Gegen Qinlian tablets delay Alzheimer's disease progression via inhibiting glial neuroinflammation and remodeling gut microbiota homeostasis.

BACKGROUND: Current therapeutic agents for AD have limited efficacy and often induce undesirable side effects. Gegen Qinlian tablets (GGQLT) are a well-known clearingheat formula used in clinical treatment of inflammatory diseases. Based on traditional Chinese medicine (TCM) theory, the strategy of clearing-heat is then compatible with the treatment of AD. However, it remains unknown whether GGQLT can exert neuroprotective effects and alleviate neuroinflammation in AD. PURPOSE: This study aimed to evaluate the anti-AD effects of GGQLT and to decipher its intricate mechanism using integrative analyses of network pharmacology, transcriptomic RNA sequencing, and gut microbiota. METHODS: The ingredients of GGQLT were analyzed using HPLC-ESI-Q/TOF-MS. The AD model was established by bilateral injection of Aß1-42 into the intracerebroventricular space of rats. The Morris water maze was used to evaluate the cognitive function of the AD rats. The long-term toxicity of GGQLT in rats was assessed by monitoring their body weights and pathological alterations in the liver and kidney. Reactive astrocytes and microglia were assessed by immunohistochemistry by labeling GFAP and Iba-1. The levels of inflammatory cytokines in the hippocampus were evaluated using ELISA kits, RT-PCR, and Western blot, respectively. The potential anti-AD mechanism was predicted by analyses of RNA-sequencing and network pharmacology. Western blot and immunohistochemistry were utilized to detect the phosphorylation levels of IκBα, NF-κB p65, p38, ERK and JNK. The richness and composition of gut bacterial and fungal microflora were investigated via 16S rRNA and ITS sequencing. RESULTS: Typical ingredients of GGQLT were identified using HPLC-ESI-Q/TOF-MS. GGQLT significantly improved the cognitive function of AD rats by suppressing the activation of microglia and astrocytes, improving glial morphology, and reducing the neuroinflammatory reactions in the hippocampus. RNA-sequencing, network and experimental pharmacological studies demonstrated that GGQLT inhibited the activation of NF-κB/MAPK signaling pathways in the hippocampus. GGQLT could also restore abnormal gut bacterial and fungal homeostasis and no longer-term toxicity of GGQLT was observed. CONCLUSIONS: Our findings, for the first time, demonstrate GGQLT exhibit anti-AD effects and is worthy of further exploration and development.

Total paeony glycoside relieves neuroinflammation to exert antidepressant effect via the interplay between NLRP3 inflammasome, pyroptosis and autophagy.

BACKGROUND: Depression is a common mental illness characterised by abnormal and depressed emotions. Total paeony glycoside (TPG) is a naturally active saponin extracted from the traditional Chinese medicine Radix Paeoniae rubra. However, the antidepressant and neuroinflammatory effects of TPG have not been thoroughly studied. PURPOSE: To study the therapeutic potential of TGP in depression caused by neuronal injury and neuroinflammation and to explore the mechanism of TGP and the relationship between the NLRP3 inflammasome, pyroptosis, and autophagy. STUDY DESIGN: A chronic unpredictable mild stress (CUMS)-induced depression model and a cell model of corticosterone (CORT)-induced hippocampal neuron injury were established to evaluate the therapeutic effects of TPG. METHODS: The composition of TPG was analysed using high-performance liquid chromatography and mass spectrometry. The effects of TPG and fluoxetine on depression-like behaviour, neuronal injury, neuroinflammation, pyroptosis, and mitochondrial autophagy in the mice models were evaluated. RESULTS: TGP alleviated depression-like behaviours in mice and inhibited hippocampal neuronal apoptosis. The secretion of inflammatory cytokines was significantly reduced in CORT-induced hippocampal neuron cells and in the serum of a mouse model of CUMS-induced depression. In addition, TGP treatment reduced the levels of NLRP3 family pyrin structural domains, including NLRP3, pro-caspase-1, caspase-1, and IL-1ß, and the pyroptosis related proteins such as GSDMD-N. Importantly, TPG attenuated mitochondrial dysfunction, promoted the clearance of damaged mitochondria, and the activation of mitochondrial autophagy, which reduced ROS accumulation and NLRP3 inflammasome activation. An in-depth study observed that the regulatory effect of TPG on autophagy was attenuated by the autophagy inhibitor 3-methyladenine (3-MA) in vitro and in vivo. However, administration of the caspase-1 inhibitor Belnacasan (VX-765) successfully inhibited pyroptosis and showed a synergistic therapeutic effect with TPG. CONCLUSION: These results indicate that TPG can repair neuronal damage by activating autophagy, restoring mitochondrial function, and reducing inflammation-mediated pyroptosis, thereby playing an important role in the alleviation of neuroinflammation and depression. This study suggests new potential drugs and treatment strategies for neuroinflammation-related diseases and depression.

Echinacoside ameliorates post-stroke depression by activating BDNF signaling through modulation of Nrf2 acetylation.

BACKGROUND: Post-stroke depression (PSD) affects approximately one-third of stroke survivors, leading to adverse outcomes in rehabilitation, reduced quality of life, and increased mortality rates. Despite these implications, the underlying causes of PSD remain unclear, posing challenges for prevention and treatment. Echinacoside (ECH), a natural compound with known neuroprotective and antidepressant properties, holds significant therapeutic potential for PSD. However, the precise mechanism of its action remains unknown. PURPOSE: To unravel the specific mechanism through which ECH alleviates PSD by exploring the intricate interplay between ECH and Nrf2, as well as its impact on the BDNF/TrkB signaling axis. STUDY DESIGN AND METHODS: A rat PSD model was established though middle cerebral artery occlusion coupled with chronic unpredictable mild stress, followed by ECH treatment. The rats' depressive state was evaluated using the sucrose preference test and force swimming test. Brain damage was assessed through TTC staining, Nissl staining, and TUNEL assay. The multifaceted mechanism of ECH in PSD was investigated using immunofluorescence, immunohistochemistry, RT-qPCR, dual-luciferase assay, and western blotting. Additionally, the interaction between ECH and Nrf2 was explored through molecular docking and microscale thermophoresis. RESULTS: Our findings unveiled a novel facet of ECH action, demonstrating its unique ability to upregulate Nrf2 through acetylation within the hippocampus of PSD-affected rats (p < 0.05). Moreover, ECH showcased its distinctive potential by enhancing BDNF transcriptional activity, activating the BDNF/TrkB signaling axis, and orchestrating a comprehensive response against oxidative stress and apoptosis, thereby alleviating PSD symptoms in rats (p < 0.05). CONCLUSIONS: This study not only provides insights into the pivotal role of Nrf2 in mediating the BDNF/TrkB axis activation by ECH but also highlights the novelty of ECH's mechanism in addressing PSD. The elucidation of these unique aspects positions ECH as a groundbreaking candidate for further exploration and development in the realm of PSD intervention.

Lancao decoction alleviates cognitive dysfunction: A new therapeutic drug and its therapeutic mechanism.

BACKGROUND: Cognitive dysfunction (CD) is a neurodegenerative disease characterized primarily by the decline of learning and memory abilities. The physiological and pathological mechanisms of CD are very complex, which is mainly related to normal function of the hippocampus. Lancao decoction (LC) is a Chinese medicine formula, which has been used to treat neurodegenerative disorders. However, the potential of LC for the treatment of CD, as well as its underlying mechanisms, is unclear. PURPOSE: In the study, we aimed to reveal the functional and neuronal mechanisms of LC's treatments for CD in scopolamine-induced mice. METHODS: Gas chromatography (GC) was used to determine the stability of LC's extraction. CD model was established by the chronic induction of scopolamine (Scop, 1 mg/kg/day) for 1 week. Behavioral tests including morris water maze (MWM) and y-maze were used to evaluate learning and memory abilities of mice after LC's treatments. Immunofluorescence was used to detected the expressions of cFOS, Brdu and Ki67 after LC's treatments. Pharmacological blockade experiments explored the role of α-Amino-3­hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in LC's treatments for CD and its relationships with regeneration, activities and differentiation of neurons. RESULTS: The results showed that LC was capable of improving spatial learning and memory and spontaneous alternating abilities in Scop-induced mice, which was similar to donepezil. LC could increase the number of cFOS positive cells, which was used as a marker of neuronal activity to upregulate by neuronal activities in hippocampus, but donepezil did not. Moreover, LC could strengthen neurogenesis and neuro-differentiation by increasing the number of Brdu and Ki67 positive cells in hippocampal dentate gyrus (DG), meanwhile, donepezil could only enhance the number of Ki67 positive cells. Transient inhibition of AMPAR by NBQX blunted the function of LC's treatment for CD and inhibited the enhanced effect of LC on Scop-induced hippocampal neuronal excitability and neurogenesis in mice. CONCLUSION: To sum up, our study demonstrated that LC had the function of treating CD by enhancing content of acetylcholine (ACh) to activate AMPAR, which further up-regulated neurogenesis and neuronal differentiation to strengthen neuroactivities in hippocampus.

Curculigoside, a traditional Chinese medicine monomer, ameliorates oxidative stress in Alzheimer's disease mouse model via suppressing ferroptosis.

Alzheimer's disease (AD) is a neurodegenerative disorder where oxidative stress, induced by ferroptosis, has been linked to neuronal damage and cognitive deficits. The objective of this study is to investigate if the potential therapeutic agent, Curculigoside (CUR), could ameliorate AD by inhibiting ferroptosis. The potential therapeutic targets, such as GPX4 and SLC7A11, were identified using weighted gene co-expression network analysis (WGCNA). Concurrently, CUR was also screened against these potential targets using various analytical methods. For the in vivo studies, intragastric administration of CUR significantly ameliorated cognitive impairment in AD model mice induced by scopolamine and okadaic acid (OA). In vitro, CUR protected neuronal cells by altering the levels of ferroptosis-related specific markers in OA and scopolamine-induced neurotoxicity. The administration of CUR through intragastric route significantly reduced the levels of AD-promoting factors (such as Aß1-42, p-tau) and ferroptosis-promoting factors in the hippocampus and cortex of AD mice. Furthermore, CUR up-regulated the expression of GPX4 and decreased the expression of SLC7A11 in the ferroptosis signaling pathway, thereby increasing the ratio of glutathione (GSH)/oxidized glutathione (GSSG) in vivo and vitro. In conclusion, the cumulative results suggest that the natural compound CUR may serve as a promising therapeutic agent to ameliorate AD by inhibiting ferroptosis.

The neuroprotective effect of exogen melatonin upon fetal hippocampus damage caused by high-dose caffeine administration in pregnant rats.

OBJECTIVE: The aim of this study is to evaluate whether exogenous melatonin (MEL) mitigates the deleterious effects of high-dose caffeine (CAF) administration in pregnant rats upon the fetal hippocampus. MATERIALS AND METHODS: A total of 32 adult Wistar albino female rats were divided into four groups after conception (n = 8). At 9-20 days of pregnancy, intraperitoneal (i.p.) MEL was administered at a dose of 10 mg/kg/day in the MEL group, while i.p. CAF was administered at a dose of 60 mg/kg/day in the CAF group. In the CAF plus MEL group, i.p. CAF and MEL were administered at a dose of 60 and 10 mg/kg/day, respectively, at the same period. Following extraction of the brains of the fetuses sacrificed on the 21st day of pregnancy, their hippocampal regions were analyzed by hematoxylin and eosin and Cresyl Echt Violet, anti-GFAP, and antisynaptophysin staining methods. RESULTS: While there was a decrease in fetal and brain weights in the CAF group, it was found that the CAF plus MEL group had a closer weight average to that of the control group. Histologically, it was observed that the pyramidal cell layer consisted of 8-10 layers of cells due to the delay in migration in hippocampal neurons in the CAF group, while the MEL group showed similar characteristics with the control group. It was found that these findings decreased in the CAF plus MEL group. CONCLUSION: It is concluded that high-dose CAF administration causes a delay in neurogenesis of the fetal hippocampus, and exogenous MEL is able to mitigate its deleterious effects.

Gastrodin regulates the TLR4/TRAF6/NF-κB pathway to reduce neuroinflammation and microglial activation in an AD model.

BACKGROUND: Gastrodia elata (Orchidaceae) is a medicinal plant used in traditional Chinese medicine. The rhizomes contain numerous active components, of which Gastrodin (p-hydroxymethylphenyl-B-D-glucopyranoside) forms the basis of the traditional medicine Gastrodiae Rhizoma. Gastrodin is also found in other medicinal plants and has neuroprotective, antioxidant, and anti-inflammatory effects. Neuroinflammation plays a crucial role in neurodegeneration. Research indicates that consuming meals and drinks containing Gastrodiaelata can enhance cognitive functioning and memory in elderly patients. The mechanisms relevant to the problem have not been completely understood. PURPOSE: The aim was to examine the in vivo and in vitro anti-neuroinflammatory effects of Gastrodin. STUDY DESIGN: The neuroprotective effects of Gastrodin on the TLR4/TRAF6/NF-κB pathway and Stat3 phosphorylation in LPS-treated C57BL/6 mice and BV-2 cells were investigated. METHODS: 1. C57BL/6 mice were assigned to model, gastrodin, donepezil, and control groups (n = 10 per group). The Gastrodin group received 100 mg/kg/d for five days, and the Dopenezil group 1.3 mg/kg/d. A neuroinflammation model was established by administering intraperitoneal injections of 2 mg/kg LPS to all groups, excluding the control. To induce microglial activation in Gastrodin-treated mouse microglial BV-2 cells, 1 µg/ml LPS was introduced for 24 h Morris water mazes were utilized to evaluate learning and spatial memory. Expression and subcellular localization of TLR4/TRAF6/NF-κB axis-related proteins and p-Stat3, Iba-1, GFAP, iNOS, and CD206 were assessed by immunofluorescence, western blots, and ELISA. qRT-PCR was performed to determine and measure IL-1ß, TNF-α, cell migration, and phagocytosis. Overexpression of TRAF6 was induced by transfection, and the effect of Gastrodin on IL-1ß and p-NF-κB p65 levels was assessed. RESULTS: 1. In mice, gastrodin treatment mitigated LPS-induced deficits in learning and spatial memory, as well as reducing neuroinflammation in the hippocampus, expression of TLR4/TRAF6/NF-κB pathway proteins, activation of microglia and astrocytes, and phosphorylation of Stat3. 2. Gastrodin pretreatment improved LPS-induced inflammation in vitro, reducing expression of TLR4/TRAF6/NF-κB-associated proteins and p-Stat3, inducing microglial transformation from M1 to M2, and inhibiting migration and phagocytosis. Overexpression of TRAF6 inhibited the Gastrodin-induced effects. CONCLUSION: Gastrodin suppresses neuroinflammation and microglial activation by modifying the TLR4/TRAF6/NF-κB pathway and Stat3 phosphorylation.

The protective effect of methanolic extract of Verbascum cheiranthifolium and Biebersteinia multifida DC on hippocampus damage induced by diazinon in male Wistar rats: An experimental study.

Diazinon (DZN) an organophosphate (OP), with the most important mechanism of action of DZN being induction of oxidative stress (OS) and inhibition of the enzyme acetylcholinesterase (AChE). Verbascum cheiranthifolium (VER) and Biebersteinia multifida (BM) belong to the Scrophulariaceae and Biebersteiniaceae family respectively. These plants are widely used in Iranian traditional medicine due to their beneficial effects. Thus, this research aimed to appraise the protective effects of the methanolic extract of the VER and BM on changes in the level of expression of α7 and α4 subunits of nicotinic acetylcholine receptors (nAChRs) in hippocampus (HPC) of DZN-treated rats. In this research, 36 male Wistar rats were used and randomly divided into six groups: Control, DZN (40 mg/kg), VER (1 g/kg), DZN+VER (40 mg/kg+1 g/kg), BM (150 mg/kg), and DZN+BM (40 mg/kg+150 mg/kg). At the end of treatment periods, the animals of all groups underwent the Morris water maze (MWM) test. The rats were anesthetized, and blood sampling was performed. Eventually, the brain was removed for histological study and evaluation of OS parameters. The results indicated that DZN increased the extent of expression of nAChRs in the HPC and significantly inhibited cholinesterase (ChEs) activity plus OS parameters. Also, in MWM, the time to find the platform was significantly longer in the DZN group, while the time and the distance in the probe test were lower than in the control groups. VER and BM extract in the treatment groups simultaneously improved the extent of expression of nAChRs, ChEs activity, as well as the parameters of OS and spatial memory significantly. In conclusion, our results support the neuroprotective properties of VER and BM extract versus DZN in rats. Accordingly, the extracts of VER and BM may be useful as an approach for the treatment of learning disorders and memory enhancement.

The effects of postnatal erythropoietin and nano-erythropoietin on behavioral alterations by mediating K-Cl co-transporter 2 in the valproic acid-induced rat model of autism.

In this study, based on the excitatory/inhibitory imbalance theory of autism, the time window of GABA switch, the role of K-Cl co-transporter 2 (KCC2) in adjustment GABA switch, and brain permeability to erythropoietin (EPO), the effects of postnatal -EPO and- nano- erythropoietin (NEPO) have been evaluated in the valproic acid (VPA) rat model of autism. The VPA was administered for animal modeling of autism at gestational day (GD) 12.5 (600 mg/kg). Male offsprings were injected with EPO and NEPO in a clinically proper postnatal dosing regimen on postnatal days (PND) 1-5, and autistic-like behaviors were tested at the end of the first month. Then animals were sacrificed, and neuron morphology and KCC2 expression were examined by Nissl staining and Western blot. According to our findings, high-dose NEPO improved autism-associated phenotypes. Neuroprotective effects of EPO and NEPO have been shown in the hippocampus. Postnatal NEPO treatment reversed KCC2 expression abnormalities induced by prenatal VPA. Our results might support the role of KCC2 in ASD and the excitatory/inhibitory imbalance hypothesis. We suggested Nano- erythropoietin and other KCC2 interventions as a new approach to the early treatment and prevention of autism.

Isoflavone-Enriched Soybean Leaves (Glycine Max) Alleviate Cognitive Impairment Induced by Ovariectomy and Modulate PI3K/Akt Signaling in the Hippocampus of C57BL6 Mice.

(1) Background: The estrogen decline during perimenopause can induce various disorders, including cognitive impairment. Phytoestrogens, such as isoflavones, lignans, and coumestans, have been tried as a popular alternative to avoid the side effects of conventional hormone replacement therapy, but their exact mechanisms and risk are not fully elucidated. In this study, we investigated the effects of isoflavone-enriched soybean leaves (IESLs) on the cognitive impairment induced by ovariectomy in female mice. (2) Methods: Ovariectomy was performed at 9 weeks of age to mimic menopausal women, and the behavior tests for cognition were conducted 15 weeks after the first administration. IESLs were administered for 18 weeks. (3) Results: The present study showed the effects of IESLs on the cognitive function in the OVX (ovariectomized) mice. Ovariectomy markedly increased the body weight and fat accumulation in the liver and perirenal fat, but IESL treatment significantly inhibited them. In the behavioral tests, ovariectomy impaired cognitive functions, but administration of IESLs restored it. In addition, in the OVX mice, administration of IESLs restored decreased estrogen receptor (ER) ß and PI3K/Akt expression in the hippocampus. (4) Conclusions: The positive effects of IESLs on cognitive functions may be closely related to the ER-mediated PI3/Akt signaling pathway in the hippocampus.

Melatonin attenuates chronic stress-induced hippocampal inflammatory response and apoptosis by inhibiting ADAM17/TNF-α axis.

Melatonin, as a dietary supplement, has a potent neuroprotective effect and exerts a certain antidepressant effect. This study explored the molecular mechanisms and targets of melatonin on chronic stress-induced hippocampal damage from the perspective of inhibiting inflammatory cytokines release. Our results indicated that melatonin alleviated chronic restraint stress (CRS)-induced inflammatory response and apoptosis, thus improving hippocampal structural damage and subsequent depression-like behaviors in rats. The radar map displayed that the change of TNF-α content was the most significant. Meanwhile, correlation analysis showed that TNF-α content was highly positively correlated with apoptosis. Molecular autodocking studies suggested that TNF-α converting enzyme ADAM17 as a potential target has a priority in docking with melatonin. Molecular mechanism studies indicated that melatonin inhibited CRS-induced activation of the ADAM17/TNF-α axis and its downstream proteins p38 and p53 phosphorylation in the hippocampus. Analogously, Both ADAM17 inhibitor TMI-1 and TNF-α inhibitor thalidomide relieved the effects of CRS on ADAM17/TNF-α axis and its downstream proteins phosphorylation, hippocampal apoptosis, hippocampal inflammatory response, and depression-like behaviors in rats. Altogether, these findings reveal that melatonin relieves CRS-induced inflammatory response and apoptosis, and subsequent depression-like behaviors by inhibiting ADAM17/TNF-α axis.

Mucuna pruriens seed protects the hippocampal neurons and abrogates seizure indices in chemically-convulsed mice: Evidence of the Nrf2 expression defense pathway.

The anti-convulsant mechanisms and neuroprotective effects of Mucuna pruriens (MP) seed in male BALB/c mice were evaluated. Ninety mice were kindled with picrotoxin, strychnine, or pilocarpine hydrochloride at the 30th minute of intraperitoneal injection (i.p) of normal saline (0.2 ml), MP (200, 100, 50 mg/kg), diazepam (7.5 mg/kg), or haloperidol (5 mg/kg). The onset of convulsion and percentage mortality was recorded. The histoarchitectural and immunohistochemical profiles of the brains were determined. Data were expressed as mean ± SEM with a one-way analysis of variance (ANOVA), while p < 0.05 was considered significant. There was a significant prolongation of the latency to first seizure across the treatment groups following picrotoxin, and pilocarpine-induced convulsion; a decrease in percentage mortality in the MP (50 mg/kg) treatment group, and an increase in the hippocampal nuclear factor erythroid 2-related factor 2 count, and Neu-N expression in the MP (200 mg/kg, and 100 mg/kg) treated mice. Treatment with MP seed may abolish seizure occurrence and consequential mortality; mechanisms traceable to its GABAergic expression and hippocampal NRF 2 and Neu N expression.

Berberine protects against chronic cerebral hypoperfusion-induced cognitive impairment and hippocampal damage via regulation of the ERK/Nrf2 pathway.

Vascular cognitive impairment caused by chronic cerebral hypoperfusion (CCH) seriously affects the quality of life of elderly patients and places a great burden on society and family. With the development of traditional Chinese medicine (TCM), TCM approaches to the prevention and treatment of senile ischemic cerebrovascular disease has received increasing attention. In this study, rats with bilateral common carotid artery occlusion (BCCAO) were treated with berberine (BBR). Their learning and memory function, neuronal injury and repair, the extracellular regulatory protein kinase (ERK)/nuclear factor-E2-related factor 2 (Nrf2) signaling pathway, and impairment and improvement of the blood-brain barrier (BBB) were evaluated. This study found that BBR can alleviate the pathological injury to the brain, reduce neuronal loss and promote neuronal cell survival after CCH by interfering with the ERK/Nrf2 signaling pathway. BBR can reduce BBB injury in CCH rats by inhibiting the expression of VEGF-A and MMP-9 in plasma, which reveals a protective effect of BBR on vascular cognitive impairment. This study provides a new research direction for BBR in the treatment of ischemic cerebrovascular disease.

Anticonvulsive and Neuroprotective Effects of Eupafolin in Rats Are Associated with the Inhibition of Glutamate Overexcitation and Upregulation of the Wnt/ß-Catenin Signaling Pathway.

Several plant compounds have been found to possess neuroactive properties. The aim of this study was to investigate the anticonvulsant effect of eupafolin, a major active component extracted from Salvia plebeia, a herb used in traditional medicine for its anti-inflammatory properties. To this end, we assessed the anticonvulsant effects of eupafolin in rats intraperitoneally (i.p.) injected with kainic acid (KA) to elucidate this mechanism. Treatment with eupafolin (i.p.) for 30 min before KA administration significantly reduced behavioral and electrographic seizures induced by KA, similar to carbamazepine (i.p.), a widely used antiepileptic drug. Eupafolin treatment also significantly decreased KA seizure-induced neuronal cell death and glutamate elevation in the hippocampus. In addition, eupafolin notably reversed KA seizure-induced alterations in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluR2, glutamate decarboxylase 67 (GAD67, GABAergic enzyme), and Wnt signaling-related proteins, including porcupine, Wnt1, phosphorylated-glycogen synthase kinase-3ß, ß-catenin, and Bcl-2 in the hippocampus. Furthermore, the increased level of Dickkopf-related protein 1 (Dkk-1, a Wnt signaling antagonist) and the decreased level of Disheveled1 (Dvl-1, a Wnt signaling activator) in the hippocampus of KA-treated rats were reversed by eupafolin. This study provides evidence of the anticonvulsant and neuroprotective properties of eupafolin and of the involvement of regulation of glutamate overexcitation and Wnt signaling in the mechanisms of these properties. These findings support the benefits of eupafolin in treating epilepsy.

Does Resveratrol Prevent Sevoflurane Toxicity in Newborn Rats?

Inhalation anesthetics have been shown to cause neurodevelopmental disorders and neurotoxic effects. In this study, we aimed to investigate the effect of resveratrol on the possible neurotoxic effect of sevoflurane and the brain-derived neurotrophic factor (BDNF) pathway in newborn rats. The animals were divided into four groups: control, sevoflurane, sevoflurane+resveratrol 25 mg/kg, and sevoflurane+resveratrol 50 mg/kg. The groups that received anesthesia were given 3% sevoflurane for 2 h on the postnatal seventh, eighth, and ninth days. Control gas was applied to the control group. The Morris water maze (MWM) test was performed on postnatal 35th day. After performing the open field test on the postnatal 41st day, the animals were dissected, and the hippocampal BDNF levels were determined by Western blot method. In the MWM test, there was a significant decrease in the time spent in the target quadrant in the sevoflurane anesthesia group compared with control group. This reduction was reversed with the resveratrol pretreatment. Sevoflurane exposure significantly decreased hippocampal BDNF levels compared with the control group. The resveratrol 25 mg/kg pretreatment did not reverse this reduction, whereas resveratrol 50 mg/kg ameliorated this impairment. Sevoflurane did not cause any significant difference in the rats' performance in the open field test. However, 50 mg/kg resveratrol pretreatment caused a statistically significant increase in this performance. Our results showed that sevoflurane impaired learning and memory functions in newborn rats and resveratrol reversed this deterioration. Also BDNF might play a role in this beneficial effect of resveratrol.

[Comparative proteomic profiling of hippocampi in mice treated with Jingui Shenqi Pills and Liuwei Dihuang Pills].

The effects of Jingui Shenqi Pills(Jingui) and Liuwei Dihuang Pills(Liuwei) which respectively tonify kidney Yang and kidney Yin on brain function have attracted great attention, while the differences of protein expression regulated by Jingui and Liuwei remain to be studied. This study explored the difference of protein expression profiles in the hippocampi of mice orally administrated with the two drugs for 7 days. The protein expression was quantified using LC-MS/MS. The results showed that among the 5 860 proteins tested, 151, 282 and 75 proteins responded to Jingui alone, Liuwei alone, and both drugs, respectively. The ratio of up-regulated proteins to down-regulated proteins was 1.627 in Jingui group while only 0.56 in Liuwei group. The proteins up-regulated by Jingui were mainly involved in membrane transport, synaptic vesicle cycle, serotonergic synapse, dopaminergic synapse and so on, suggesting that Jingui may play a role in promoting the transport of neurotransmitter in the nervous system. The proteins down-regulated by Liuwei were mainly involved in membrane transport, synapse, ion transport(potassium and sodium transport), neurotransmitter transport, innate and acquired immune responses, complement activation, inflammatory response, etc. In particular, Liuwei showed obvious down-regulation effect on the members of solute carrier(SLC) superfamily, which suggested that Liuwei had potential inhibitory effect on membrane excitation and transport. Finally, consistent results were obtained in the normal mouse and the mouse model with corticosterone-induced depressive-like behavior. This study provides an experimental basis for understanding the effect of Jingui and Liuwei on brain function from protein network.

A Mixture of Ginkgo biloba L. Leaf and Hericium erinaceus (Bull.) Pers. Fruit Extract Attenuates Scopolamine-Induced Memory Impairments in Mice.

Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by loss of memory and cognitive impairment via dysfunction of the cholinergic nervous system. In cholinergic dysfunction, it is well known that impaired cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) signaling are major pathological markers and are some of the strategies for the development of AD therapy. Therefore, this study is aimed at evaluating whether a mixture comprising Ginkgo biloba L. leaf (GL) and Hericium erinaceus (Bull.) Pers. (HE) fruit extract (GH mixture) alleviated cognitive impairment induced in a scopolamine-induced model. It was discovered that GH reduced neuronal apoptosis and promoted neuronal survival by activating BDNF signaling in an in vitro assay. In addition, the GH (p.o. 240 mg/kg) oral administration group significantly restored the cognitive deficits of the scopolamine-induced mouse group (i.p. 1.2 mg/kg) in the behavior tests such as Y-maze and novel object recognition task (NORT) tests. This mixture also considerably enhanced cholinergic system function in the mouse brain. Furthermore, GH markedly upregulated the expressed levels of extracellular signal-regulated kinase (ERK), CREB, and BDNF protein levels. These results demonstrated that GH strongly exerted a neuroprotective effect on the scopolamine-induced mouse model, suggesting that an optimized mixture of GL and HE could be used as a good material for developing functional foods to aid in the prevention of neurodegenerative diseases, including AD.

Effects of Stevia rebaudiana Bertoni extracts in the rat model of epilepsy induced by pentylenetetrazol: Sirt-1, at the crossroads between inflammation and apoptosis.

The current study investigated the effects of stevia extracts on a PTZ-induced epileptic rat model and its potential mechanism. Thirty male Sprague-Dawley rats were equally subdivided into 3 groups; (1) normal control (NC) group, (2) PTZ-group: received PTZ (50 mg/kg, i.p. every other day) for 2 weeks, and (3) PTZ+ Stevia group: received PTZ and stevia (200 mg/kg orally daily) for 4 weeks (2 weeks before the start of PTZ treatment and 2 weeks with PTZ administration). The first jerk latency and the seizure score were assessed in rats. Also, brain tissue samples were collected by the end of the experiment, and oxidative stress markers (catalase, MDA, and total antioxidant capacity (TAC)) were measured by biochemical analysis in hippocampal brain homogenates. Also, in the hippocampus, the expression of IL6 and Bcl-2 at the mRNA level and expression of Sirt-1, P53, caspase-3, GFAP, and NF-kB in CA3 hippocampal region by immunohistochemistry was investigated. PTZ substantially increased the seizure score and decreased the seizure latency. Also, PTZ significantly increased MDA, GFAP, IL-6, NF-kB, caspase-3, and p53 and significantly reduced Sirt-1, TAC, and Bcl-2 in hippocampal tissues compared to the control group (p < 0.01). However, Stevia Rebaudiana Bertoni (Stevia R.) significantly attenuated the PTZ-induced seizures, improved oxidative stress markers, downregulated GFAP, IL-6, NF-kB, caspase-3, and p53, and upregulated Sirt-1 and Bcl-2 in the CA3 hippocampal region (p < 0.01). In conclusion, Stevia R. exhibits neuroprotective and antiepileptic actions in PTZ-induced epilepsy due to its antioxidant, anti-apoptotic, and anti-inflammatory effects. Additionally, the Sirt-1 pathway might be involved in the antiepileptic and neuroprotective effects of stevia in PTZ-kindled epileptic rat model.

Preventive treatment with fish oil facilitates the antidepressant-like effect of antidepressant drugs in type-1 diabetes mellitus rats: Implication of serotonergic system.

Treating depression associated with type-1 diabetesmellitus(T1DM) is a major clinical challenge. Fish oil (FO), composed mostly of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), has been pointed out as quite promising for the treatment of depression given its neuroprotective property. Although DHA and EPA exert several physiological actions, DHA is known to play a critical role in postnatal brain development. This study aimed to investigate the effect of preventive treatment with FO (with more DHA in the composition) alone or associated with antidepressant drugs on depression-like behaviors and brain monoamines levels of juvenile induced-T1DM rats. Thus, prepubescent rats were submitted to a prolonged treatment with vehicle (VEH) or FO (50% of DHA and 20% EPA) starting 4 weeks before the induction of experimental T1DM (on day 28) by streptozotocin. When combined, the treatment with vehicle, fluoxetine (FLX, a selective serotonin reuptake inhibitor) or imipramine (IMI, a tricyclic antidepressant) started at week 6 (day 42) and lasted for 2 weeks (until day 56). The behavioral tests were conducted on days 55 and 56, followed by hippocampal and prefrontal cortex dissection for neurochemical analyses. Our results showed that induced-T1DM rats pretreated with FO showed a significant increase of EPA and DHA in plasma, indicative of an increase in the systemic availability of these acids. As previously observed, induced-T1DM rats presented increased immobility and decreased swimming and climbing frequencies in the modified forced swimming test, indicative of depressive-like behavior. Only the combined treatment - FO plus antidepressants (FLX or IMI - both in the highest dose) - was able to induce a significant improvement of depressive-like behaviors. Here, it is noteworthy that swimming behavior has been associated with an increase in serotonergic neurotransmission. Interestingly, our data showed that the combined treatment (FO + antidepressants - including the ineffective dose of FLX) was able to increase the swimming of animals more significantly compared to animals not pretreated with FO. In addition, confirming these assumptions, the decreased 5-HT levels in the hippocampus from induced-T1DM rats were increased after treatment with FLX (highest dose) or IMI (both doses), being this increase more pronounced in animal pretreated with FO. Intriguingly, in these animals pretreated with FO, the ineffective dose of FLX in association with FO was able to increase the levels of 5-HT. The decreased hippocampal levels of noradrenaline were increased only after IMI treatment, not being influenced by FO pretreatment. In conclusion, ours results pointed out that the choice of the DHA/EPA ratio may be an important factor to be considered for the FO antidepressant-like effectper se,but the FO treatment in this composition associated with the antidepressant drugs - especially that ones that increase preferentially the availability of 5-HT -, may represent a better alternative of treatment to individuals with T1DM-associated depression.

Hydroxysafflor yellow A can improve depressive behavior by inhibiting hippocampal inflammation and oxidative stress through regulating HPA axis.

Depression is characterized by indifferent and slow thinking, leading to highly unfavorable social and economic burden. Hydroxysafflor yellow A (HSYA) is a traditional Chinese medicine and has many pharmacological properties, such as anti-oxidative and anti-inflammatory activities. However, the underlying mechanism unraveling the effect of HSYA on depression is still unclear. Here, depression animal model was established. It was demonstrated that HSYA improved depressive behavior in rat model of depression, which increased horizontal movement, vertical movement, sucrose percent index and decreased immobility of depressed rats. Moreover, HSYA inhibited the activation of HPA signaling, inflammation and oxidative stress in brain of depressed rats. HSYA played an opposite effect on production of chronic unpredicted mild stress (CUMS)-induced pro-inflammatory cytokines (TNF-α, IL-6 and IL-1ß). CUMS increased MDA expression but decreased SOD and GSH-Px expression, which were reversed by HSYA treatment. Furthermore, HSYA exerted a suppressive role in TLR4/NF-jB signaling pathway in brain of depressed rats. In conclusion, these findings indicted that HSYA can improve depressive behavior through inhibiting HPA signaling, repressing hippocampal inflammation and oxidative stress, which will provide a new therapeutic method for treating depression.