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Hepatic encephalopathy (HE) is one of the most prevalent and severe hepatic and brain disorders in which escalation of the oxidative, inflammatory and apoptotic trajectories pathologically connects acute liver injury with neurological impairment. Mirabegron (Mira) is a beta3 adrenergic receptor agonist with proven antioxidant and anti-inflammatory activities. The current research pointed to exploring Mira's hepato-and neuroprotective impacts against thioacetamide (TAA)-induced HE in rats. Rats were distributed into three experimental groups: the normal control group, the TAA group, received TAA (200 mg/kg/day for three consecutive days) and the Mira-treated group received Mira (10 mg/kg/day; oral gavage) for 15 consecutive days and intoxicated with TAA from the 13th to the 15th day of the experimental period. Mira counteracted hyperammonemia, enhanced rats' locomotor capability and motor coordination. It attenuated hepatic/neurological injuries by its antioxidant, anti-apoptotic as well as anti-inflammatory potentials. Mira predominantly targeted cyclic adenosine monophosphate (cAMP)/phosphorylated extracellular signal-regulated kinase (p-Erk1/2)/peroxisome proliferator-activated receptor gamma (PPARγ) dependent pathways via downregulation of p S536-nuclear factor kappa B p65 (p S536 NF-κB p 65)/tumor necrosis alpha (TNF-α) axis. Meanwhile, it attenuated nuclear factor erythroid 2-related factor (Nrf2) depletion in parallel with restoring of the neuroprotective defensive pathway by upregulation of cerebral cAMP/PPAR-γ/p-ERK1/2 and p-CREB/BDNF/TrkB besides reduction of GFAP immunoreactivity. Mira showed anti-apoptotic activity through inhibition of Bax immunoreactivity and elevation of Bcl2. To summarize, Mira exhibited a hepato-and neuroprotective effect against TAA-induced HE in rats via shielding antioxidant defense and mitigation of the pathological inflammatory and apoptotic axis besides upregulation of neuroprotective signaling pathways.
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Bisphenol A (BPA), an endocrine disruptor, is commonly used to produce epoxy resins and polycarbonate plastics. Continuous exposure to BPA may contribute to the development of diseases in humans and seriously affect their health. Previous research suggests a significant relationship between the increased incidence of neurological diseases and the level of BPA in the living environment. Syringic acid (SA), a natural derivative of gallic acid, has recently considered much attention due to neuromodulator activity and its anti-oxidant, anti-apoptotic, and anti-inflammatory effects. Therefore, in this study, we aimed to investigate the effects of SA on oxidative stress, apoptosis, memory and locomotor disorders, and mitochondrial function, and to identify the mechanisms related to Alzheimer's disease (AD) in the brain of rats receiving high doses of BPA. For this purpose, male Wistar rats received BPA (50, 100, and 200 mg/kg) and SA (50 mg/kg) for 21 days. The results showed that BPA exposure significantly altered the rats' neurobehavioral responses. Additionally, BPA, by increasing the level of ROS, and MDA level, increased the level of oxidative stress while reducing the level of antioxidant enzymes, such as SOD, CAT, GPx, and mitochondrial GSH. The administration of BPA at 200 mg/kg significantly decreased the expression of ERRα, TFAM, irisin, PGC-1α, Bcl-2, and FNDC5, while it increased the expression of TrkB, cytochrome C, caspase 3, and Bax. Moreover, the Western blotting results showed that BPA increased the levels of P-AMPK, GSK3b, p-tau, and Aß, while it decreased the levels of PKA, P-PKA, Akt, BDNF, CREB, P-CREB, and PI3K. Meanwhile, SA at 50 mg/kg reversed the behavioral, biochemical, and molecular changes induced by high doses of BPA. Overall, BPA could lead to the development of AD by affecting the mitochondria-dependent apoptosis pathway, as well as AMPK/PGC-1α/FNDC5 and CREB/BDNF/TrkB signaling pathways, and finally, by increasing the expression of tau and Aß proteins. In conclusion, SA, as an antioxidant, significantly reduced the toxicity of BPA.
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Proteínas Quinasas Activadas por AMP , Compuestos de Bencidrilo , Factor Neurotrófico Derivado del Encéfalo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Ácido Gálico , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Fenoles , Ratas Wistar , Transducción de Señal , Animales , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Masculino , Transducción de Señal/efectos de los fármacos , Compuestos de Bencidrilo/toxicidad , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Ácido Gálico/farmacología , Ácido Gálico/análogos & derivados , Fenoles/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Fibronectinas/metabolismo , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/metabolismo , Ratas , Apoptosis/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismoRESUMEN
Introduction: Dimethyl fumarate (DMF) is FDA-approved for use in patients with relapsing multiple sclerosis, and it processes neuroprotection in several experimental settings; however, its impact on combating Huntington's disease (HD) remains elusive. This study aimed to explore the role of DMF post-treatment on HD mediated endoplasmic reticulum (ER) stress response in a selective striatal degeneration HD model. Methods: Rats, exposed to 3-nitropropionic acid, were either left untreated or post-treated with DMF for 14 days. Results and Discussion: DMF reduced locomotion deficits in both the open field and beam walk paradigms, boosted the striatal dopamine (DA) content, improved its architecture at the microscopic level, and hindered astrogliosis. Mechanistically, DMF limited the activation of two of the ER stress arms in the striatum by reducing p-IRE1α, p-JNK, and p-PERK protein expressions besides the CHOP/GADD153 content. Downstream from both ER stress arms' suppression, DMF inhibited the intrinsic apoptotic pathway, as shown by the decrease in Bax and active caspase-3 while raising Bcl-2. DMF also decreased oxidative stress markers indicated by a decline in both reactive oxygen species and malondialdehyde while boosting glutathione. Meanwhile, it enhanced p-AKT to activate /phosphorylate mTOR and stimulate the CREB/BDNF/TrkB trajectory, which, in a positive feedforward loop, activates AKT again. DMF also downregulated the expression of miRNA-634, which negatively regulates AKT, to foster survival kinase activation. Conclusion: This study features a focal novel point on the DMF therapeutic ability to reduce HD motor manifestations via its ability to enhance DA and suppress the IRE1α/JNK and PERK/CHOP/GADD153 hubs to inhibit the mitochondrial apoptotic pathway through activating the AKT/mTOR and BDNF/TrkB/AKT/CREB signaling pathways and abating miRNA-634 and oxidative stress.
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OBJECTIVES: The scientific research community devotes stupendous efforts to control the arguable counterbalance between the undesirable effects of hormone replacement therapy (HRT) and post-menopausal syndrome. The recent emergence of 3rd generation selective estrogen receptor modulators and phytoestrogens has provided a promising alternative to HRT. Hence, we assessed the potential effects of combined Bazedoxifene and Genistein on hippocampal neuro-alterations induced by experimental ovariectomy. METHODS: For this purpose, we utilized forty-eight healthy sexually mature female Wistar rats assorted to control, ovariectomy (OVX), Genistein-treated ovariectomized (OVX+GEN) and Bazedoxifene and Genistein-treated ovariectomized (OVX+BZA+GEN) groups. Hippocampi samples from various groups were examined by H&E, silver stains and immunohistochemical examination for calbindin-D28k, GFAP, and BAX proteins. We also assessed hippocampal mRNA expression of ERK, CREB, BDNF and TrkB. RESULTS: Our histopathological results confirmed that combined BZA+GEN induced restoration of hippocampal neuronal architecture, significant reduction of GFAP and BAX mean area % and significant upregulation of calbindin-D28k immunoexpression. Furthermore, we observed significant upregulation of ERK, CREB, BDNF and TrkB mRNA expression in the BZA+GEN group compared to the OVX group. CONCLUSION: Taken together, our findings have provided a comprehensive assessment of histological, immunohistochemical and cyto-molecular basis of combined Genistein and Bazedoxifene ameliorative impacts on hippocampal neuro-alterations of OVX rats via upregulation of Calbindin, CERB, BDNF, Trk-B and ERK neuronal expression.
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Factor Neurotrófico Derivado del Encéfalo , Genisteína , Ratas , Femenino , Animales , Humanos , Genisteína/farmacología , Genisteína/uso terapéutico , Factor Neurotrófico Derivado del Encéfalo/farmacología , Proteína X Asociada a bcl-2/farmacología , Densidad Ósea , Calbindina 1 , Ratas Wistar , Transducción de Señal , Ovariectomía/efectos adversos , Hipocampo , ARN MensajeroRESUMEN
Posttraumatic stress disorder (PTSD) is one of the most common psychiatric diseases, which is characterized by the typical symptoms such as re-experience, avoidance, and hyperarousal. However, there are few drugs for PTSD treatment. In this study, conditioned fear and single-prolonged stress were employed to establish PTSD mouse model, and we investigated the effects of Tanshinone IIA (TanIIA), a natural product isolated from traditional Chinese herbal Salvia miltiorrhiza, as well as the underlying mechanisms in mice. The results showed that the double stress exposure induced obvious PTSD-like symptoms, and TanIIA administration significantly decreased freezing time in contextual fear test and relieved anxiety-like behavior in open field and elevated plus maze tests. Moreover, TanIIA increased the spine density and upregulated synaptic plasticity-related proteins as well as activated CREB/BDNF/TrkB signaling pathway in the hippocampus. Blockage of CREB remarkably abolished the effects of TanIIA in PTSD model mice and reversed the upregulations of p-CREB, BDNF, TrkB, and synaptic plasticity-related protein induced by TanIIA. The molecular docking simulation indicated that TanIIA could interact with the CREB-binding protein. These findings indicate that TanIIA ameliorates PTSD-like behaviors in mice by activating the CREB/BDNF/TrkB pathway, which provides a basis for PTSD treatment.
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Productos Biológicos , Factor Neurotrófico Derivado del Encéfalo , Abietanos , Animales , Ansiedad/tratamiento farmacológico , Productos Biológicos/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína de Unión a CREB/metabolismo , Proteína de Unión a CREB/farmacología , Miedo , Hipocampo/metabolismo , Ratones , Simulación del Acoplamiento Molecular , Transducción de SeñalRESUMEN
BACKGROUND: High rates of co-morbidity have been reported in patients with diabetes mellitus with depression (DD). Danggui Buxue Decoction (DBD), a Traditional Chinese Medicine formula composed of Angelica and Astragalus, has been historically used for the treatment of diabetes. PURPOSE: This study aimed to investigated whether DBD and its main active component, ferulic acid (FA) from Angelica, could ameliorate depression-like behavior in DD and the underlying mechanisms. METHODS: Goto-Kakizaki (GK) rats were administered DBD (4 or 8 g/kg) by oral gavage during a 4-week period of chronic unpredictable mild stress. After 4 weeks, blood glucose, glycated serum protein, serum insulin, oral glucose tolerance and depression-like behavior were examined, along with brain-derived neurotrophic factor (BDNF)-related signaling pathway proteins and the ultrastructure of hippocampal tissues. UPLC-QTOF-MS was adopted to detect the absorption of FA in the serum and hippocampus. Rat primary hippocampal cells were cultured in a DD model. Protein and mRNA levels of genes involved in BDNF-related signaling and neuroplasticity were analyzed. RESULTS: DBD effectively improved glucose tolerance in DD rats and relieved depression-like behavior. Upregulation of cAMP response element binding protein (CREB), BDNF, and tropomyosin receptor kinase B (TrkB) and improvement of the hippocampal neuron ultrastructure supported the antidepressant-Like effects of DBD on the hippocampal neurons. In addition, DBD enhanced the protein and mRNA levels of components of the CREB/BDNF/TrkB pathway in rat primary hippocampal cells induced by elevated glycemia and cortisol. Interestingly, FA, the main component of DBD absorbed in the blood and hippocampus, showed similar effects as DBD on primary hippocampal cells. CONCLUSION: This study suggests that the TCM formula DBD effectively serves as a potential therapeutic agent for prevention of DD through regulatory effects on the CREB/BDNF/TrkB pathway to protect and remodel hippocampal neurons. Moreover, FA contributes significantly to the treatment effects of DBD.
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Antidepresivos , Factor Neurotrófico Derivado del Encéfalo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Medicamentos Herbarios Chinos/farmacología , Receptor trkB , Animales , Antidepresivos/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Células Cultivadas , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Hipocampo/citología , Hipocampo/metabolismo , Neuronas/efectos de los fármacos , Neuronas/ultraestructura , Ratas , Receptor trkB/metabolismo , Receptor trkB/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
Schizophrenia (SZ) is a serious mental condition and is associated with cognitive impairments. Brain-derived neurotrophic factor (BDNF) is one of the learning- and memory-related molecules found in the CNS and its level was reported to be reduced in SZ brain, while ω-3 polyunsaturated fatty acids (ω-3PUFAs) could improve SZ symptoms, but its mechanism of action remains unknown. Using MK801 injection-induced SZ rat model, we here found that supplementation with ω-3PUFAs improved the levels of p-CREB, BDNF, and p-TrkB in the brain of SZ rats, and restore hippocampal neuronal damage, thereby reducing cognitive impairments in SZ rats. However, overexpression of AAV9/CREB S133A (CREB inactivated mutation) downregulated BDNF/TrkB signaling pathway and remarkably abolished the preventive effect of ω-3PUFAs in MK801-induced schizophrenia. Interestingly, AAV9/CREB S133D (CREB activated mutation) improved synaptic dysfunctions and cognitive defects in MK801 rats. In conclusion, these findings indicate that MK801-induced SZ lesions dephosphorylate CREB at Ser133 site, leading to neuron damage, and ω-3PUFAs improve SZ cognitive impairments by upregulating the CREB/BDNF/TrkB pathway, which provides new clues for the mechanism of SZ cognitive impairments, and a basis for therapeutic intervention.
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Factor Neurotrófico Derivado del Encéfalo/metabolismo , Disfunción Cognitiva/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Ácidos Grasos Omega-3/uso terapéutico , Receptor trkB/metabolismo , Esquizofrenia/metabolismo , Animales , Células Cultivadas , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Maleato de Dizocilpina/toxicidad , Antagonistas de Aminoácidos Excitadores/toxicidad , Ácidos Grasos Omega-3/farmacología , Masculino , Técnicas de Cultivo de Órganos , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Ratas , Ratas Sprague-Dawley , Esquizofrenia/inducido químicamente , Esquizofrenia/tratamiento farmacológico , Serina/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
It has been documented that M2 macrophage polarization plays a suppressive role in atherosclerosis in diabetes mellitus (DM). In addition, prostaglandin E2 (PGE2) is implicated in the development of M2 macrophage polarization. Therefore, the study aimed to investigate the specific mechanism of PGE2 in M2 macrophage polarization in diabetic coronary atherosclerosis (DMAS). Initially, clinical samples were obtained and DMAS mouse model was established. The expression of BDNF was determined, and M1 and M2 macrophage polarizations were evaluated. Then, the levels of BDNF and PGE2 were modified in DMAS mice and the serum indicator, atherosclerotic plaque, lipid uptake by PBMCs, as well as M1 and M2 macrophage polarization were determined. Macrophages were isolated and the effects of PGE2 and the CREB/BDNF/TrkB signaling pathway on M2 macrophage polarization were explored. BDNF was downregulated and macrophages were differentiated into M1 in DMAS patients and mice. BDNF and PGE2 were observed to promote M2 macrophage polarization, where atherosclerotic plaque and lipid uptake by PBMCs were reduced, and DMAS was alleviated in mice. Overexpression of BDNF activated the CREB/BDNF/TrkB signaling pathway and stimulated M2 macrophage polarization in macrophages. PGE2 stimulated M2 macrophage polarization by inducing KLF4 via the activation of the CREB/BDNF/TrkB signaling pathway. This study demonstrates that PGE2 promotes M2 macrophage polarization by activating the CREB/BDNF/TrkB signaling pathway, thus alleviating DMAS.
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Aterosclerosis/tratamiento farmacológico , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Polaridad Celular/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Dinoprostona/farmacología , Activación de Macrófagos/efectos de los fármacos , Glicoproteínas de Membrana/metabolismo , Receptor trkB/metabolismo , Animales , Aterosclerosis/metabolismo , Diferenciación Celular/efectos de los fármacos , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/metabolismo , Diabetes Mellitus/metabolismo , Femenino , Humanos , Factor 4 Similar a Kruppel , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/metabolismo , Células RAW 264.7 , Transducción de Señal/efectos de los fármacosRESUMEN
Objective:To investigate the effect of Wendantang on cyclic adenosine monophosphate （cAMP）-response element binding protein（CREB） gene silencing hippocampal cell activity， apoptosis and signal pathway of brain-derived neurotrophic factor/protomyosin related receptor kinase B/adenosine cyclophosphate effector binding protein （BDNF/TrkB/CREB）. Method:Wendantang-containing serum was prepared. Animal grouping： SD male rats were randomly divided into high， medium， low-dose groups， clozapine group and normal saline group， with 10 rats in each group， while 15 rats for the normal group. Dosage： 20 mL·kg-1 normal saline was given to normal group N， clozapine 0.02 g·kg-1 was given to dozapine group X， while high， medium and low-dose Wendantang groups were respectively given the same amount of Wendantang concentrated crude drug， with concentrations of 2， 1 and 0.5 g·mL-1 respectively once a day for 8 days continuously， and then blood was taken from femoral artery， and centrifuged for 15 min at 5 000 r·min-1. Supernatant was taken， inactivated， stored at -80 ℃ for standby. The CREB gene silenced hippocampal neuron cell line was constructed through transfection of liposomes into hippocampal cells， and Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to verify the effect of small interfering RNA （siRNA） transcription. The mRNA expressions of BDNF， TrkB， CREB and CaMKⅡ in normal hippocampal cells and CREB gene silenced hippocampal cells were measured. Result:Compared with normal group， the apoptosis of the normal gene silencing group was significantly increased （P<0.01）， compared with the normal gene silencing group， the apoptosis of each group was significantly reduced （P<0.01）. As for the mRNA expressions of BDNF， TrkB， CREB and CaMKⅡ， compared with the normal group， the mRNA expression of CREB， BDNF in the normal gene silencing group was significantly decreased （P<0.01）. Compared with the normal gene silencing group， the mRNA expression of BDNF in each administration group was highly increased （P<0.01）， but with no statistically significant difference between TrkB and CaMKⅡ groups. Conclusion:The Wendantang-containing serum could improve the mRNA expression of BDNF， protect hippocampal neurons and prevent cognitive impairment of schizophrenia by regulating BDNF/TrkB/CREB signal pathway.
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This study was to determine the protective effect of ω-3 polyunsaturated fatty acids (ω-3PUFAs) on MK-801-induced cognitive impairment in schizophrenia (SZ) rats and the underlying mechanism. A rat model of schizophrenia was induced by MK-801. The cognitive function of rats was assessed using a Morris water maze. The number of hippocampal neurons was measured by Nissl staining. The expression of CREB, p-CREB, BDNF, TrkB, p-TrkB, AKT, p-AKT, ERK, and p-ERK in the hippocampus of rats was detected by Western blotting. The results showed that ω-3PUFAs attenuated MK-801-induced cognitive impairment and hippocampal neurons loss, reversed the injury of the CREB/BDNF/TrkB pathway induced by MK-801, and antagonized MK-801-induced down-regulation of p-AKT and p-ERK in the hippocampus of rats. In conclusion, ω-3PUFAs enhances the CREB/BDNF/TrkB pathway by activating ERK and AKT, thereby increasing the synaptic plasticity and decreasing neuron loss, and antagonizing MK-801-induced cognitive impairment in schizophrenic rats.
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Factor Neurotrófico Derivado del Encéfalo/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/prevención & control , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Ácidos Grasos Omega-3/uso terapéutico , Receptor trkB/metabolismo , Esquizofrenia/tratamiento farmacológico , Animales , Recuento de Células , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/complicaciones , Maleato de Dizocilpina , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Ácidos Grasos Omega-3/farmacología , Hipocampo/patología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Esquizofrenia/complicaciones , Transducción de Señal/efectos de los fármacos , Aprendizaje EspacialRESUMEN
This study was to determine the protective effect of ω-3 polyunsaturated fatty acids (ω-3PUFAs) on MK-801-induced cognitive impairment in schizophrenia (SZ) rats and the underlying mechanism.A rat model of schizophrenia was induced by MK-801.The cognitive function of rats was assessed using a Morris water maze.The number of hippocampal neurons was measured by Nissl staining.The expression of CREB,p-CREB,BDNF,TrkB,p-TrkB,AKT,p-AKT,ERK,and p-ERK in the hippocampus of rats was detected by Western blotting.The results showed that ω-3PUFAs attenuated MK-801-induced cognitive,impairment and hippocampal neurons loss,reversed the injury of the CREB/BDNF/TrtB pathway induced by MK-801,and antagonized MK-801-induced down-regulation of p-AKT and p-ERK in the hippocampus of rats.In conclusion,ω-3PUFAs enhances the CREB/BDNF/TrkB pathway by activating ERK and AKT,thereby increasing the synaptic plasticity and decreashng neuron loss,and antagonizing MK-801-induced cognitive impairment in schizophrenic rats.
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Alpha-linolenic acid (ALA) is a major precursor of the essential n-3 polyunsaturated fatty acid (PUFA), whose deficiency alters the structure and function of membranes and induces cerebral dysfunctions. The major purpose of this study was to investigate the protective effect of prolonged ALA intake on cognitive function during natural aging. Female Sprague-Dawley rats aged 6 months were chronically treated with ALA and/or lard per day for 12 months. Regular diet-treated rats, both young and old (4 and 18 months old, respectively) served as controls. Rats fed on regular diet during aging showed memory deficits in Morris water maze, which were further exacerbated by lard intake. However, supplementation with ALA for 12 months dose-dependently improved the performance in spatial working memory tasks. Memory performance correlated well with the activation of cAMP response element-binding protein (CREB) and increases in both levels of brain-derived neurotrophic factor (BDNF) and its specific receptor tyrosine kinase B (TrkB) phosphorylation in the hippocampus. Further study identified that hippocampal extracellular signal-related kinase (ERK) and Akt rather than calcium calmodulin kinase IV (CaMKIV) and protein kinase A (PKA), the upstream signalings of CREB, were also activated by ALA supplement. Moreover, memory improvement was accompanied with alterations of hippocampal synaptic structure and number, suggestive of enhancement in synaptic plasticity. Together, these results suggest that long-term dietary intake of ALA enhances CREB/BDNF/TrkB pathway through the activation of ERK and Akt signalings in hippocampus, which contributes to its ameliorative effects on cognitive deficits in natural aging.