Potential Neuroprotective Mechanism Research Articles

The Ethanolic Extract of Caesalpinia sappan Heartwood Inhibits Cerebral Ischemia/Reperfusion Injury in a Rat Model Through a Multi-Targeted Pharmacological Mechanism.

Background: Caesalpinia sappan L. (C. sappan) is a traditional Chinese medicinal plant. The dried heartwood of C. sappan (also known as Sappan wood) has been widely used for the folkloric medical treatment of ischemic cerebral stroke in China. However, the detailed underlying pharmacological mechanism still remains largely unexplored.Methods: In this study, a middle cerebral artery occlusion (MCAO) rat model was employed to elucidate the mechanism of the anti-cerebral ischemic effects of C. sappan ethanolic extract (CEE). Moreover, systemic multi-target identification coupled with gene ontology biological process (GO BP) and reactome pathway analysis was used to investigate the potential neuroprotective mechanism. Furthermore, the presumed mechanism was confirmed through biological analysis by determining the effects of CEE on the identified signaling pathways in PC12 cells model-induced by oxygen-glucose deprivation/reperfusion (OGD/R).Results: Our study demonstrates that CEE (both through in vivo administration at a dosage of 300 mg/kg and through in vitro incubation at a dosage of 2.4 μg/mL) is a neuroprotective agent that can effectively inhibit neuronal damage, promote synaptic generation, and suppress the activation of neutrophils, microglia, and astrocytes. Moreover, the neuroprotective mechanism of CEE is mediated via regulating 150 potential target proteins, which are associated with 6 biological processes and 10 pathways, including JAK-STAT, HSP90 and DNA damage/telomere stress.Conclusion: CEE can exert neuroprotective effect through multi-target pharmacological mechanisms to prevent ischemia/reperfusion-induced cerebral injury.

Abstract WP143: Acute Treatment With Purinergic Receptor P2X4 Inhibitors Show Neuroprotective and Neuro-Rehabilitation Potential in Ischemic Stroke

Introduction: Stroke remains a leading cause of disability in the United States. Despite recent advances, interventions to reduce damage and enhance recovery after stroke is lacking. Therefore, validating new drug targets is critical for stroke treatment. P2X4, a receptor for adenosine triphosphate ATP, regulate activation of myeloid immune cells (both infiltrating monocytes/macrophages and brain-resident microglia) after stroke injury. Over-stimulation of P2X4Rs, due to excessive ATP release from the dying or damaged neuronal cells, contributes to ischemic injury. In this study, we pharmacologically targeted P2X4R to control immune response of myeloid cells during acute stroke phase and studied recovery at acute or chronic time point after stroke. Methods: We subjected 8-12 weeks old wild type mice of both sexes to 60 min right middle cerebral artery occlusion (MCAo) followed by 3 (acute) or 30 (chronic) days of reperfusion. We performed histological, behavioral (sensorimotor, anxiety and depressive), and flow cytometric analyses to determine the acute and chronic outcomes after P2X4R inhibitor 5-BDBD (1mg/kg P.O daily x3 days started after 4 hrs. of MCAo) treatment. Results: Treatment with 5-BDBD for 3 days not only significantly (*P<0.05) reduced infarct volume (40.94 ± 7.512 N=7 vs 21.21 ± 7.372 N=11, unpaired t-test) and neurological deficit (ND) score at 3 days post-stroke but also showed a progressive recovery on motor and balance coordination using rotarod test (*P<0.05) during chronic recovery at 30 days. 5-BDBD treatments also improved (*P<0.01) anxiety like behavior during the chronic recovery. We did not see any effect on depression like behavior. Flow cytometric analysis reveals that 5-BDBD treatment significantly reduced (*P<0.05) total number of infiltrated leukocytes. Subsequent analysis revealed that among those infiltrated leukocytes the number of Ly6C +hi pro-inflammatory monocytes was reduced in 5-BDBD vs. vehicle treated mice. Conclusions: Acute P2X4R inhibition protects against ischemic injury at both acute and chronic time point after stroke. Reduced number of infiltrated Ly6C +hi proinflammatory monocyte in 5-BDBD treated mice suggests its potential mechanism of neuroprotection after stroke.

Neuroprotection by urate on the mutant hSOD1-related cellular and Drosophila models of amyotrophic lateral sclerosis: Implication for GSH synthesis via activating Akt/GSK3β/Nrf2/GCLC pathways

Oxidative stress has been considered as a principal mechanism of motor neuron death in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease which could be caused by dominant mutations in an antioxidant enzyme superoxide dismutase-1 (SOD1). The aim of the present study was to investigate the potential neuroprotective effects and mechanisms of urate, an important endogenous antioxidant and a biomarker of favorable ALS progression rates, in the mutant human SOD1-related cellular and Drosophila models of ALS. Our results showed that urate treatment provided neuroprotective effects as confirmed by enhanced survival, attenuated motor impairments, reduced oxidative damage and increased antioxidant defense in hSOD1-G85R-expressing Drosophila models of ALS. In vitro studies, we demonstrated that urate protected motor neurons (NSC-34 cells) against hSOD1-G93A-induced cell damage and apoptosis by decreasing reactive oxygen specials (ROS) production and oxidative damage. Moreover, urate markedly increased the expression and activation of nuclear factor erythroid 2-related factor 2 (Nrf2), stimulated Nrf2-targeted antioxidant gene glutathione cysteine ligase catalytic subunit (GCLC) expression and glutathione (GSH) synthesis by upregulating Akt/GSK3β pathway. Furthermore, the inhibition of Akt pathway with LY294002 abolished urate-mediated elevation of GSH synthesis and neuroprotective effects both in vivo and in vitro. Overall, these results suggested that, in addition to its direct scavenging of ROS, urate markedly enhanced GSH expression by activating Akt/GSK3β/Nrf2/GCLC pathway, and thus offering neuroprotective effects on motor neurons against oxidative stress.

Exosomes Derived From Bone Mesenchymal Stem Cells Ameliorate Early Inflammatory Responses Following Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of mortality and disability worldwide. Although treatment guidelines have been developed, no best treatment option or medicine for this condition exists. Recently, mesenchymal stem cells (MSCs)-derived exosomes have shown lots of promise for the treatment of brain disorders, with some results highlighting the neuroprotective effects through neurogenesis and angiogenesis after TBI. However, studies focusing on the role of exosomes in the early stages of neuroinflammation post-TBI are not sufficient. In this study, we investigated the role of bone mesenchymal stem cells (BMSCs)-exosomes in attenuating neuroinflammation at an early stage post-TBI and explored the potential regulatory neuroprotective mechanism. We administered 30 μg protein of BMSCs-exosomes or an equal volume of phosphate-buffered saline (PBS) via the retro-orbital route into C57BL/6 male mice 15 min after controlled cortical impact (CCI)-induced TBI. The results showed that the administration of BMSCs-exosomes reduced the lesion size and improved the neurobehavioral performance assessed by modified Neurological Severity Score (mNSS) and rotarod test. In addition, BMSCs-exosomes inhibited the expression of proapoptosis protein Bcl-2-associated X protein (BAX) and proinflammation cytokines, tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β, while enhancing the expression of the anti-apoptosis protein B-cell lymphoma 2 (BCL-2). Furthermore, BMSCs-exosomes modulated microglia/macrophage polarization by downregulating the expression of inducible nitric oxide synthase (INOS) and upregulating the expression of clusters of differentiation 206 (CD206) and arginase-1 (Arg1). In summary, our result shows that BMSCs-exosomes serve a neuroprotective function by inhibiting early neuroinflammation in TBI mice through modulating the polarization of microglia/macrophages. Further research into this may serve as a potential therapeutic strategy for the future treatment of TBI.

Triterpenic Acids from Potentilla parvifolia and Their Protective Effects against Okadaic Acid Induced Neurotoxicity in Differentiated SH-SY5Y Cells.

Six triterpenic acids were separated and purified from the ethyl acetate extractive fraction of ethanol extracts of Potentilla parvifolia FISCH. using a variety of chromatographic methods. The neuroprotective effects of these triterpenoids were investigated in the present study, in which the okadaic acid induced neurotoxicity in human neuroblastoma SH-SY5Y cells were used as an Alzheimer's disease cell model in vitro. The cell model was established with all trans-retinoic acid (5 µmol/L, 4 d) and okadaic acid (40 nmol/L, 6 h) treatments to induce tau phosphorylation and synaptic atrophy. Subsequently, the neuroprotective effects of these triterpenic acids were evaluated in vitro by this cell model. Results from the Western blot and morphology analysis suggested that compounds 3-6 had the better neuroprotective effects. Furthermore, we tested the level of mitochondrial reactive oxygen species and mitochondrial membrane potential of these compounds in SH-SY5Y cells by flow cytometry technology to investigate the potential neuroprotective mechanism of these compounds. All of the results indicated that maybe the mechanism of compounds 5 and 6 is to protect the cell from mitochondrial oxidative stress injuries.

Protective effect of vinpocetine against neurotoxicity of manganese in adult male rats.

Manganese (Mn) is required for many essential biological processes as well as in the development and functioning of the brain. Extensive accumulation of Mn in the brain may cause central nervous system dysfunction known as manganism, a motor disorder associated with cognitive and neuropsychiatric deficits similar to parkinsonism. Vinpocetine, a synthetic derivative of the alkaloid vincamine, is used to improve the cognitive function in cerebrovascular diseases. It possesses antioxidant and antiinflammatory properties. The present work was designed to explore the potential neuroprotective mechanisms exerted by vinpocetine in the Mn-induced neurotoxicity in rats. Rats were allocated into four groups. First group was given saline. The other three groups were given MnCl2; two of them were treated with either L-dopa, the gold standard antiparkinsonian drug, or vinpocetine. Rats receiving MnCl2 exhibited lengthened catalepsy duration in the grid and bar tests, motor impairment in the open-field test and short-term memory deficit in the Y-maze test. Additionally, histological examination revealed structural alterations and degeneration in different brain regions. Besides, striatal monoamines and mitochondrial complex I contents were declined, apoptotic biomarker caspase-3 expression and acetylcholinesterase activity were elevated. Moreover, oxidative stress and inflammation were detected in the striata. L-dopa or vinpocetine exerted protective effects against MnCl2-induced neurotoxicity. It could be hypothesized that modulation of monoamines, upregulation of mitochondrial complex I, antioxidant, antiinflammatory, and antiapoptotic activities are significant mechanisms underlying the neuroprotective effect of vinpocetine in the Mn-induced neurotoxicity model in rats.

Therapeutic time window and regulation of autophagy by mild hypothermia after intracerebral hemorrhage in rats

Although recent studies have shown that mild hypothermia has neuroprotective effects on intracerebral hemorrhage (ICH), the therapeutic time window of the therapy and the role of autophagy as a potential neuroprotective mechanism remain unclear. This study was aimed to investigate the appropriate time window of mild hypothermia and the regulation of autophagy during the treatment in a rat model of autologous blood-injected ICH injury. The rats were divided into Sham, normothermic (NT) and hypothermic (HT) groups. HT groups received mild hypothermia (33 °C–35 °C) for 48 h starting from 3 h (HT3), 6 h (HT6), and 12 h (HT12) respectively after ICH. The neurological function, brain edema, blood brain barrier (BBB) permeability and volume of tissue loss were tested. The expression of metrix metalloproteinase 9 (MMP-9) and tight junction (TJ) protein including Occludin and Claudin-5 around the hematoma were detected by Western blot. Moreover, autophagy after ICH was detected by the ratio of LC3B-II/I, and the expression of Beclin-1 and p62, while apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dURP nick end labelling (TUNEL) staining and expression of Bcl-2, Bim, cleaved Caspase-3. Compared with NT group, neurological deficit, brain edema and BBB permeability were attenuated in HT6 and HT12 groups, but not in HT3 group, while volume of tissue loss was reduced only in HT12 group. The expression of MMP-9 and the degradation of Occludin and Claudin-5 were suppressed only in HT6 and HT12 groups, especially in the latter one. Moreover, neuronal autophagy and apoptosis induced by ICH were downregulated in HT12 group. The results suggested that mild hypothermia initiated at 6 h or 12 h post-injury was neuroprotective in ICH model of rats, especially at 12 h post-injury, via suppression of autophagy upregulated by ICH.

Melatonin promotes neuroprotection of induced pluripotent stem cells-derived neural stem cells subjected to H2O2-induced injury in vitro

Melatonin is a neurohormone mainly extracted from the pineal gland with neuroprotective effects. It has antioxidant, anti-inflammatory, and antiapoptotic functions. However, the mechanism of melatonin against reactive oxygen species is unclear. Here, we explore the potential proliferative and neuroprotective mechanism of melatonin on induced pluripotent stem cells (iPSC)-derived neural stem cells (NSCs) exposed to hydrogen peroxide (H2O2). NSCs were induced from iPSCs, then pretreated with 500 μM H2O2, 1 μM melatonin, 1 μM melatonin receptor antagonist (Luzindole), or 10 μM Phosphatidylinositide 3 kinase (PI3K) inhibitor (LY294002). The results showed that melatonin stimulated proliferation of iPSC-derived NSCs on H2O2 exposure. Melatonin also markedly improved stabilization of the mitochondrial membrane potential and reduced the rate of apoptosis. Treatment with Luzindole or LY294002 inhibited the increasing proliferative and neuroprotective effects of melatonin on iPSC-derived NSCs with H2O2 treatment. Our results further demonstrated that these promotional effects of melatonin were related with the activity of phosphorylation of AKT. Therefore, these outcomes propose that melatonin protects iPSC-derived NSCs from H2O2-induced injury through the mediation of melatonin receptor and PI3K/AKT signaling pathway.

Neuroprotective effects of progesterone in acute brain trauma and its physiological mechanism

Traumatic brain injury (TBI) is the leading cause of death and neurological disability in young adults worldwide. This work aims to review the role of progesterone in traumatic brain injury and the usefulness as a possible treatment. We searched pubmed database (2000-2017) for articles containing “progesterone and brain traumatic injury”. Basic science studies have advanced knowledge of the mechanisms of secondary brain injury, creating prospects for the medical and pharmacological management of TBI. Although several comparative studies evaluated both the efficacy and safety of several groups of drugs, in which, corticosteroids, tranexamic acid, β receptor antagonists, erythropoiesis-stimulating agents, reductase inhibitors include hydroxymethyl glutaryl-CoA inhibitors (statins), among others. Several studies even evaluated the role of progesterone in the treatment of TBI, which is providing growing evidence about its potential neuroprotective mechanisms during the acute phase of trauma. Despite recent advances in the field of management of TBI care in the emergency units, intensive care and the multiple trials for more than 20 years to find useful pharmacological treatments, most of these efforts failed in pre-clinical stages (II and III).

Progesterone suppresses Aβ42-induced neuroinflammation by enhancing autophagy in astrocytes

Autophagy is an intracellular catabolic mechanism essential for recycling intracellular unfolding protein and eliminating toxic protein aggregates. Several studies have shown that deficient autophagy is implicated in the development of Alzheimer's disease (AD) progression. To date, rapidly emerging evidence suggests that neurosteroid progesterone (PG) may play an important role in ameliorating AD. However, the role of PG and its neuroprotective mechanism in regulating autophagy still require further investigation. Here, we investigated the protective effects of PG against Aβ-induced inflammatory responses in astrocytes and its underlying mechanism in mediating autophagy. Remarkably, Aβ induced astrocyte dysfunction in autophagic activation and up-regulated inflammatory secretion. However, the autophagy inducer rapamycin (RAPA) significantly suppressed Aβ-induced inflammation in astrocytes. In astrocytes, treatment with Aβ caused autophagy deficiency, whereas PG significantly increased autophagy activation. Finally, PG suppressed Aβ-induced neuroinflammatory production via enhancing autophagy together with regulating mTOR signaling. Taken together, these results show that autophagy is a vital mechanism against Aβ-induced neuroinflammatory responses in astrocytes and demonstrate the potential neuroprotective mechanism of PG in suppressing neuroinflammatory responses by enhancing autophagy. Therefore, uncovering the neuroprotective mechanism of PG may provide new insight into novel therapies for the amelioration of AD.

Fingolimod induces neuronal-specific gene expression with potential neuroprotective outcomes in maturing neuronal progenitor cells exposed to HIV

Fingolimod (FTY720), a structural analogue of sphingosine, targets sphingosine-1-phosphate receptor signaling and is currently an immunomodulatory therapy for multiple sclerosis. Fingolimod accesses the central nervous system (CNS) where its active metabolite, fingolimod phosphate (FTY720-P), has pleotropic neuroprotective effects in an inflammatory microenvironment. To investigate potential neuronal-specific mechanisms of fingolimod neuroprotection, we cultured the human neuronal progenitor cell line, hNP1, in differentiation medium supplemented with HIV- or Mock-infected supernatants, with or without FTY720-P. Gene expression was investigated using microarray and functional genomics. FTY720-P treatment increased differentially expressed (DE) neuronal genes by 33% in HIV-exposed and 40% in Mock-exposed cultures. FTY720-P treatment broadened the functional profile of DE genes in HIV-exposed versus Mock-exposed neurons, including not only immune responses but also transcriptional regulation and cell differentiation, among others. FTY720-P treatment downregulated the gene for follistatin, the antagonist of activin signaling, in all culture conditions. FTY720-P treatment differentially affected both glycolysis-related and immune response genes in Mock- or HIV-exposed cultures, significantly upregulating 11 glycolysis-related genes in HIV-exposed neurons. FTY720-P treatment also differentially upregulated genes related to innate immune responses and antigen presentation in Mock-exposed and more so in HIV-exposed neurons. However, in HIV-exposed neurons, FTY720-P depressed the magnitude of differential expression in almost half the genes, suggesting an anti-inflammatory potential. Moreover, in HIV-exposed neurons, FTY720-P reduced expression of the amyloid precursor protein (APP) gene, resulting in reduced expression of the APP protein. This study provides new evidence that fingolimod alters neuronal gene expression in inflammatory, viral-infected microenvironments, with the potential for neuroprotective effects.

Ginsenosides Rd and Re co-treatments improve rotenone-induced oxidative stress and mitochondrial impairment in SH-SY5Y neuroblastoma cells

Oxidative stress and mitochondrial dysfunction play key roles in Parkinson's disease (PD) initiation and progression. Ginsenosides are major compounds of Ginseng species and they are responsible for pharmacological activity. The aim of this study was to investigate the potential neuroprotective effects and mechanism of the major ginsenosides Rd and Re in rotenone-induced oxidative stress model in human neuroblastoma SH-SY5Y cells. Co-treatments with both ginsenosides inhibited the increased intracellular ROS production and by-products lipid peroxidation accumulation caused by rotenone. Moreover, these ginsenosides upregulated SOD and aconitase enzymes activities, and glutathione system; these antioxidant properties are related to Nrf2 induction and radical scavenger effect. Additionally, the results showed that both Rd and Re attenuated the extent of depolarization of mitochondrial membrane potential and restored calcium levels. Furthermore, these compounds prevented apoptosis by modulating Bax and Bcl-2 proteins and inhibiting cytochrome c release and caspase-3 activation. The ginsenoside Rd resulted to be more active than ginsenoside Re. These findings highlighted the efficacy of these compounds as neuroprotectant compounds for PD prevention and treatment through reducing oxidative stress, improving mitochondrial integrity and functions, and inhibiting apoptosis.

Nerve growth factor pretreatment inhibits lidocaine‑induced myelin damage via increasing BDNF expression and inhibiting p38 mitogen activation in the rat spinal cord.

The present study aimed to investigate the effect of exogenous nerve growth factor (NGF) pretreatment on demyelination in the spinal cord of lidocaine-treated rats, and explored the potential neuroprotective mechanisms of NGF. A total of 36 rats were randomly assigned to three groups (n=12 per group): Sham group; Lido group, received intrathecal injection of lidocaine; NGF group, received intrathecal injection of NGF followed by intrathecal injection of lidocaine. Tail-flick tests were used to evaluate neurobehavioral function. Ultrastructural alternations were analyzed by transmission electron microscopy. Immunofluorescence was used to examine the expression of myelin basic protein (MBP) and brain-derived neurotrophic factor (BDNF). ELISA was used to determine serum levels of MBP and proteolipid protein (PLP). Western blotting was used to detect the expression of phosphorylated mitogen activated protein kinase (MAPK). NGF pretreatment reduced lidocaine-induced neurobehavioral damage, nerve fiber demyelination, accompanied by a decrease in MBP expression in the spinal cord and an increase in MBP and PLP in serum. In addition, NGF pretreatment increased BDNF expression in the spinal cord of lidocaine-treated rats. Furthermore, NGF pretreatment reduced p38 MAPK phosphorylation in the spinal cord of lidocaine-treated rats. NGF treatment reduces lidocaine-induced neurotoxicity via the upregulation of BDNF and inhibition of p38 MAPK. NGF therapy may improve the clinical use of lidocaine in intravertebral anesthesia.

Neuroglobin Protects Rats from Sepsis-Associated Encephalopathy via a PI3K/Akt/Bax-Dependent Mechanism.

Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, and has no generally accepted treatment due to its complicated pathophysiology. Previously, we demonstrated the protective role of neuroglobin (Ngb) in SAE rats, but the exact mechanism has not been determined. To investigate the potential neuroprotective roles and mechanisms of Ngb, Sprague-Dawley rats were used. Overexpression of Ngb via intracerebroventricular injection with Ngb plasmids attenuated brain damage assessed by hematoxylin and eosin (HE) staining and neurological dysfunction assessed by Morris water maze test. Western blot analysis also showed that the phosphorylation of Akt increased and the protein level of Bax decreased. Furthermore, the protective effect can be abolished by PI3K/Akt pathway inhibitor LY294002. Our results demonstrate that Ngb can protect rats from SAE via a PI3K/Akt/Bax-dependent mechanism.

SK2 channels regulate mitochondrial respiration and mitochondrial Ca2+ uptake.

Mitochondrial calcium ([Ca2+]m) overload and changes in mitochondrial metabolism are key players in neuronal death. Small conductance calcium-activated potassium (SK) channels provide protection in different paradigms of neuronal cell death. Recently, SK channels were identified at the inner mitochondrial membrane, however, their particular role in the observed neuroprotection remains unclear. Here, we show a potential neuroprotective mechanism that involves attenuation of [Ca2+]m uptake upon SK channel activation as detected by time lapse mitochondrial Ca2+ measurements with the Ca2+-binding mitochondria-targeted aequorin and FRET-based [Ca2+]m probes. High-resolution respirometry revealed a reduction in mitochondrial respiration and complex I activity upon pharmacological activation and overexpression of mitochondrial SK2 channels resulting in reduced mitochondrial ROS formation. Overexpression of mitochondria-targeted SK2 channels enhanced mitochondrial resilience against neuronal death, and this effect was inhibited by overexpression of a mitochondria-targeted dominant-negative SK2 channel. These findings suggest that SK channels provide neuroprotection by reducing [Ca2+]m uptake and mitochondrial respiration in conditions, where sustained mitochondrial damage determines progressive neuronal death.

Lumbee traditional medicine: Neuroprotective activities of medicinal plants used to treat Parkinson's disease-related symptoms

Ethnopharmacological relevanceParkinson's disease (PD) is a neurodegenerative disorder characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta and the presence in surviving neurons of Lewy body inclusions enriched with aggregated forms of the presynaptic protein α-synuclein (aSyn). Although current therapies provide temporary symptomatic relief, they do not slow the underlying neurodegeneration in the midbrain. In this study, we analyzed contemporary herbal medicinal practices used by members of the Lumbee tribe to treat PD-related symptoms, in an effort to identify safe and effective herbal medicines to treat PD. Aim of the studyThe aims of this study were to (i) document medicinal plants used by Lumbee Indians to treat PD and PD-related symptoms, and (ii) characterize a subset of plant candidates in terms of their ability to alleviate neurotoxicity elicited by PD-related insults and their potential mechanisms of neuroprotection. Materials and methodsInterviews of Lumbee healers and local people were carried out in Pembroke, North Carolina, and in surrounding towns. Plant samples were collected and prepared as water extracts for subsequent analysis. Extracts were characterized in terms of their ability to induce activation of the nuclear factor E2-related factor 2 (Nrf2) antioxidant response in cortical astrocytes. An extract prepared from Sambucus caerulea flowers (elderflower extract) was further examined for the ability to induce Nrf2-mediated transcription in induced pluripotent stem cell (iPSC)-derived astrocytes and primary midbrain cultures, to ameliorate mitochondrial dysfunction, and to alleviate rotenone- or aSyn-mediated neurotoxicity. ResultsThe ethnopharmacological interviews resulted in the documentation of 32 medicinal plants used to treat PD-related symptoms and 40 plants used to treat other disorders. A polyphenol-rich extract prepared from elderflower activated the Nrf2-mediated antioxidant response in cortical astrocytes, iPSC-derived astrocytes, and primary midbrain cultures, apparently via the inhibition of Nrf2 degradation mediated by the ubiquitin proteasome system. Furthermore, the elderflower extract rescued mitochondrial functional deficits in a neuronal cell line and alleviated neurotoxicity elicited by rotenone and aSyn in primary midbrain cultures. ConclusionsThese results highlight potential therapeutic benefits of botanical extracts used in traditional Lumbee medicine, and they provide insight into mechanisms by which an elderflower extract could suppress neurotoxicity elicited by environmental and genetic PD-related insults.

Abstract TP270: Ischemic Preconditioning-afforded Neuroprotection Against Ischemic Stroke is Associated With Altered Peripheral Immune Responses

The limb remote ischemic preconditioning (RIPC) is considered a clinical feasible protective strategy against ischemia-reperfusion injury after stroke. However, its mechanisms of protection remain elusive. Here, we used a rat model of non-invasive RIPC by tourniquet to study the impact of RIPC on the immune cell and cytokine profiles after transient middle cerebral artery occlusion. Our data indicates that RIPC protects against focal ischemia and preserves neurological functions 3 days after stroke. Meanwhile, RIPC results in dramatic changes in several immune cell populations after stroke. Specifically, the RIPC ameliorated the post-MCAO reduction of blood CD3+CD8+ T cells and abolished the reduction of CD3+/CD161a+ NKT cells. Another striking change is that RIPC significantly elevated the B cell percentage in peripheral blood, which reversed the otherwise reduced B cell population after stroke. RIPC also markedly elevated the percentage of CD43+/CD172a+ non-inflammatory residential monocytes, while showing no effect on the percentage CD43-/CD172a+ inflammatory monocytes. In addition, we found that RIPC induced IL-6 expression and enhanced the elevation of TNFα after stroke. Collectively, our results reveal potential immune mechanisms of RIPC-afforded neuroprotection against cerebral ischemia. Further exploration about these immune elements in RIPC-afforded ischemic tolerance may lead to the development of systemically administered immune therapies for stroke patients.

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

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

Focal cerebral ischemia and neurovascular protection: a bench-to-bedside update.

To date, many pharmacological approaches, or combination of approaches, have been applied to experimental models of focal cerebral ischemia (FCI), but their translation to clinically effective agents has proved unsuccessful. To date, only thrombolysis with recombinant tissue-type plasminogen activator, or other 'clot-breaking' or 'clot-removal' approaches, have proved effective for acute stroke. This review, therefore, focuses on the 'vascular' phenomena involved in the development of FCI. Recent advances in the experimental literature on FCI describe the microvascular characteristics of the ischemic penumbra, the consequences of cortical spreading depression on impairing cerebral perfusion, and the potential neuroprotective mechanisms of ischemic preconditioning via antithrombotic effects on the neurovascular unit. This review provides a perspective about the neurovascular components contributing to the pathophysiology of FCI, and some relevant clinical strategies available on the horizon that hold promise for improved cerebral perfusion in FCI.

Neuroglobin Attenuates Beta Amyloid-Induced Apoptosis Through Inhibiting Caspases Activity by Activating PI3K/Akt Signaling Pathway.

Excessive accumulation and deposition of amyloid-beta (Aβ) has been considered as a pivotal event in the pathogenesis of Alzheimer's disease (AD). Neuronal apoptosis is one of the characteristics of AD, which is a possible mechanism underlying Aβ-induced neuronal neurotoxicity. Neuroglobin (Ngb) is a newly discovered vertebrate heme protein that exhibits neuroprotective functions against cell death associated with hypoxic and amyloid insult. However, until now, the exact mechanism of neuroglobin's protective action has not been determined. To investigate the potential neuroprotective roles and mechanisms of Ngb, transgenic AD mice (APPswe/PSEN1dE9) and SH-SY5Y cells transfected with pAPPswe were enrolled into the study. In vivo, overexpression of Ngb via intracerebroventricular injection with pNgb attenuated memory, cognitive impairment, and plaque generations. In pAPPswe transfected SH-SY5Y cells, Ngb not only decreased the generation of Aβ42, but also attenuated mitochondrial dysfunction and apoptosis through suppressing the activation of caspase-3, caspase-9 by Akt activating phosphorylation, which were restrained by phosphatidylinositol 3-kinase inhibitor (LY294002). Our data indicate the anti-apoptotic property of Ngb may play a neuroprotective role against AD.