic neuronal cells against hydrogen peroxide-induced cell injury by inhibiting autophagy and apoptosis

Alpha-lipoic acid (ALA) is a naturally occurring antioxidant and has been previously used to treat diabetes and cardiovascular disease. However, the autophagy effects of ALA against oxidative stress-induced dopaminergic neuronal cell injury remain unclear. The aim of this study was to investigate the role of ALA in autophagy and apoptosis against oxidative stress in the SH-SY5Y human dopaminergic neuronal cell line. We examined SH-SY5Y phenotypes using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay (cell viability/proliferation), 4′,6-diamidino-2-phenylindole dihydrochloride nuclear staining, Live/Dead cell assay, cellular reactive oxygen species (ROS) assay, immunoblotting, and immunocytochemistry. Our data showed ALA attenuated hydrogen peroxide (H2O2)-induced ROS generation and cell death. ALA effectively suppressed Bax up-regulation and Bcl-2 and BclxL down-regulation. Furthermore, ALA increased the expression of the antioxidant enzyme, heme oxygenase-1. Moreover, the expression of Beclin-1 and LC-3 autophagy biomarkers was decreased by ALA in our cell model. Combined, these data suggest ALA protects human dopaminergic neuronal cells against H2O2-induced cell injury by inhibiting autophagy and apoptosis.

Erratum: Xiao et al., "The c-Abl-MST1 Signaling Pathway Mediates Oxidative Stress-Induced Neuronal Cell Death".

Erratum: Xiao et al., "The c-Abl-MST1 Signaling Pathway Mediates Oxidative Stress-Induced Neuronal Cell Death".

Protective Role of Transduced Tat-Thioredoxin1 (Trx1) against Oxidative Stress-Induced Neuronal Cell Death via ASK1-MAPK Signal Pathway

Oxidative stress plays a crucial role in the development of neuronal disorders including brain ischemic injury. Thioredoxin 1 (Trx1), a 12 kDa oxidoreductase, has anti-oxidant and anti-apoptotic functions in various cells. It has been highly implicated in brain ischemic injury. However, the protective mechanism of Trx1 against hippocampal neuronal cell death is not identified yet. Using a cell permeable Tat-Trx1 protein, protective mechanism of Trx1 against hydrogen peroxide-induced cell death was examined using HT-22 cells and an ischemic animal model. Transduced Tat-Trx1 markedly inhibited intracellular ROS levels, DNA fragmentation, and cell death in H2O2-treatment HT-22 cells. Tat-Trx1 also significantly inhibited phosphorylation of ASK1 and MAPKs in signaling pathways of HT-22 cells. In addition, Tat-Trx1 regulated expression levels of Akt, NF-κB, and apoptosis related proteins. In an ischemia animal model, Tat-Trx1 markedly protected hippocampal neuronal cell death and reduced astrocytes and microglia activation. These findings indicate that transduced Tat-Trx1 might be a potential therapeutic agent for treating ischemic injury.

Synthesis and neuroprotective effects of novel chalcone-triazole hybrids

The development of novel neuroprotective agents is urgently needed for the treatment of neurodegenerative diseases, affecting aging individuals worldwide. In this study, a new set of chalcone-triazole hybrids (6a-g) was synthesized and evaluated for their biological properties including cytotoxicity, antioxidant, anti-apoptosis, and neuroprotection using SH-SY5Y cells. The results showed that 6a and 6e provided neuroprotection in oxidative stress-induced neuronal cell damage. Both compounds significantly improved the morphology of neurons and obviously increased cell survival rate of neuronal cells induced by oxidative stress. Additionally, 6a and 6e counteracted H2O2‑induced mitochondrial dysfunction, which was supported by maintaining mitochondrial membrane potential, attenuating BAX protein, and increasing BCL‑2 protein within the mitochondria as well as upregulating SOD2 mitochondrial antioxidant enzyme. Interestingly, these compounds promoted neuroprotection via SIRT-FOXO3a signaling pathway similar to resveratrol. The data indicated that the chalcone-triazole derivatives (6a and 6e) could be considered to be promising compounds toward the discovery of disease-modifying candidates for a neurodegenerative therapy.

Tat-Biliverdin Reductase A Exerts a Protective Role in Oxidative Stress-Induced Hippocampal Neuronal Cell Damage by Regulating the Apoptosis and MAPK Signaling.

Reactive oxygen species (ROS) is major risk factor in neuronal diseases including ischemia. Although biliverdin reductase A (BLVRA) plays a pivotal role in cell survival via its antioxidant function, its role in hippocampal neuronal (HT-22) cells and animal ischemic injury is not clearly understood yet. In this study, the effects of transducible fusion protein Tat-BLVRA on H2O2-induced HT-22 cell death and in an animal ischemia model were investigated. Transduced Tat-BLVRA markedly inhibited cell death, DNA fragmentation, and generation of ROS. Transduced Tat-BLVRA inhibited the apoptosis and mitogen activated protein kinase (MAPK) signaling pathway and it passed through the blood-brain barrier (BBB) and significantly prevented hippocampal cell death in an ischemic model. These results suggest that Tat-BLVRA provides a possibility as a therapeutic molecule for ischemia.

Transduced Tat-aldose Reductase Protects Hippocampal Neuronal Cells against Oxidative Stress-induced Damage.

Aldose reductase (AR) protein, a member of the NADPH-dependent aldo-keto reductase family, reduces a wide range of aldehydes and enhances cell survival by inhibition of oxidative stress. Oxidative stress is known as one of the major pathological factor in ischemia. Since the precise function of AR protein in ischemic injury is fully unclear, we examined the function of AR protein in hippocampal neuronal (HT-22) cells and in an animal model of ischemia in this study. Cell permeable Tat-AR protein was produced by fusion of protein transduction domain in Tat for delivery into the cells. Tat-AR protein transduced into HT-22 cells and significantly inhibited cell death and regulated the mitogen-activate protein kinases (MAPKs), Bcl-2, Bax, and Caspase-3 under oxidative stress condition. In an ischemic animal model, Tat-AR protein transduced into the brain tissues through the blood-brain barrier (BBB) and drastically decreased neuronal cell death in hippocampal CA1 region. These results indicate that transduced Tat-AR protein has protective effects against oxidative stress-induced neuronal cell death in vitro and in vivo, suggesting that Tat-AR protein could be used as potential therapeutic agent in ischemic injury.

Annona atemoya Leaf Extract Improves Scopolamine-Induced Memory Impairment by Preventing Hippocampal Cholinergic Dysfunction and Neuronal Cell Death.

We explored the preventative effect of Annona atemoya leaf (AAL) extract on memory impairment in a scopolamine (SCO)-induced cognitive deficit mouse model. Fifty-eight mice were randomly divided into six groups and orally treated with AAL extract at (50, 100, or 200 mg/kg) or tacrine (TAC) for 21 days. Memory deficits were induced by a single injection of 1 mg/kg SCO (i.p.) and memory improvement was evaluated by using behavioral tests such as the passive avoidance task and Y-maze test. The levels of cholinergic functions, neuronal cell death, reactive oxygen species, and protein expression related to hippocampal neurogenesis were examined by immunohistochemical staining and western blotting. The administration of AAL extract improved memory impairment according to increased spontaneous alternation in the Y-maze and step-through latency in passive avoidance test. AAL extract treatment increased the acetylcholine content, choline acetyltransferase, and acetylcholinesterase activity in the hippocampus of SCO-stimulated mice. In addition, AAL extract attenuated oxidative stress-induced neuronal cell death of hippocampal tissue. In terms of the regulatory mechanisms, AAL extract treatment reversed the SCO-induced decreases in the expression of Akt, phosphorylation of cAMP response element binding protein, and brain-derived neurotrophic factor. Our findings demonstrate that AAL extract has the ability to alleviate memory impairment through preventative effect on cholinergic system dysfunction and oxidative stress-related neuronal cell death in a SCO-induced memory deficit animal model. Overall, AAL may be a promising plant resource for the managing memory dysfunction due to neurodegenerative diseases, such as Alzheimer’s disease (AD).

Inhibition of Oxidative Neurotoxicity and Scopolamine-Induced Memory Impairment by γ-Mangostin: In Vitro and In Vivo Evidence.

Among a series of xanthones identified from mangosteen, the fruit of Garcinia mangostana L. (Guttifereae), α- and γ-mangostins are known to be major constituents exhibiting diverse biological activities. However, the effects of γ-mangostin on oxidative neurotoxicity and impaired memory are yet to be elucidated. In the present study, the protective effect of γ-mangostin on oxidative stress-induced neuronal cell death and its underlying action mechanism(s) were investigated and compared to that of α-mangostin using primary cultured rat cortical cells. In addition, the effect of orally administered γ-mangostin on scopolamine-induced memory impairment was evaluated in mice. We found that γ-mangostin exhibited prominent protection against H2O2- or xanthine/xanthine oxidase-induced oxidative neuronal death and inhibited reactive oxygen species (ROS) generation triggered by these oxidative insults. In contrast, α-mangostin had no effects on the oxidative neuronal damage or associated ROS production. We also found that γ-mangostin, not α-mangostin, significantly inhibited H2O2-induced DNA fragmentation and activation of caspases 3 and 9, demonstrating its antiapoptotic action. In addition, only γ-mangostin was found to effectively inhibit lipid peroxidation and DPPH radical formation, while both mangostins inhibited β-secretase activity. Furthermore, we observed that the oral administration of γ-mangostin at dosages of 10 and 30 mg/kg markedly improved scopolamine-induced memory impairment in mice. Collectively, these results provide both in vitro and in vivo evidences for the neuroprotective and memory enhancing effects of γ-mangostin. Multiple mechanisms underlying this neuroprotective action were suggested in this study. Based on our findings, γ-mangostin could serve as a potentially preferable candidate over α-mangostin in combatting oxidative stress-associated neurodegenerative diseases including Alzheimer's disease.