OBJECTIVES: To explore the therapeutic mechanism of Chaihu Shugan (CHSG) Decoction for improving cognitive impairment in rats with epilepsy induced by lithium chloride and pilocarpine. METHODS: Male SD rat models of cognitive impairment model after epilepsy induced by intraperitoneal injection with lithium chloride and pilocarpine were randomly divided into 5 groups (n=12) for treatment with daily gavage of saline, donepezil (90 mg/kg), or CHSG Decoction at 2.5, 5.0, 10, 20 and 40 g/kg for 4 consecutive weeks, with 10 rats with intraperitoneal injection with saline as the blank control group. Morris water maze test was used to evaluate cognitive and behavioral changes of the rats after treatment. The mRNA and protein expressions of ASIC1, NR1, NR2A and NR2B in the hippocampus of rats were detected using RT-qPCR and Western blotting. RESULTS: Compared with those with saline treatment, the rat models treated with CHSG Decoction at 5 and 10 g/kg showed significantly shortened escape latency and prolonged stay in the target quadrant with increased number of platform crossings in Morris water maze test. CHSG Decoction treatment at the two doses significantly increased ASIC1, NR1, NR2A and NR2B protein expressions in the hippocampus of the rat models, and their mRNA expression levels were all increased significantly after the treatment at the doses above 2.5 g/kg. CONCLUSIONS CHSG Decoction can improve cognitive impairment in rats after epilepsy possibly by regulating the expression and channel activity of NMDAR protein and its subunit protein via upregulating ASIC1 to modulate neuronal excitability and synaptic plasticity in the hippocampus.
Animals ; Hippocampus/drug effects* ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Acid Sensing Ion Channels/metabolism* ; Rats, Sprague-Dawley ; Male ; Rats ; Epilepsy/complications* ; Cognitive Dysfunction/drug therapy* ; Drugs, Chinese Herbal/therapeutic use* ; Up-Regulation ; Maze Learning

OBJECTIVES: To exple the mechanism of Qixiong Zuogui Granules (QXZG) for enhancing synaptic plasticity in aging rats. METHODS: Forty SD rats were randomized into control group, aging model group, donepezil treatment group, and QXZG treatment group (n=10). Except for the control rats, all the rats were subjected to daily intraperitoneal injection of D-galactose for 8 consecutive weeks to induce brain aging, and donepezil hydrochloride and QXZG suspension were administered by gavage during modeling. After the interventions, the rats were evaluated for general conditions, behavioral changes, oxidative stress indicators, hippocampal pathologies, and expressions of the brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) pathway, p16, and synaptic plasticity-associated proteins. RESULTS: The rats in the model group exhibited obvious aging phenotypes such as yellowing of the teeth and hair, body weight loss, and impaired learning and memory abilities, with decreased serum SOD and GSH-Px activities and increased serum MDA level. The rat models also showed obvious pathological changes, reduced Nissl bodies, and elevated p16 protein expression in the hippocampal CA1 region, with significantly decreased expression levels of BDNF, TrkB, CREB and synaptic plasticity proteins SYN, GAP43, and PSD95. Treatment with QXZG alleviated the aging phenotypes in the rat models, improved their learning and memory abilities and pathological changes in the hippocampal CA1 region, reduced oxidative stress and p16 protein expression, and promoted the expressions of the BDNF/TrkB pathway proteins and synaptic plasticity proteins. CONCLUSIONS QXZG enhances synaptic plasticity and reduces oxidative stress in aging rats possibly by upregulating the BDNF/TrkB signaling pathway proteins, thereby delaying brain aging and improving learning and memory abilities of the rats.
Animals ; Brain-Derived Neurotrophic Factor/metabolism* ; Neuronal Plasticity/drug effects* ; Signal Transduction/drug effects* ; Rats, Sprague-Dawley ; Receptor, trkB/metabolism* ; Rats ; Aging ; Drugs, Chinese Herbal/pharmacology* ; Male ; Oxidative Stress ; Hippocampus/metabolism*

OBJECTIVES: To clarify the role of hippocampal glutamate system in regulating HPA axis in mediating the effect of electroacupuncture (EA) at the heart meridian for improving myocardial injury in rats with acute myocardial ischemia (AMI). METHODS: Male SD rats were randomized into sham-operated group, AMI group, EA group, and L-glutamic acid+EA group (n=9). Rat models of AMI were established by left descending coronary artery ligation, and EA was applied at the "Shenmen-Tongli" segment; the rats in L-glutamic acid+EA group were subjected to microinjection of L-glutamic acid into the bilateral hippocampus prior to AMI modeling and EA treatment. Cardiac functions of the rats were evaluated using echocardiography, and ECG and heart rate variation (HRV) were analyzed using PowerLab and LabChart. Pathological changes in the myocardial tissue was examined using HE staining, and serum levels of myocardial enzymes were detected with ELISA. Myocardial expressions of TH and GAP43 were detected with immunohistochemistry, and colocalization of VGLUT1, VGLUT2 and c-fos were observed using immunofluorescence staining; the expressions of VGLUT1, VGLUT2, NMDAR1 and NMDAR2B were detected using Western blotting. RESULTS: The rat models of AMI showed significantly decreased LVEF and LVFS and increased serum levels of myocardial enzymes in positive correlation with the HPA axis. Numerous TH- and GAP43-positive cells were observed in the hippocampus, where the expressions of NE and E, neurons colabeled with VGLUT1, VGLUT2 and c-fos, and expressions of VGLUT1, VGLUT2, NMDAR1, NMDAR2B and Glu increased significantly. All these changes were significantly improved by interventions with EA as compared with those in AMI and L-Glutamate+EA groups. CONCLUSIONS In rats with AMI, EA at the heart meridian can regulate excessive glutamate release in the hippocampus, thereby inhibiting HPA axis hyperactivity and reducing sympathetic nerve activity to protect the myocardial tissue.
Animals ; Electroacupuncture ; Male ; Rats, Sprague-Dawley ; Hippocampus/metabolism* ; Rats ; Glutamic Acid/metabolism* ; Myocardial Ischemia/physiopathology* ; Hypothalamo-Hypophyseal System/physiopathology* ; Pituitary-Adrenal System/physiopathology* ; Receptors, N-Methyl-D-Aspartate/metabolism*

OBJECTIVES: To explore the role of C1q, the promoter of the classical pathway of the complement system, in regulating postpartum depressive-like behaviors in mice and the therapeutic mechanism of C1q-neutralizing antibodies. METHODS: Female C57BL/6 mouse models of postpartum depression established by hormone-simulated pregnancy (HSP) were evaluated for depression-like behaviors, and peripheral blood levels and hippocampal expressions of C1q were detected using ELISA and Western blotting. Immunofluorescence staining was used for detecting co-labeling of C1q and microglia, and the differentially expressed mRNAs in the hippocampus of HSP mice were analyzed using RNA sequencing. The Edinburgh Postnatal Depression Scale was used to screen patients with postpartum depression, from whom peripheral blood mononuclear cells were extracted for detecting C1q expression levels with Western blotting. The HSP mice were subjected to stereotactic injection of C1q-neutralizing antibody or a control IgG in the hippocampus, and the changes in depressive-like behaviors and hippocampal expression of C3 were examined. RESULTS: The HSP mice exhibited obvious depressive behaviors, demonstrated by significantly decreased preference for sugar water and increased forced swimming and tail suspension time. The mouse models showed significantly increased peripheral blood C1q level and hippocampal expression level of C1q, accompanied by an increase in Iba1 and C1q co-labeling in the hippocampus. The expression level of C1q in peripheral monocytes was also significantly increased in patients with postpartum depression. In HSP mice, stereotactic injection of C1q-neutralizing antibody, but not the control IgG, obviously alleviated depressive-like behaviors, shown by significantly increased preference for sugar water and decreased forced swimming and tail suspension time, resulting also in decreased expression of C3 in the hippocampus and lowered serum levels of IL-6 and TNF-α. CONCLUSIONS C1q-neutralizing antibodies improve postpartum depressive-like behaviors in mice possibly by regulating the C1q/C3 signaling pathway.
Animals ; Female ; Depression, Postpartum ; Complement C1q/metabolism* ; Antibodies, Neutralizing/pharmacology* ; Mice, Inbred C57BL ; Mice ; Hippocampus/metabolism* ; Pregnancy ; Disease Models, Animal

OBJECTIVES: To investigate the mechanism underlying the therapeutic effect of electroacupuncture (EA) on post-traumatic stress disorder (PTSD) in rats. METHODS: Forty male SD rats were randomized equally into blank control group, PTSD model group, sham-acupuncture group, paroxetine group, and EA group. In the latter 3 groups, the rat models of PTSD, induced by continuous single-prolonged stress and plantar electrical stimulation, were treated with EA at GV20, GV24, BL18 and BL23 acupoints for 15 min (5 times a week for 3 weeks), sham-acupuncture without electrical stimulation, or gavage with paroxetine suspension on the same schedule. Behavioral changes of the rats were evaluated using open field test (OFT) and elevated plus maze (EPM) test. Hippocampal pathologies and neuronal changes were examined with HE and Nissl staining, and mitochondrial ultrastructure was examined using electron microscopy. The mRNA and protein expression levels of Bcl-2, Bax, and caspase-3 were detected by RT-qPCR and immunofluorescence staining. RESULTS: The rat models of PTSD showed significantly reduced total distance traveled in OFT and distance and time spent in the open arms of the EPM, with decreased hippocampal neurons, obvious neuronal and mitochondrial pathologies, decreased hippocampal expression of Bcl-2, and increased Bax and caspase-3 expressions. Treatments with paroxetine and EA both significantly improved behavioral changes of the rat models, increased the number of Nissl-stained neurons, obviously alleviated pathologies in the hippocampal neurons and mitochondrial ultrastructure, increased hippocampal Bcl-2 expression, and lowered caspase-3 expressions. Paroxetine showed significantly better effect than EA for improving performance of the rats in EPM test, whereas sham-acupuncture did not produce any significant improvement. CONCLUSIONS EA alleviates PTSD in rats possibly by upregulating Bcl-2 and downregulating Bax and caspase-3, thereby ameliorating hippocampal mitochondrial damage.
Animals ; Electroacupuncture ; Stress Disorders, Post-Traumatic/metabolism* ; Hippocampus/pathology* ; Rats, Sprague-Dawley ; Male ; Rats ; Mitochondria/pathology* ; Signal Transduction ; bcl-2-Associated X Protein/metabolism* ; Caspase 3/metabolism* ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; Disease Models, Animal

Vascular damage plays a significant role in the onset and progression of Alzheimer's disease (AD). However, the precise molecular mechanisms underlying the induction of neuronal injury by vascular damage remain unclear. The present study aimed to examine the impact of fibrinogen (Fg) on tau pathology. The results showed that Fg deposits in the brains of tau P301S transgenic mice interact with tau, enhancing the cytotoxicity of pathological tau aggregates and promoting tau phosphorylation and aggregation. Notably, Fg-modified tau fibrils caused enhanced neuronal apoptosis and synaptic damage compared to unmodified fibrils. Furthermore, intrahippocampal injection of Fg-modified tau fibrils worsened the tau pathology, neuroinflammation, synaptic damage, neuronal apoptosis, and cognitive dysfunction in tau P301S mice compared to controls. The present study provides compelling evidence linking Fg and tau, thereby connecting cerebrovascular damage to tau pathology in AD. Consequently, inhibiting Fg-mediated tau pathology could potentially impede the progression of AD.
Animals ; tau Proteins/metabolism* ; Alzheimer Disease/metabolism* ; Fibrinogen/metabolism* ; Mice, Transgenic ; Mice ; Disease Models, Animal ; Memory Disorders/metabolism* ; Male ; Mice, Inbred C57BL ; Brain/metabolism* ; Hippocampus/metabolism* ; Protein Aggregation, Pathological/metabolism* ; Apoptosis ; Phosphorylation

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, causing dementia and affecting millions of individuals. One prominent characteristic in the brains of AD patients is glucose hypometabolism. In the context of galactose metabolism, intracellular glucose levels are heightened. Galactose mutarotase (GALM) plays a crucial role in maintaining normal galactose metabolism by catalyzing the conversion of β-D-galactose into α-D-galactose (α-D-G). The latter is then converted into glucose-6-phosphate, improving glucose metabolism levels. However, the involvement of GALM in AD progression is still unclear. In the present study, we found that the expression of GALM was significantly increased in AD patients and model mice. Genetic knockdown of GALM using adeno-associated virus did not change the expression of amyloid precursor protein (APP) and APP-cleaving enzymes including a disintegrin and metalloprotease 10 (ADAM10), β-site APP-cleaving enzyme 1 (BACE1), and presenilin-1 (PS1). Interestingly, genetic overexpression of GALM reduced APP and Aβ deposition by increasing the maturation of ADAM10, although it did not alter the expression of BACE1 and PS1. Further electrophysiological and behavioral experiments showed that GALM overexpression significantly ameliorated the deficits in hippocampal CA1 long-term potentiation (LTP) and spatial learning and memory in AD model mice. Importantly, direct α-D-G (20 mg/kg, i.p.) also inhibited Aβ deposition by increasing the maturation of ADAM10, thereby improving hippocampal CA1 LTP and spatial learning and memory in AD model mice. Taken together, our results indicate that GALM shifts APP processing towards α-cleavage, preventing Aβ generation by increasing the level of mature ADAM10. These findings indicate that GALM may be a potential therapeutic target for AD, and α-D-G has the potential to be used as a dietary supplement for the prevention and treatment of AD.
Animals ; ADAM10 Protein/metabolism* ; Alzheimer Disease/pathology* ; Amyloid Precursor Protein Secretases/metabolism* ; Disease Models, Animal ; Humans ; Mice ; Amyloid beta-Peptides/metabolism* ; Male ; Mice, Transgenic ; Membrane Proteins/metabolism* ; Cognitive Dysfunction/pathology* ; Mice, Inbred C57BL ; Amyloid beta-Protein Precursor/metabolism* ; Female ; Hippocampus/metabolism* ; Long-Term Potentiation/physiology*

Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits. The dorsal hippocampus (dHPC), a well-defined region responsible for learning and memory, displays maladaptive plasticity upon injury, which is assumed to underlie pain hypersensitivity and cognitive deficits. However, much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes. Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix (ECM) and decreases ECM rigidity in the dHPC. Despite this, it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits. Laminin, a key element of the ECM, consists of α-, β-, and γ-chains and has been implicated in several pathophysiological processes. Here, we showed that peripheral nerve injury downregulates laminin β1 (LAMB1) in the dHPC. Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction. Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrin β1, leading to decreased Ca²⁺ levels in pyramidal neurons, which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits. In this study, we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits, and reveal a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified hippocampal LAMB1/integrin β1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.
Animals ; Laminin/genetics* ; Hippocampus/metabolism* ; Neuralgia/metabolism* ; Cognitive Dysfunction/etiology* ; Male ; Peripheral Nerve Injuries/metabolism* ; Extracellular Matrix/metabolism* ; Integrin beta1/metabolism* ; Pyramidal Cells/metabolism* ; Signal Transduction

Epilepsy is a chronic neurological disorder affecting ~65 million individuals worldwide. Abnormal synaptic plasticity is one of the most important pathological features of this condition. We investigated how ubiquitin-specific peptidase 47 (USP47) influences synaptic plasticity and its link to epilepsy. We found that USP47 enhanced excitatory postsynaptic transmission and increased the density of total dendritic spines and the proportion of mature dendritic spines. Furthermore, USP47 inhibited the degradation of the ubiquitinated α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit glutamate receptor 1 (GluR1), which is associated with synaptic plasticity. In addition, elevated levels of USP47 were found in epileptic mice, and USP47 knockdown reduced the frequency and duration of seizure-like events and alleviated epileptic seizures. To summarize, we present a new mechanism whereby USP47 regulates excitatory postsynaptic plasticity through the inhibition of ubiquitinated GluR1 degradation. Modulating USP47 may offer a potential approach for controlling seizures and modifying disease progression in future therapeutic strategies.
Animals ; Receptors, AMPA/metabolism* ; Neuronal Plasticity/physiology* ; Seizures/physiopathology* ; Disease Models, Animal ; Mice, Inbred C57BL ; Mice ; Ubiquitin Thiolesterase/genetics* ; Male ; Excitatory Postsynaptic Potentials/physiology* ; Ubiquitination ; Dendritic Spines/metabolism* ; Hippocampus/metabolism*

One of the basic questions in the aging field is whether there is a fundamental difference between the aging of lower invertebrates and mammals. A major difference between the lower invertebrates and mammals is the abundancy of noncoding RNAs, most of which are not conserved. We have previously identified a noncoding RNA Terc-53 that is derived from the RNA component of telomerase Terc. To study its physiological functions, we generated two transgenic mouse models overexpressing the RNA in wild-type and early-aging Terc-/- backgrounds. Terc-53 mice showed age-related cognition decline and shortened life span, even though no developmental defects or physiological abnormality at an early age was observed, indicating its involvement in normal aging of mammals. Subsequent mechanistic study identified hyaluronan-mediated motility receptor (Hmmr) as the main effector of Terc-53. Terc-53 mediates the degradation of Hmmr, leading to an increase of inflammation in the affected tissues, accelerating organismal aging. adeno-associated virus delivered supplementation of Hmmr in the hippocampus reversed the cognition decline in Terc-53 transgenic mice. Neither Terc-53 nor Hmmr has homologs in C. elegans. Neither do arthropods express hyaluronan. These findings demonstrate the complexity of aging in mammals and open new paths for exploring noncoding RNA and Hmmr as means of treating age-related physical debilities and improving healthspan.
Animals ; Mice ; RNA, Untranslated/metabolism* ; Aging/genetics* ; Mice, Transgenic ; Telomerase/metabolism* ; RNA/genetics* ; Hippocampus/metabolism* ; Humans ; Mice, Inbred C57BL