Neuroinflammation has been implicated in cognitive deficits of neurological and neurodegenerative diseases. There is abundant evidence that the application of ghrelin, an orexigenic hormone ...regulating appetite and energy balance, abrogates neuroinflammation and rescues associated memory impairment. However, the underlying mechanism is uncertain. In this study, we find that both intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration of lipopolysaccharide (LPS) impairs spatial memory in mice. LPS treatment causes neuroinflammation and microglial activation in the hippocampus. Ghsr1a deletion suppresses LPS-induced microglial activation and neuroinflammation, and rescued LPS-induced memory impairment. Our findings thus suggest that GHS-R1a signaling may promote microglial immunoactivation and contribute to LPS-induced neuroinflammation. GHS-R1a may be a new therapeutic target for cognitive dysfunction associated with inflammatory conditions.
•GHS-R1a deficiency abrogates spatial learning and memory impairment induced by i.p. administration of LPS.•GHS-R1a deficiency abrogates spatial memory impairment induced by i.c.v. administration of LPS.•GHS-R1a deficiency abrogates LPS-induced impairment in spatial memory retrieval.•GHS-R1a deletion protects again LPS-induced microglial activation in the hippocampus.
Display omitted
Sleep is a fundamental state for maintaining the organism homeostasis. Disruptions in sleep patterns predispose to the appearance of memory impairments and mental disorders, including ...depression. Recent pre-clinical studies have highlighted the antidepressant-like properties of the synthetic compound 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1). To further investigate the neuromodulatory effects of SeBZF1, this study aimed to assess its therapeutic efficacy in ameliorating neurobehavioral impairments induced by sleep deprivation (SD) in mice. For this purpose, a method known as multiple platforms over water was used to induce rapid eye movement (REM) SD. Two hours after acute SD (24 h), male Swiss mice received a single treatment of SeBZF1 (5 mg/kg, intragastric route) or fluoxetine (a positive control, 20 mg/kg, intraperitoneal route). Subsequently, behavioral tests were conducted to assess spontaneous motor function (open-field test), depressive-like behavior (tail suspension test), and memory deficits (Y-maze test). Brain structures were utilized to evaluate oxidative stress markers, monoamine oxidase (MAO) and acetylcholinesterase (AChE) activities. Our findings revealed that SD animals displayed depressive-like behavior and memory impairments, which were reverted by SeBZF1 and fluoxetine treatments. SeBZF1 also reverted the increase in lipoperoxidation levels and glutathione peroxidase activity in the pre-frontal cortex in mice exposed to SD. Besides, the increase in hippocampal AChE activity induced by SD was overturned by SeBZF1. Lastly, cortical MAO-B activity was reestablished by SeBZF1 in mice that underwent SD. Based on the main findings of this study, it can be inferred that the compound SeBZF1 reverses the neurobehavioral alterations induced by sleep deprivation in male Swiss mice.
Melatonin acts as a pleiotropic agent in various age‐related neurodegenerative diseases. In this study, we examined the underlying neuroprotective mechanism of melatonin against D‐galactose‐induced ...memory and synaptic dysfunction, elevated reactive oxygen species (ROS), neuroinflammation and neurodegeneration. D‐galactose was administered (100 mg/kg intraperitoneally (i.p.)) for 60 days. After 30 days of D‐galactose administration, vehicle (same volume) or melatonin (10 mg/kg, i.p.) was administered for 30 days. Our behavioral (Morris water maze and Y‐maze test) results revealed that chronic melatonin treatment alleviated D‐galactose‐induced memory impairment. Additionally, melatonin treatment reversed D‐galactose‐induced synaptic disorder via increasing the level of memory‐related pre‐and postsynaptic protein markers. We also determined that melatonin enhances memory function in the D‐galactose‐treated mice possibly via reduction of elevated ROS and receptor for advanced glycation end products (RAGE). Furthermore, Western blot and morphological results showed that melatonin treatment significantly reduced D‐galactose‐induced neuroinflammation through inhibition of microgliosis (Iba‐1) and astrocytosis (GFAP), and downregulating other inflammatory mediators such as p‐IKKβ, p‐NF‐KB65, COX2, NOS2, IL‐1β, and TNFα. Moreover, melatonin lowered the oxidative stress kinase p‐JNK which suppressed various apoptotic markers, that is, cytochrome C, caspase‐9, caspase‐3 and PARP‐1, and prevent neurodegeneration. Hence, melatonin attenuated the D‐galactose‐induced memory impairment, neuroinflammation and neurodegeneration possibly through RAGE/NF‐KB/JNK pathway. Taken together, our data suggest that melatonin could be a promising, safe and endogenous compatible antioxidant candidate for age‐related neurodegenerative diseases such as Alzheimer's disease (AD).
Amnestic mild cognitive impairment (aMCI) is defined by memory impairment but executive function (EF) deficits could be also a common feature. This study examined the underlying neurocognitive ...processes associated with executive function (EF) deficits in patients with aMCI using the Wisconsin Card Sorting Test (WCST) and computational modeling. Forty-two patients with aMCI and thirty-eight matched Controls performed the WSCT and underwent neurocognitive assessment. The Attentional Learning Model was applied the WCST. Patients with aMCI demonstrated deficits in feedback-learning. More specifically, patients showed increased Reward-Sensitivity and reduced Punishment-Sensitivity. These alterations were associated with poor WSCT performance and deficits in EF and Memory. Goal-directed deficits in aMCI, as observed in the WCST, are associated with difficulties in updating attention after feedback as its changes too rapidly following positive feedback and too slowly following negative feedback. Consequently, memory and EF deficits interact and reinforce each other generating performance deficits in patients with aMCI.
Alzheimer’s disease (AD) is characterized by cognitive impairment, loss of learning and memory, and abnormal behaviors. Scopolamine (SCOP) is a non-selective antagonist of muscarinic acetylcholine ...receptors that exhibits the behavioral and molecular hallmarks of AD. Vanillic acid (VA), a phenolic compound, is obtained from the roots of a traditional plant called Angelica sinensis, and has several pharmacologic effects, including antimicrobial, anti-inflammatory, anti-angiogenic, anti-metastatic, and antioxidant properties. Nevertheless, VA’s neuroprotective potential associated with the memory has not been thoroughly investigated. Therefore, this study investigated whether VA treatment has an ameliorative effect on the learning and memory impairment induced by SCOP in rats. Behavioral experiments were utilized to assess the learning and memory performance associated with the hippocampus. Using western blotting analysis and assay kits, the neuronal damage, oxidative stress, and acetylcholinesterase activity responses of hippocampus were evaluated. Additionally, the measurement of long-term potentiation was used to determine the function of synaptic plasticity in organotypic hippocampal slice cultures. In addition, the synaptic vesicles’ density and the length and width of the postsynaptic density were evaluated using electron microscopy. Consequently, the behavioral, biochemical, electrophysiological, and ultrastructural analyses revealed that VA treatment prevents learning and memory impairments caused by SCOP in rats. The study’s findings suggest that VA has a neuroprotective effect on SCOP-induced learning and memory impairment linked to the hippocampal cholinergic system, oxidative damage, and synaptic plasticity. Therefore, VA may be a prospective therapeutic agent for treating AD.
Qifu Yin (QFY) originates from “Jingyue Quanshu · Volume 51 · New Fang Bazhen · Buzhen” a work by Zhang Jingyue, a distinguished Chinese medical practitioner from the Ming Dynasty. QFY is composed of ...Ginseng Radix et Rhizoma, Rehmanniae Radix Praeparata, Angelicae Sinensis Radix, Atractylodis Macrocephalae Rhizoma, Glycyrrhizae Radix et Rhizoma Praeparata Cum Melle, Ziziphi Spinosae Semen, and Polygalae Radix. QFY is frequently employed to address memory loss and cognitive impairment stemming from vascular dementia, Alzheimer's disease (AD), and related conditions. Our findings indicate that QFY can mitigate nerve cell damage. Moreover, the study explores the impact of QFY on the calcium ion pathway and sphingolipid metabolism in mice with myocardial infarction, presenting a novel perspective on QFY's mechanism in ameliorating myocardial infarction through lipidomics. While this research provides an experimental foundation for the clinical application of QFY, a comprehensive and in-depth analysis of its improvement mechanism remains imperative.
To clarify the regulatory mechanism of QFY on intestinal microecology in mice with memory impairment (MI).
The memory impairment mouse model was established by intraperitoneal injection of scopolamine hydrobromide. Kunming (KM) mice were randomly divided into blank group, Ginkgo tablet group (0.276 g/kg), QFY high, medium and low dose groups (17.2 g/kg, 8.6 g/kg, 4.3 g/kg). The effect on memory ability was evaluated by open field and step-down behavioral experiments. The morphological changes of nerve cells in the hippocampus of mice were observed by pathological method. The contents of superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT) and glutathione peroxidase (GSH-Px) in the brain tissue of mice were detected. The expression levels of CREB, Brain-Derived Neurotrophic Factor (BDNF) and Recombinant Amyloid Precursor Protein (APP) in the hippocampus of mice were determined using immunohistochemistry. The expression of N-methyl-D-aspartate receptor (NMDAR) and cAMP response element binding protein (CREB) related factors in the serum of mice was analyzed by ELISA. The levels of apoptosis signal-regulating kinase-1 (ASK1) and c-Jun N-terminal kinase (JNK) mRNA in the hippocampus were detected by quantitative real-time fluorescence polymerase chain reaction (qPCR). The intestinal feces of mice were collected, and the 16 S rDNA technology was used to detect the changes in intestinal microbiota microecological structure of feces in each group.
Behavioral experiments showed that the high-dose QFY group exhibited a significant increase in exercise time (P<0.05) and a decrease in diagonal time (P<0.05) compared to the model group. The medium-dose group of QFY showed a reduction in diagonal time (P<0.05). Additionally, the latency time significantly increased in the medium and high-dose groups of QFY (P<0.01). The number of errors in the low, medium and high dose groups was significantly decreased (P<0.05, P<0.01, P<0.01). The nerve cells in the CA1 and CA3 regions of QFY-treated mice demonstrated close arrangement and clear structure. Furthermore, the content of SOD significantly increased (P<0.01) and the content of MDA significantly decreased (P<0.05) in the low and high-dose QFY groups. The content of CAT in the medium-dose group significantly increased (P < 0.05). Immunohistochemical analysis showed a significant reduction in the number of APP expression particles in the CA1 and CA3 regions of all QFY groups. Moreover, BDNF expression significantly increased in the medium and high-dose groups, while CREB expression significantly increased in the low and medium-dose groups of QFY within the CA1 and CA3 regions. Serum analysis revealed significant increases in CREB content in the low, medium, and high dose groups of QFY (P<0.01, P<0.05, P<0.05), and decreases in NMDAR content across all QFY dose groups (P<0.01). PCR analysis showed a significant decrease in the contents of ASK1 and JNK in the medium-dose group (P<0.01). Microecological analysis of intestinal microbiota demonstrated a significant restoration trend in the relative abundance of Fusobacteria, Planctomycetes, and Verrucomicrobia (P<0.01 or P<0.05) at the phylum level in the QFY groups. At the genus level, Akkermansia, Paramuribaculum, Herminiimonas, Erysipelatoclostridium and other genera in the QFY groups showed a significant trend of relative abundance restoration (P<0.01 or P<0.05).
QFY can improve the memory of MI animals induced by scopolamine hydrobromide by restoring the homeostasis of intestinal microbiota and regulating related indexes in serum and brain tissue.
Display omitted
•QFY demonstrates significant efficacy in ameliorating memory impairment.•QFY enhances learning and memory through antioxidative stress and enhancing neuroprotection.•QFY modulates the expression of ASK1 and JNK proteins involved in sphingolipid metabolism.•Restoration of intestinal flora homeostasis is associated with the memory-improving effects of Qifu Yin.
The use of NPS compounds is increasing, and impairment in spatial learning and memory is a growing concern. Alpha-pyrrolidinovalerophenone (α-PVP) consumption, as a commonly used NPS, can impair ...spatial learning and memory via the brain mitochondrial dysfunction mechanism. Liraglutide isone of the most well-known Glucagon-Like Peptide 1 (GLP-1) agonists that is used as an anti-diabetic and anti-obesity drug. According to current research, Liraglutide likely ameliorates cognitive impairment in neurodegenerative conditions and substance use disorders. Hence, the purpose of this study is examining the effect of Liraglutide on α-PVP-induced spatial learning and memory problems due to brain mitochondrial dysfunction. Wistar rats (8 in each group) received α-PVP (20 mg/kg/d for 10 consecutive days, intraperitoneally (I.P.)). Then, Liraglutide was administered at 47 and 94 μg/kg/d, I.P., for 4 weeks following the α-PVP administration. The Morris Water Maze (MWM) task evaluated spatial learning and memory 24 h after Liraglutide treatment. Bedside, brain mitochondrial activity parameters, including reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP), cytochrome c release, mitochondrial outer membrane damage and swelling, and brain ADP/ATP ratio, were studied. Our results showed that Liraglutide ameliorated α-PVP-induced spatial learning and memory impairments through alleviating brain mitochondrial dysfunction (which is indicated by increasing ROS formation, collapsed MMP, mitochondrial outer membrane damage, cytochrome c release, mitochondrial swelling, and increased brain ADP/ATP ratio). This study could be used as a starting point for future studies about the possible role of Liraglutide in ameliorating mitochondrial dysfunction leading to substance use disorder- induced cognitive impairment.
Display omitted
•α-PVP 20 mg/kg for ten consecutive days impairs spatial learning and memory in rats.•4-week Liraglutide administration reduces α-PVP indued spatial memory impairment.•Liraglutide improves mitochondrial dysfunction by reducing ROS over-production.
Display omitted
•This study revealed mechanisms of diabetes-related memory impairment in vivo and in vitro.•TP ameliorated memory impairment and neuronal apoptosis in aged T2DM rats.•TP improved ...hippocampal glucose uptake/metabolism and O-GlcNAc glycosylation/phosphorylation of Tau.•This study not only involves glycolysis and the TCA in glucose metabolism, but also focuses on the hexosamine biosynthesis pathway.•It provides new insights into the beneficial effect of TP on diabetes-related memory impairment.
Diabetes mellitus (DM) plays a causative role in memory impairment. Neuroprotective effects of tea polyphenol (TP), a unique and vital functional component of tea, have been widely investigated in neurodegenerative diseases, but the exact mechanisms have still not been entirely clarified yet. Here, we conducted the experiment to assess whether TP could protect the aged T2DM rats from memory impairment and its potential mechanisms. Our study revealed that memory impairment in aged T2DM rats was alleviated after TP treatment. Both in vivo and in vitro experiments showed that TP raised expression of GLUT4, activities of key enzymes of glucose metabolism and production of ATP in the model group, along with elevated O-GlcNAc glycosylation and reduced phosphorylation of Tau. Collectively, TP ameliorates memory impairment in aged T2DM rats via modulating hippocampal glucose uptake/metabolism and O-GlcNAc glycosylation/phosphorylation of Tau, which provides new insights into the beneficial effect of TP on DM-related memory impairment.
Alzheimer’s disease (AD) is a primary neurodegenerative disease. It can be caused by aging and brain trauma and severely affects the abilities of cognition and memory of patients. Therefore, it ...seriously threatens the mental and physical health of humans worldwide. As a traditional Chinese medicine, ginsenosides have been proven to have a variety of pharmacological activities. Ginsenoside Rh4 (Rh4) is one of the rare ginsenosides with higher pharmacological activity than ordinary ginsenosides, but its effect on alleviating AD and its molecular mechanism have not been studied. Here, we investigated the anti-AD effects of Rh4 and its potential mechanisms using an AD mouse model induced by a combination of AlCl3·6H2O and d-galactose. The results showed that Rh4 could significantly improve the ability of cognizance and reduce neuronal damage in mice. Concurrently, Rh4 attenuates amyloid β accumulation, increases the density of dendritic spines, and logically inhibits synaptic structural damage as a result of neuronal excessive apoptosis and autophagy. Rh4 can not only inhibit the inflammatory response caused by the overactivation of microglia and astrocytes, reduce the levels of pro-inflammatory factors, increase the level of antioxidant enzymes in serum, and significantly improve the activity of antioxidant enzyme SOD1 in the hippocampus but also inhibit the hyperphosphorylation of tau protein in the hippocampus of mice by regulating the Wnt2b/GSK-3β/SMAD4 signaling pathway. Together, this study provides a theoretical basis for Rh4 in the treatment of AD and reveals that Rh4 is a potential drug for the treatment of AD.
Preeclampsia (PE) is a hypertensive disorder of pregnancy that is associated with memory impairment, cognitive decline and brain atrophy later in life in women at ages as young as early-to-mid 40 s. ...PE increases the risk of vascular dementia three-fold, however, long-lasting effects of PE on the vasculature of vulnerable brain regions involved in memory and cognition, such as the hippocampus, remain unknown. Here, we used a rat model of experimental PE (ePE) induced by maintaining rats on a 2% cholesterol diet beginning on day 7 of gestation to investigate hippocampal function later in life. Hippocampal-dependent memory and hippocampal arteriole (HA) function were determined in Sprague Dawley rats 5 months after either a healthy pregnancy or ePE (
= 8/group). Rats that had ePE were hypertensive and had impaired vasoreactivity of HAs to mediators involved in matching neuronal activity with local blood flow (i.e., neurovascular coupling). ePE rats also had impaired long-term memory, but not spatial memory. Thus, this model of ePE mimics some of the long-lasting cardiovascular and cognitive consequences that occur in women who previously had PE. These findings suggest endothelial and vascular smooth muscle dysfunction of HAs were present months after PE that could impair hippocampal neurovascular coupling. This represents a novel vascular mechanism by which PE causes early-onset dementia.
