Protection Of Hippocampal Neurons Research Articles

Comprehensive characterization of the neurogenic and neuroprotective action of a novel TrkB agonist using mouse and human stem cell models of Alzheimer’s disease

BackgroundNeural stem cell (NSC) proliferation and differentiation in the mammalian brain decreases to minimal levels postnatally. Nevertheless, neurogenic niches persist in the adult cortex and hippocampus in rodents, primates and humans, with adult NSC differentiation sharing key regulatory mechanisms with development. Adult neurogenesis impairments have been linked to Alzheimer’s disease (AD) pathology. Addressing these impairments by using neurotrophic factors is a promising new avenue for therapeutic intervention based on neurogenesis. However, this possibility has been hindered by technical difficulties of using in-vivo models to conduct screens, including working with scarce NSCs in the adult brain and differences between human and mouse models or ethical limitations.MethodsHere, we use a combination of mouse and human stem cell models for comprehensive in-vitro characterization of a novel neurogenic compound, focusing on the brain-derived neurotrophic factor (BDNF) pathway. The ability of ENT-A011, a steroidal dehydroepiandrosterone derivative, to activate the tyrosine receptor kinase B (TrkB) receptor was tested through western blotting in NIH-3T3 cells and its neurogenic and neuroprotective action were assessed through proliferation, cell death and Amyloid-β (Aβ) toxicity assays in mouse primary adult hippocampal NSCs, mouse embryonic cortical NSCs and neural progenitor cells (NPCs) differentiated from three human induced pluripotent stem cell lines from healthy and AD donors. RNA-seq profiling was used to assess if the compound acts through the same gene network as BDNF in human NPCs.ResultsENT-A011 was able to increase proliferation of mouse primary adult hippocampal NSCs and embryonic cortical NSCs, in the absence of EGF/FGF, while reducing Aβ-induced cell death, acting selectively through TrkB activation. The compound was able to increase astrocytic gene markers involved in NSC maintenance, protect hippocampal neurons from Αβ toxicity and prevent synapse loss after Aβ treatment. ENT-A011 successfully induces proliferation and prevents cell death after Aβ toxicity in human NPCs, acting through a core gene network shared with BDNF as shown through RNA-seq.ConclusionsOur work characterizes a novel BDNF mimetic with preferable pharmacological properties and neurogenic and neuroprotective actions in Alzheimer’s disease via stem cell-based screening, demonstrating the promise of stem cell systems for short-listing competitive candidates for further testing.

Young Astrocytic Mitochondria Attenuate the Elevated Level of CCL11 in the Aged Mice, Contributing to Cognitive Function Improvement

Aging drives cognitive decline, and mitochondrial dysfunction is a hallmark of age-induced neurodegeneration. Recently, we demonstrated that astrocytes secrete functional mitochondria (Mt), which help adjacent cells to resist damage and promote repair after neurological injuries. However, the relationship between age-dependent changes in astrocytic Mt function and cognitive decline remains poorly understood. Here, we established that aged astrocytes secret less functional Mt compared to young astrocytes. We found the aging factor C-C motif chemokine 11 (CCL11) is elevated in the hippocampus of aged mice, and that its level is reduced upon systemic administration of young Mt, in vivo. Aged mice receiving young Mt, but not aged Mt improved cognitive function and hippocampal integrity. Using a CCL11-induced aging-like model in vitro, we found that astrocytic Mt protect hippocampal neurons and enhance a regenerative environment through upregulating synaptogenesis-related gene expression and anti-oxidants that were suppressed by CCL11. Moreover, the inhibition of CCL11-specific receptor C-C chemokine receptor 3 (CCR3) boosted the expression of synaptogenesis-related genes in the cultured hippocampal neurons and restored the neurite outgrowth. This study suggests that young astrocytic Mt can preserve cognitive function in the CCL11-mediated aging brain by promoting neuronal survival and neuroplasticity in the hippocampus.

Eleutheroside E supplementation prevents radiation-induced cognitive impairment and activates PKA signaling via gut microbiota

Radiation affects not only cognitive function but also gut microbiota. Eleutheroside E (EE), a principal active compound of Acanthopanax senticosus, has a certain protective effect on the nervous system. Here, we find a four-week EE supplementation to the 60Co-γ ray irradiated mice improves the cognition and spatial memory impairments along with the protection of hippocampal neurons, remodels the gut microbiota, especially changes of Lactobacillus and Helicobacter, and altered the microbial metabolites including neurotransmitters (GABA, NE, ACH, 5-HT) as well as their precursors. Furthermore, the fecal transplantation of EE donors verifies that EE alleviated cognition and spatial memory impairments, and activates the PKA/CREB/BDNF signaling via gut microbiota. Our findings provide insight into the mechanism of EE effect on the gut-brain axis and underpin a proposed therapeutic value of EE in cognitive and memory impairments induced by radiation.

Activation of Cannabinoid Receptor 2 Protects Rat Hippocampal Neurons against Chronic, Oligomeric A_-induced Neuronal Hyperexcitation

There is a significantly elevated incidence of epilepsy in Alzheimer’s disease (AD). Burgeoning evidence indicates that soluble beta-amyloid peptides oligomers (oAβ) are vital players in driving neuronal hyperactivity in AD. It is well known that the modulations of the cannabinoid system exhibit neuroprotective effects in various neurological diseases, including AD. However, a consensus is yet to emerge as to the impact of hippocampal cannabinoid receptor 2 (CB2R) in protecting hippocampal neurons against Aβ-induced neuronal hyperexcitation. Here, we report that chronic treatment of primary hippocampal neuronal cultures with 100 nM Aβ1–42 oligomers for 7 days results in a neuronal hyperexcitation. Further, pre-treatments of CB2R agonist (JWH133, 1 μM with Aβ1–42 for 7 days) significantly protect hippocampal neurons against Aβ-increased hyperexcitation, including prolonged action potential (AP) initiation, enhanced after hyperpolarization (AHP), and decreased AP numbers. These effects are eliminated by a selective CB2R antagonist, AM630. Furthermore, when the oAβ-increased neuronal hyperexcitation has already formed (pretreated with oAβ1–42 for 5 days), the addition of JWH133 also abolishes the Aβ’s effects. Collectively, our results suggest that the selective activation of hippocampal CB2Rs not only prevents Aβ-increased neuronal hyperexcitation, but also abolishes the established neuronal hyperexcitation, which underlies our recent findings that CB2Rs play a critical role in protection of hippocampal neurons against the Aβ-induced neuronal toxicity and degeneration. This novel finding suggests a potentially therapeutic strategy for the treatment of AD using CB2R agonists.

Embelin prevents amyloid-beta accumulation via modulation of SOD1 in a Streptozotocin-induced AD-like condition: An evidence from in vitro investigation.

Embelin is a neuroprotective compound with therapeutic benefit against experimental Alzheimer's disease (AD)-like condition. In the quest of untangling the underlying mechanism behind the neuroprotective effect of Embelin in AD, an in-vitro study of Embelin against neuronal damage induced by Streptozotocin (STZ) in rat hippocampal neuronal culture was performed. Current findings demonstrated that Embelin (2.5-10μM) has efficiently protected hippocampal neurons against STZ (8mM)-induced neurotoxicity. An increase in amyloid precursor protein (APP), microtubule-associated protein tau (MAPT), glycogen synthase kinase 3 alpha (GSK-3α) and glycogen synthase kinase 3 beta (GSK-3β) expression levels was observed when STZ (8mM) stimulation was done for 24h in the hippocampal neurons. A significant downregulation in the mRNA expression levels of APP, MAPT, GSK-3α, and GSK-3β upon pre-treatment with different doses of Embelin (2.5μM, 5μM and 10μM) reflects that Embelin attenuated STZ-induced dysfunction of insulin signaling (IR). Embelin significantly modulated the mRNA expression of scavenger enzyme Superoxide dismutase (SOD1). Furthermore, STZ had significantly upregulates an expression of Aβ. On the contrary, pre-treatment with three doses of Embelin reversed an Aβ-induced neuronal death. Our findings suggest that, Embelin prevents Aβ accumulation via SOD1 pathway to protect against AD-like condition.

Role of the p38MAPK signaling pathway in hippocampal neuron autophagy in rats with chronic intermittent hypoxia.

This study explored the role of the p38 mitogen-activated protein kinase (MAPK) signaling pathway in hippocampal neuron autophagy in rats with chronic intermittent hypoxia (CIH). Male Sprague-Dawley rats were randomly divided to normoxic control (CON), CIH (optimal modeling time was determined prior by measuring the expression of several proteins after 2-, 4-, and 6-wk intermittent hypoxia), solvent (CIH+Veh), or p38MAPK inhibitor (CIH+SB203580) groups. DMSO and SB203580 were injected intraperitoneally 30 min before hypoxia in CIH+Veh and CIH+SB203580 group rats, respectively. Rat learning and memory were evaluated via the Morris water maze test. Ultrastructural changes in the hippocampal CA1 region autophagic vesicles and neurons were observed under transmission electron and light microscopy. Hippocampal microtubule-associated proteins were detected by western blot. Morris water maze test showed that CIH+SB203580 group rats spent significantly more time on the platform quadrant and crossed the platform more times than CIH+Veh group rats (P < 0.01). Hematoxylin-eosin (HE) staining showed greater rat cell damage in the CIH+SB group than in the CIH and CIH+Veh groups. Western blot analysis showed that CIH+SB group rats had significantly lower p-p38MAPK/p38MAPK, LC3I, and p62 expression and higher beclin-1 expression than CIH+Veh group rats (P < 0.01). Electron microscopy showed that CIH+SB203580 group rats had several small hippocampal neuron autophagic vesicles. On immunofluorescence analyses, it showed a higher LC3II expression in CIH+SB203580 group rats than in CIH+Veh group rats (P < 0.01). These results indicate that inhibition of the CIH p38MAPK signaling pathway can activate autophagy and protect hippocampal neurons in rats.NEW & NOTEWORTHY The pathophysiological processes related to autophagy obstructive sleep apnea-hypopnea syndrome (OSAHS) are unclear. This study clarified that the inhibition of the p38MAPK signaling pathway could further activate autophagy in hippocampal nerve cells, thus reducing nerve cell injury.

Ameliorative effects of olibanum essential oil on learning and memory in Aβ1-42-induced Alzheimer’s disease mouse model

Purpose: To study the effect of olibanum essential oil (OEO) on learning and memory in Alzheimer’s disease (AD) mouse.Methods: Mice were administered the 42-amino acid form of amyloid β-peptide (Aβ1-42) to induce AD and then treated with OEO at 150, 300, and 600 mg/kg, p.o. for two weeks. Following treatment, the AD mice were assessed by step-down test (SDT), dark avoidance test (DAT), and Morris water maze test (MWM). Blood and brain tissues were collected for biochemical assessments. Gas chromatographymass spectroscopy was used to analyze the main constituents of OEO.Results: The main constituents of OEO were limonene, α-pinene, and 4-terpineol. Treatment with OEO prolonged t latency in SDT and DAT, but decreased error times. Escape latency decreased and crossing times were rose in the MWM following OEO treatment (p &lt; 0.5). Treatment with OEO also enhanced the acetylcholine levels and decreased the acetylcholinesterase levels in serum and brain tissue (p &lt; 0.5). Additionally, OEO reduced amyloid plaques in the hippocampus and protected hippocampal neurons from damage. Furthermore, OEO decreased c-fos expression in hippocampus tissues from AD mice (p &lt; 0.5).Conclusion: OEO has significant ameliorative effect AD-induced deterioration in learning and memory in AD mouse induced by Aβ1-42. The mechanisms of these effects are related to increased acetylcholine contents, reduction of amyloid plaques, protection of hippocampal neurons, and downregulation of c-fos in brain tissues. The results justify the need for further investigation of candidate drugs derived from OEO for the management of AD.&#x0D; Keywords: Olibanum, Essential oil, Learning, Memory, AD

Probiotics protect against gut dysbiosis associated decline in learning and memory

Gut-Brain-Axis imbalance due to gut dysbiosis by antibiotics may lead to neurobehavioral changes. Here we determine neuroprotective effect of probiotic against gut dysbiosis associated decline in learning and memory. Oral Ampicillin was used to induce gut dysbiosis while probiotic was administered along with antibiotic as treatment in Swiss albino mice. Antibiotic decreased Lactobacillus, Bifidobacterium, Firmicutes and Clostridium level. This was followed by reduced cognition, hippocampal neuronal density, intestinal crypt depth, villus length and increased corticohippocampal acetylcholinesterase, myeloperoxidase activity and oxidative stress which were partially reversed by probiotic treatment. Probiotic protected hippocampal neurons from gut dysbiosis associated inflammatory and oxidative damage in mice.

Activation of cannabinoid receptor 2 protects rat hippocampal neurons against Aβ-induced neuronal toxicity

Alzheimer’s disease (AD) is a dementing, neurodegenerative disorder characterized by increased accumulation of beta-amyloid peptides (Aβ), degeneration of hippocampal neurons and the gradual development of learning and memory deficits. Therapeutically, there are still no ideal medicines available and this represents an urgent need for the development of new strategies to treat AD. Emerging lines of evidence suggest that modulation of the cannabinoid system exhibits neuroprotective effects in various neurological diseases, including AD. However, a consensus is yet to emerge as to the impact of hippocampal cannabinoid receptor 2 (CB2R) in protection of hippocampal neurons against Aβ induced neuronal toxicity. Here, we report that chronic treatment of primary hippocampal neuronal cultures with 100 nM Aβ1–42 oligomers for 7 days results in neurotoxicity, which includes increases in lactate dehydrogenase (LDH) levels, suggesting an Aβ1–42 –induced neuron apoptosis. Further, chronic Aβ1–42 reduces the ratio of phosphorylated Akt (pAkt)/Akt, in turn decreases neuronal Bcl-2/Bax ratio, and leads to an increase of caspase-3, which likely underlines the signal pathway of chronic Aβ1–42–induced neuron apoptosis. Interestingly, pre-treatments of CB2R agonist (JWH133, 10 μM) with Aβ1–42 prevents Aβ1–42-induced the decrease of pAkt/Akt ratio, the decrease of Bcl-2/Bax ratio, and the increase of caspase-3, and protects hippocampal neurons against Aβ1–42-induced apoptosis. All neuroprotective effects of JWH133 are abolished by a selective CB2R antagonist, AM630. Taken together, the activation of hippocampal CB2Rs protects neurons against Aβ1–42 toxicity, and the CB2R-mediated enhancement of the pAkt signaling is likely involved in the protection of hippocampal neurons against Aβ1–42-induced neuronal toxicity.

LncRNA RPPH1 attenuates Aβ25-35-induced endoplasmic reticulum stress and apoptosis in SH-SY5Y cells via miR-326/PKM2

Background The durative endoplasmic reticulum stress (ERS) and subsequent apoptosis contributes to the development and progression of Alzheimer’s disease (AD). MiR-326 can reduce pyruvate kinase M2 (PKM2) expression, leading to ERS. Whereas, lncRNA RPPH1 is able to increase dendritic spine density and protect hippocampal pyramidal neurons through targeting miR-326. Our study aims to investigate the regulation of lncRNA RPPH1 and miR-326/PKM2 on ERS and related apoptosis in AD. Methods SH-SY5Y cells treated with Aβ25-35 were selected as an in vitro AD model. RPPH1 and miR-326 overexpression and silencing cells were established by transforming vectors. The expression of RPPH1 and miR-326 were detected by qRT-PCR. MTT, flow cytometric, intracellular calcium assay and Western blot were used to test the functions of RPPH1 and miR-326 in SH-SY5Y cell proliferation, apoptosis and ERS. Dual-luciferase assay was used to detect the interaction among RPPH1, miR-326 and PKM2. Results RPPH1 overexpression enhanced the viability of SH-SY5Y cells, and attenuated the apoptosis of of SH-SY5Y cells. Moreover, RPPH1 overexpression down-regulated ER stress related proteins such as GRP78, CHOP and cleaved caspase-12. Mechanistically, RPPH1 directly targeted miR-326, thereby counteracting its inhibitory effect on PKM2 expression, contributing to attenuation of apoptosis and ERS induced by Aβ25-35. Conclusion Aβ25-35-induced ERS and apoptosis in SH-SY5Y cells can be attenuated by lncRNA RPPH1 through regulating miR-326/PKM2 axis. This study provided therapeutic options for AD patients.

Upregulation of neuronal PGC-1α ameliorates cognitive impairment induced by chronic cerebral hypoperfusion.

Rationale: Mitochondrial dysfunction and oxidative stress occur in vascular dementia (VaD), but the specific molecular mechanism regulating these events remains unclear. Peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) is a master regulator for mitochondrial function. This study aims to investigate whether PGC-1α is involved in the pathophysiology of VaD.Methods: We firstly generated PGC-1αf/f Eno2-Cre mice to induce neuron-specific overexpression of PGC-1α by crossbreeding PGC-1αf/f mice with Eno2-cre mice. Then, the mice were subjected to bilateral common carotid artery stenosis to induce chronic cerebral hypoperfusion. Neurological function and hippocampal PGC-1α expression was evaluated. Next, RNA-Seq analysis and Seahorse assay were performed on the hippocampal neurons. In addition, mitochondrial antioxidants, uncoupling proteins, ROS production and the activation of glial cells were also measured.Results: Our results showed that hippocampal PGC-1α expression is down-regulated in the mouse VaD model induced by chronic cerebral hypoperfusion. In contrast, neuronal PGC-1α overexpression significantly ameliorated cognitive deficits. RNA-Seq analysis indicated that PGC-1α improved energy metabolism of neurons under hypoxic condition, and Seahorse assay confirmed that PGC-1α increases the metabolic activity of neurons. Further study demonstrated that PGC-1α boosted the expressions of mitochondrial antioxidants and uncoupling proteins (UCPs), including SOD2, Prx3, GPx1, UCP2, UCP4 and UCP5, which in turn reduced reactive oxygen species (ROS) production. Moreover, the activation of microglia and astrocytes was also found to decrease in the hippocampus. All of these changes greatly contributed to protect hippocampal neurons against ischemic insults.Conclusions: PGC-1α could suppress the excessive ROS and neuroinflammation in the hippocampus, opening up a potential therapeutic target for cognitive impairment.

Short erythropoietin-derived peptide enhances memory, improves long-term potentiation, and counteracts amyloid beta–induced pathology

Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by the irreversible neuronal loss and memory impairment, and current treatments are merely symptomatic. Erythropoietin (EPO) has been shown to possess neurotrophic, neuroprotective, anti-inflammatory, and memory-enhancing effects, which could be therapeutically beneficial in the different aspects of AD. However, the hematopoietic effect of EPO has hampered its potential as a neuroprotective and procognitive agent. In this study, we characterized a novel small peptide, NL100, derived from a conserved C-helix region of EPO. NL100 was shown to bind to the EPO receptor, induce neuritogenesis, and protect hippocampal neurons from oxidative- and Aβ25-35-induced neurodegeneration in vitro. Importantly, long-term NL100 treatment did not induce hematopoiesis, overcoming this challenge associated with EPO. Memory-enhancing effects were demonstrated after NL100 treatment in social recognition test for short-term memory, in both healthy rats and rats challenged centrally with Aβ25-35 peptide, and in the Morris water maze test for spatial memory. Moreover, NL100 was shown to reverse Aβ25-35-induced hippocampal degeneration and gliosis as well as pilocarpine-induced suppression of long-term potentiation in rats. In conclusion, NL100 is a novel EPO-derived nonhematopoietic peptide with neuroprotective and memory-enhancing effects and could therefore be a potential candidate for the development of new treatments for neurodegenerative disorders and dementia.

(-)-Epigallocatechin-3-Gallate Protects Against Lithium-Pilocarpine-Induced Epilepsy by Inhibiting the Toll-Like Receptor 4 (TLR4)/Nuclear Factor-κB (NF-κB) Signaling Pathway.

BackgroundTemporal lobe epilepsy (TLE) is the most common type of intractable epilepsy in humans, and it is often accompanied by cognitive impairment. In this study, we examined the effects of (−)-Epigallocatechin-3-gallate (EGCG) after SE on behavior in the rat lithium-pilocarpine model of TLE.Material/MethodsThe rats were randomly divided into 3 groups: (1) the control group, in which 12 rats received no treatment; (2) the epilepsy (EP) group, in which 15 rats were treated with saline after status epilepticus (SE); and (3) the EP+EGCG group, in which 15 rats were treated with EGCG (25 mg/kg/d, intraperitoneal) after SE. The SE model was induced with lithium chloride-pilocarpine, and electroencephalography and a high-definition camera were used to monitor SRS. The Morris water maze test and hippocampal late-phase long-term potentiation (L-LTP) recordings were used to evaluate cognitive impairment, and TLR4, NF-κB, and IL-1β levels were determined using Western blot analysis.ResultsWe concluded that EGCG treatment after SE (1) markedly reduced SRS frequency in pilocarpine-treated rats, (2) improved epilepsy-induced cognitive impairment and reversed epilepsy-induced synaptic dysfunction in L-LTP in vivo, (3) protected hippocampal neurons from damage after SRS, and (4) significantly attenuated the increase in TRL-4 and IL-1β hippocampal levels. The above findings clearly show that EGCG exerts antiepileptogenesis and neuroprotective effects on pilocarpine-induced epilepsy.ConclusionsWe found that EGCG can suppress seizures and inhibit hippocampal neuronal apoptosis, as well as improving cognitive function of epileptic rats. Our findings suggest that EGCG may a novel adjuvant therapeutic approach in epilepsy by improving epileptic behavior and cognitive dysfunction.

Ginsenoside Rb1 Prevents MPTP-Induced Changes in Hippocampal Memory via Regulation of the α-Synuclein/PSD-95 Pathway

Memory deficiency is a common non-motor symptom of Parkinson's disease (PD), and conventionally, α-synuclein is considered to be an important biomarker for both motor and cognitive characteristics attributed to PD. However, the role of physiological α-synuclein in cognitive impairment remains undetermined. Ginsenoside Rb1 has been shown to protect dopaminergic neurons (DA) from death and inhibit α-synuclein fibrillation and toxicity in vitro. Our recent study also revealed that ginsenoside Rb1 ameliorates motor deficits and prevents DA neuron death via upregulating glutamate transporter GLT-1 in the 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Whether Rb1 can improve memory deficiency and the underlying mechanism is still unknown. In this study, we found that Rb1 can prevent the spatial learning and memory deficits, increase long-term potentiation (LTP) and hippocampal glutamatergic transmission, and protect hippocampal neurons from death in the MPTP mouse model. The underlying neuroprotective mechanism involves Rb1 improving hippocampal CA3 α-synuclein expression, restoring the glutamate in the CA3-schaffer collateral-CA1 pathway, and sequentially increasing postsynaptic density-95 (PSD-95) expression. Thus, we provide evidence that Rb1 modulates memory function, synaptic plasticity, and excitatory transmission via the trans-synaptic α-synuclein/PSD-95 pathway. Our findings suggest that Rb1 may serve as a functional drug in treating the memory deficiency in PD. Funding Statement: This project was supported by the National Natural Science Foundation of China (Nos. 81870991 and U1603281 to SQ, No. 81704130 to YZ), the Natural Science Foundation of Fujian Province of China (No. 2017J05139 to YZ), the Natural Science Foundation of Guangdong Province of China (No. 2017A030310643 to YZ), and the China Postdoctoral Science Foundation (No. 2016M590598 to YZ). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: All experiments were conducted according to the National Institute of Health guidelines on the care and use of animals (NIH Publications No. 8023, revised 1978) and approved by the Institutional Animal Care and Use Committee of Guangzhou Medical University.

Hydromorphone protects CA1 neurons by activating mTOR pathway

Hydromorphone has been shown to play protective effect in rat glial cell. However, whether hydromorphone plays important roles in ischemia–reperfusion (IR) injury and the involved signaling pathway remains unclear. In this study, we detected whether HM plays protective effect in IR injury mouse model, further followed by the mechanism exploration. Preconditioning with hydromorphone was performed for continuous 4 days at the doe of 2 mg/kg before IR injury induction. Intraperitoneal injection of rapamycin (Rapa) was administrated to examine the role of mTOR in IR injury. The mRNA expression level was detected by RT-PCR, and protein expression level was detected by western blot. Latency time and apoptosis of hippocampal CA1 neurons were detected 72 h after IR injury induction. Preconditioning with hydromorphone significantly increased Latency time, decreased apoptosis of hippocampal CA1 neurons and suppressed IR induced oxidative stress. Mechanically, preconditioning with hydromorphone increased Bcl-2 and p-mTOR expression levels and decreased Bax expression levels. Rapa administration reverses the role of hydromorphone in protecting hippocampal CA1 neurons from IR injury. Hydromorphone protect hippocampal CA1 neurons from IR injury via activating mTOR signaling pathway.

RTMS ameliorated depressive-like behaviors by restoring HPA axis balance and prohibiting hippocampal neuron apoptosis in a rat model of depression

Repetitive transcranial magnetic stimulation (rTMS) has been widely used to treat depression. The mechanistic basis for the effects of rTMS is not well understood, although previous studies have suggested that it involves the regulation of hypothalamic-pituitary-adrenocortical (HPA) axis and protection of hippocampal neurons. We investigated this in the present study using a chronic unpredictable mild stress (CUMS) paradigm in Sprague-Dawley rats. The rats were subjected to rTMS for 15 consecutive days, and body weight, sucrose consumption, and locomotor activity were evaluated. B cell lymphoma-2-associated X protein (Bax) expression was assessed by immunohistochemistry; cell morphology was examined by Nissl staining; and adrenocorticotropic hormone (ACTH) and cortisol (CORT) levels in the hippocampus were measured by enzyme-linked immunosorbent assay. CUMS decreased body weight and sucrose consumption in rats along with horizontal/vertical distance traveled in the open field test. Rats subjected to CUMS also showed increased levels of Bax as well as ACTH and CORT; the hippocampal neurons in these animals had abnormal morphology and were reduced in number. rTMS reversed these changes and improved depression-like behaviors. Thus, rTMS abrogates the loss of hippocampal neurons and restores the balance of the HPA axis in the treatment of depression.

Aloe vera gel improves behavioral deficits and oxidative status in streptozotocin-induced diabetic rats

Oxidative stress has a major role in progression of diabetes-related behavioral deficits. It has been suggested that Aloe vera has anti-diabetic, antioxidative, and neuroprotective effects. The present study was designed to determine the effects of Aloe vera gel on behavioral functions, oxidative status, and neuronal viability in the hippocampus of streptozotocin (STZ)-induced diabetic rats. Fifty five adult male Wistar rats were randomly divided into five groups, including: control (normal saline 8ml/kg/day; P.O.), diabetic (normal saline 8ml/kg/day; P.O.), Aloe vera gel (100mg/kg/day; P.O.), diabetic+Aloe vera gel (100mg/kg/day; P.O.) and diabetic+NPH insulin (10 IU/kg/day; S.C.). All treatments were started immediately following confirmation of diabetes in diabetic groups and were continued for eight weeks. Behavioral functions were evaluated by employing standard behavioral paradigms. Additionally, oxidative status and neuronal viability were assessed in the hippocampus. The results of behavioral tests showed that diabetes enhanced anxiety/depression-like behaviors, reduced exploratory and locomotor activities, decreased memory performance, and increased stress related behaviors. These changes in diabetic rats were accompanied by increasing oxidative stress and neuronal loss in the hippocampus. Interestingly, eight weeks of treatment with Aloe vera gel not only alleviated all the mentioned deficits related to diabetes, but in some aspects, it was even more effective than insulin. In conclusion, the results suggest that both interrelated hypoglycemic and antioxidative properties of Aloe vera gel are possible mechanisms that improve behavioral deficits and protect hippocampal neurons in diabetic animals.

The muscarinic effect of anhydroecgonine methyl ester, a crack cocaine pyrolysis product, impairs melatonin synthesis in the rat pineal gland.

Anhydroecgonine methyl ester (AEME), also called methylecgonidine, is a pyrolysis product of crack cocaine that is neurotoxic and potentiates cocaine-induced sensitization. The sensitization induced by drugs of abuse can be influenced by melatonin, a neuroprotective pineal hormone. In the same way, drugs of abuse like alcohol and methamphetamine can modify melatonin synthesis. The aim of the present work was to investigate the AEME effects on melatonin synthesis in the rat pineal gland. Neurotransmitter systems involved in its effects, antioxidant enzyme activities and the melatonin protective role in AEME-induced toxicity were also evaluated. The animals were injected with AEME i.p. (1.12 mg per kg of body weight per day) or vehicle for 10 consecutive days and the nocturnal pineal melatonin synthesis profile and SOD, GPx and GR activities in the cerebral cortex and hippocampus were assessed. Cultured pineal glands were incubated with AEME for 30 min or 48 h before norepinephrine stimulation and melatonin synthesis, arylalkylamine N-acetyltransferase activity, cAMP and [Ca2+]i were determined. The involvement of cholinergic and glutamatergic systems was analyzed using different antagonists. The protective role of melatonin in AEME toxicity on hippocampal neurons was evaluated by a viability assay. AEME impaired melatonin synthesis both in vivo and in vitro and this effect seems to be mediated by muscarinic receptors and [Ca2+]i elevation. AEME reduced neuronal viability and melatonin was able to protected hippocampal neurons against AEME toxicity. The melatonin synthesis impairment observed could lead to the worsening of the direct AEME neurotoxicity and to the exacerbation of the crack cocaine addiction and sensitization.

Control of Granule Cell Dispersion by Natural Materials Such as Eugenol and Naringin: A Potential Therapeutic Strategy Against Temporal Lobe Epilepsy.

The hippocampus is an important brain area where abnormal morphological characteristics are often observed in patients with temporal lobe epilepsy (TLE), typically showing the loss of the principal neurons in the CA1 and CA3 areas of the hippocampus. TLE is frequently associated with widening of the granule cell layer of the dentate gyrus (DG), termed granule cell dispersion (GCD), in the hippocampus, suggesting that the control of GCD with protection of hippocampal neurons may be useful for preventing and inhibiting epileptic seizures. We previously reported that eugenol (EUG), which is an essential component of medicinal herbs and has anticonvulsant activity, is beneficial for treating epilepsy through its ability to inhibit GCD via suppression of mammalian target of rapamycin complex 1 (mTORC1) activation in the hippocampal DG in a kainic acid (KA)-treated mouse model of epilepsy in vivo. In addition, we reported that naringin, a bioflavonoid in citrus fruits, could exert beneficial effects, such as antiautophagic stress and antineuroinflammation, in the KA mouse model of epilepsy, even though it was unclear whether naringin might also attenuate the seizure-induced morphological changes of GCD in the DG. Similar to the effects of EUG, we recently observed that naringin treatment significantly reduced KA-induced GCD and mTORC1 activation, which are both involved in epileptic seizures, in the hippocampus of mouse brain. Therefore, these observations suggest that the utilization of natural materials, which have beneficial properties such as inhibition of GCD formation and protection of hippocampal neurons, may be useful in developing a novel therapeutic agent against TLE.

LC/MS-based metabolomics strategy to assess the amelioration effects of ginseng total saponins on memory deficiency induced by simulated microgravity

Microgravity-induced memory deficiency seriously affects learning and memory ability of the astronaut during spaceflight, with few effective countermeasures. Panax ginseng C. A. Mey. has been used as a nootropic herb for thousands of years in Asian countries. Saponins are recognized as its major active components. Previous studies have shown that ginseng saponins offer protection against memory deficits caused by various factors. Nevertheless, the underlying mechanisms of their nootropic effects are still largely unknown. In this study, we evaluated the memory-improving effects of ginseng total saponins (GTS) on simulated microgravity hindlimb-unloaded rats using a metabolomics approach. After being exposed to a 7-days hindlimb unloading (HU), variations of plasmatic and hippocampal metabolic profiles of rats with and without GTS intervention were examined by a liquid chromatography–mass spectrometry (LC–MS) based untargeted metabolomics method. Subsequently, 8 hippocampal neurotransmitters were determined using a LC–MS/MS method. Finally, a LC–MS/MS based targeted metabolomics was performed to validate biomarkers found in the untargeted analysis. Besides, to support the metabolomics results, passive avoidance (PA) test, Nissl staining, and plasmatic corticosterone (CORT) levels determination were performed. The results showed that HU could lead to variations of 7 neurotransmitters and significantly different plasmatic and hippocampal metabolic profiles. GTS could restore most of the imbalanced neurotransmitters, especially glutamic acid and acetylcholine, and correct the levels of various disturbed learning and memory relevant biomarkers such as asparagine, phenylalanine, tyrosine, tryptophan, and choline. In addition, GTS could markedly ameliorate HU-induced memory deficiency, protect hippocampal neurons from damage, and down-regulate elevated CORT levels. In conclusion, GTS exhibits memory-improving effects mainly through regulating the metabolism of amino acids, neurotransmitters, choline, kynurenine, and sphingolipids. The findings of this study not only can deepen our understanding of the underlying molecular mechanisms of MG-induced memory disorders, but also provide scientific evidence for choosing ginseng as a countermeasure against MG-induced memory deficiency.