OBJECTIVE: To investigate the molecular mechanisms underlying the beneficial effect of electroacupuncture (EA) in experimental models of Alzheimer's disease (AD) in vivo. METHODS: Senescence-accelerated mouse prone 8 (SAMP8) mice were used as AD models and received EA at Yingxiang (LI 20, bilateral) and Yintang (GV 29) points for 20 days. For certain experiments, SAMP8 mice were injected intravenously with human fibrin (2 mg). The Morris water maze test was used to assess cognitive and memory abilities. The changes of tight junctions of blood-brain barrier (BBB) in mice were observed by transmission electron microscope. The expressions of fibrin, amyloid- β (Aβ), and ionized calcium-binding adapter molecule 1 (IBa-1) in mouse hippocampus (CA1/CA3) were detected by reverse transcription-quantitative polymerase chain reaction (qRT-PCR), Western blot or immunohistochemical staining. The expression of fibrin in mouse plasma was detected by enzyme-linked immunosorbent assay. The expressions of tight junction proteins zonula occludens-1 and claudin-5 in hippocampus were detected by qRT-PCR and immunofluorescence staining. Apoptosis of hippocampal neurons was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. RESULTS: Fibrin was time-dependently deposited in the hippocampus of SAMP8 mice and this was inhibited by EA treatment (P<0.05 or P<0.01). Furthermore, EA treatment suppressed the accumulation of Aβ in the hippocampus of SAMP8 mice (P<0.01), which was reversed by fibrin injection (P<0.05 or P<0.01). EA improved SAMP8 mice cognitive impairment and BBB permeability (P<0.05 or P<0.01). Moreover, EA decreased reactive oxygen species levels and neuroinflammation in the hippocampus of SAMP8 mice, which was reversed by fibrin injection (P<0.05 or P<0.01). Mechanistically, EA inhibited the promoting effect of fibrin on the high mobility group box protein 1 (HMGB1)/toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE)/nicotinamide adenine dinucleotide phosphate (NADPH) signaling pathways (P<0.01). CONCLUSION EA may potentially improve cognitive impairment in AD via inhibition of fibrin/A β deposition and deactivation of the HMGB1/TLR4 and RAGE/NADPH signaling pathways.
Mice ; Humans ; Animals ; NADP/metabolism* ; Toll-Like Receptor 4 ; HMGB1 Protein/metabolism* ; Receptor for Advanced Glycation End Products/metabolism* ; Blood-Brain Barrier/metabolism* ; Neuroinflammatory Diseases ; Electroacupuncture ; Alzheimer Disease/therapy* ; Hippocampus/metabolism* ; Amyloid beta-Peptides/metabolism*

As prominent immune cells in the central nervous system, microglia constantly monitor the environment and provide neuronal protection, which are important functions for maintaining brain homeostasis. In the diseased brain, microglia are crucial mediators of neuroinflammation that regulates a broad spectrum of cellular responses. In this review, we summarize current knowledge on the multifunctional contributions of microglia to homeostasis and their involvement in neurodegeneration. We further provide a comprehensive overview of therapeutic interventions targeting microglia in neurodegenerative diseases. Notably, we propose microglial depletion and subsequent repopulation as promising replacement therapy. Although microglial replacement therapy is still in its infancy, it will likely be a trend in the development of treatments for neurodegenerative diseases due to its versatility and selectivity.
Humans ; Microglia/physiology* ; Central Nervous System ; Neurodegenerative Diseases/therapy* ; Brain/physiology* ; Homeostasis

Primary familial brain calcification (PFBC) is an inherited neurodegenerative disorder mainly characterized by progressive calcium deposition bilaterally in the brain, accompanied by various symptoms, such as dystonia, ataxia, parkinsonism, dementia, depression, headaches, and epilepsy. Currently, the etiology of PFBC is largely unknown, and no specific prevention or treatment is available. During the past 10 years, six causative genes (SLC20A2, PDGFRB, PDGFB, XPR1, MYORG, and JAM2) have been identified in PFBC. In this review, considering mechanistic studies of these genes at the cellular level and in animals, we summarize the pathogenesis and potential preventive and therapeutic strategies for PFBC patients. Our systematic analysis suggests a classification for PFBC genetic etiology based on several characteristics, provides a summary of the known composition of brain calcification, and identifies some potential therapeutic targets for PFBC.
Animals ; Brain Diseases/therapy* ; Xenotropic and Polytropic Retrovirus Receptor ; Brain/pathology*

Acupuncture-moxibustion is remarkably effective on encephalopathy, but its mechanism is unclear. With the continuous development of imaging technology, the in vivo brain imaging technology has been used increasingly in life science research and it also becomes a more effective tool for the basic research of acupuncture-moxibustion in treatment of encephalopathy. The paper summarizes the application of its technology in the basic research of acupuncture-moxibustion for encephalopathy and the characteristics of imaging, as well as the advantages and shortcomings. It is anticipated that the references may be provided for the basic research of acupuncture-moxibustion in treatment of encephalopathy and be conductive to the modernization of acupuncture-moxibustion.
Humans ; Moxibustion ; Acupuncture Therapy ; Acupuncture ; Brain Diseases/therapy* ; Neuroimaging

Objective: To observe the effects of transcranial direct current stimulation (tDCS) on nerve injury markers and prognosis in patients with acute severe carbon monoxide poisoning (ASCOP) . Methods: In May 2021, 103 ASCOP patients were treated in the emergency department of Harrison International Peace Hospital of Hebei Medical University from November 2020 to January 2021. The patients were divided into two groups according to whether they received tDCS treatment. The control group (50 cases) were given oxygen therapy (hyperbaric oxygen and oxygen inhalation) , reducing cranial pressure, improving brain circulation and cell metabolism, removing oxygen free radicals and symptomatic support, and the observation group (53 cases) was treated with 2 weeks of tDCS intensive treatment on the basis of conventional treatment. All patients underwent at least 24 h bispectral index (BIS) monitoring, BIS value was recorded at the hour and the 24 h mean value was calculated. Neuron-specific enolase (NSE) and serum S100B calcium-binding protein (S100B) were detected after admission, 3 d, 7 d and discharge. Follow-up for 60 days, the incidence and time of onset of delayed encephalopathy (DEACMP) with acute carbon monoxide poisoning in the two groups were recorded. Results: The NSE and S100B proteins of ASCOP patients were significantly increased at admission, but there was no significant difference between the two groups (P=0.711, 0.326) . The NSE and S100B proteins were further increased at 3 and 7 days after admission. The increase in the observation group was slower than that in the control group, and the difference was statistically significant (P(3 d)=0.045, 0.032, P(7 d)=0.021, 0.000) ; After 14 days, it gradually decreased, but the observation group decreased rapidly compared with the control group, with a statistically significant difference (P=0.009, 0.025) . The 60 day follow-up results showed that the incidence of DEACMP in the observation group was 18.87% (10/53) , compared with 38.00% (19/50) in the control group (P=0.048) ; The time of DEACMP in the observation group[ (16.79±5.28) d] was later than that in the control group[ (22.30±5.42) d], and the difference was statistically significant (P=0.013) . Conclusion: The early administration of tDCS in ASCOP patients can prevent the production of NSE and S100B proteins, which are markers of nerve damage. and can improve the incidence and time of DEACMP.
Humans ; Biomarkers ; Brain Diseases/therapy* ; Carbon Monoxide Poisoning/therapy* ; Oxygen ; Phosphopyruvate Hydratase ; Prognosis ; S100 Calcium Binding Protein beta Subunit ; Transcranial Direct Current Stimulation

The purpose of this study was to investigate the effect of aqueous extract of Corni Fructus on β-amyloid protein 25-35(Aβ_(25-35))-induced brain injury and neuroinflammation in Alzheimer's disease(AD) mice to provide an experimental basis for the treatment of AD by aqueous extract of Corni Fructus. Sixty C57BL/6J male mice were randomly divided into a sham group, a model group, a positive control group(huperizine A, 0.2 mg·kg~(-1)), a low-dose aqueous extract of Corni Fructus group(1.3 g·kg~(-1)), a medium-dose aqueous extract of Corni Fructus group(2.6 g·kg~(-1)), and a high-dose aqueous extract of Corni Fructus group(5.2 g·kg~(-1)). The AD model was induced by lateral ventricular injection of Aβ_(25-35) in mice except for those in the sham group, and AD model mice were treated with corresponding drugs by gavage for 24 days. The behavioral test was performed one week before animal dissection. Hematoxylin-eosin(HE) staining was performed to observe the morphology of neurons in the hippocampal region. Flow cytometry was used to detect the apoptosis level of primary hippocampal cells in mice. ELISA kits were used to detect the levels of β-amyloid protein 1-42(Aβ_(1-42)) and phosphorylated microtubule-associated protein Tau(p-Tau) in mouse brain tissues. Immunofluorescence and Western blot were used to detect the expression of related proteins in mouse brain tissues. MTT assay was used to detect the effect of compounds in aqueous extract of Corni Fructus on Aβ_(25-35)-induced N9 cell injury. Molecular docking was employed to analyze the interactions of caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-β-D-glucopyranoside, esculetin, and(+)-lyoniresinol with β-amyloid precursor protein(APP), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α). Aqueous extract of Corni Fructus could improve the learning and memory abilities of Aβ_(25-35)-induced mice by increasing the duration of the autonomous activity, the rate of autonomous alternation, the preference coefficient, and the discrimination coefficient, and reduce Aβ_(25-35)-induced brain injury and neuroinflammation in mice by increasing the expression levels of interleukin-10(IL-10) and B-cell lymphoma-2(Bcl-2) in brain tissues, decreasing the expression levels of Aβ_(1-42), p-Tau, IL-6, TNF-α, cysteine aspartate-specific protease 3(caspase-3), cysteine aspartate-specific protease 9(caspase-9), and Bcl-2-associated X protein(Bax), and decreasing the number of activated glial cells in brain tissues. The results of cell experiments showed that esculetin and(+)-lyoniresinol could improve Aβ_(25-35)-induced N9 cell injury. Molecular docking results showed that caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-β-D-glucopyranoside, esculetin, and(+)-lyoniresinol had good binding affinity with APP and weak binding affinity with IL-6 and TNF-α. Aqueous extract of Corni Fructus could ameliorate cognitive dysfunction and brain damage in Aβ_(25-35)-induced mice by reducing the number of apoptotic cells and activated glial cells in the brain and decreasing the expression level of inflammatory factors. Caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-β-D-glucopyranoside, esculetin, and(+)-lyoniresinol may be the material basis for the anti-AD effect of aqueous extract of Corni Fructus.
Mice ; Male ; Animals ; Alzheimer Disease/drug therapy* ; Amyloid beta-Peptides/metabolism* ; Cornus/metabolism* ; Neuroinflammatory Diseases ; Tumor Necrosis Factor-alpha/metabolism* ; Interleukin-6 ; Aspartic Acid ; Cysteine/therapeutic use* ; Molecular Docking Simulation ; Mice, Inbred C57BL ; Brain Injuries ; Peptide Hydrolases ; Disease Models, Animal ; Mice, Transgenic

Neurodegenerative diseases are a collective term for a large group of diseases caused by degenerative changes in nerve cells. Aging is the main risk factor for neurodegenerative diseases. The neurovascular unit(NVU) is the smallest functional unit of the brain, which regulates brain blood flow and maintains brain homeostasis. Accelerated aging of NVU cells directly impairs NVU function and leads to the occurrence of various neurodegenerative diseases. The intrinsic mechanisms of NVU cell aging are complex and involve oxidative stress damage, loss of protein homeostasis, DNA damage, mitochondrial dysfunction, immune inflammatory response, and impaired cellular autophagy. In recent years, studies have found that traditional Chinese medicine(TCM) can inhibit NVU aging through multiple pathways and targets, exerting a brain-protective effect. Therefore, this article aimed to provide a theoretical basis for further research on TCM inhibition of NVU cell aging and references for new drug development and clinical applications by reviewing its mechanisms of anti-aging, such as regulating relevant proteins, improving mitochondrial dysfunction, reducing DNA damage, lowering inflammatory response, antioxidant stress, and modulating cellular autophagy.
Humans ; Medicine, Chinese Traditional ; Neurodegenerative Diseases/drug therapy* ; Brain ; Aging ; Neurons ; Blood-Brain Barrier

Based on the CX3C chemokine ligand 1(CX3CL1)-CX3C chemokine receptor 1(CX3CR1) axis, this study explored the potential mechanism by which Zuogui Jiangtang Jieyu Formula(ZGJTJY) improved neuroinflammation and enhanced neuroprotective effect in a rat model of diabetes mellitus complicated with depression(DD). The DD rat model was established by feeding a high-fat diet combined with streptozotocin(STZ) intraperitoneal injection for four weeks and chronic unpredictable mild stress(CUMS) combined with isolated cage rearing for five weeks. The rats were divided into a control group, a model group, a positive control group, an inhibitor group, and a ZGJTJY group. The open field test and forced swimming test were used to assess the depression-like behaviors of the rats. Enzyme-linked immunosorbent assay(ELISA) was performed to measure the expression levels of the pro-inflammatory cytokines interleukin-1β(IL-1β) and tumor necrosis factor-α(TNF-α) in plasma. Immunofluorescence staining was used to detect the expression of ionized calcium-binding adapter molecule 1(Iba1), postsynaptic density protein-95(PSD95), and synapsin-1(SYN1) in the hippocampus. Hematoxylin-eosin(HE) staining, Nissl staining, and TdT-mediated dUTP nick end labeling(TUNEL) fluorescence staining were performed to assess hippocampal neuronal damage. Western blot was used to measure the expression levels of CX3CL1, CX3CR1, A2A adenosine receptor(A2AR), glutamate receptor 2A(NR2A), glutamate receptor 2B(NR2B), and brain-derived neurotrophic factor(BDNF) in the hippocampus. Compared with the model group, the ZGJTJY group showed improved depression-like behaviors in DD rats, enhanced neuroprotective effect, increased expression of PSD95, SYN1, and BDNF(P<0.01), and decreased expression of Iba1, IL-1β, and TNF-α(P<0.01), as well as the expression of CX3CL1, CX3CR1, A2AR, NR2A, and NR2B(P<0.01). These results suggest that ZGJTJY may exert its neuroprotective effect by inhibiting the CX3CL1-CX3CR1 axis and activation of hippocampal microglia, thereby improving neuroinflammation and abnormal activation of N-methyl-D-aspartate receptor(NMDAR) subunits, and ultimately enhancing the expression of synaptic-related proteins PSD95, SYN1, and BDNF in the hippocampus.
Rats ; Animals ; Depression/drug therapy* ; Brain-Derived Neurotrophic Factor ; Neuroprotective Agents ; Tumor Necrosis Factor-alpha/metabolism* ; Neuroinflammatory Diseases ; Diabetes Mellitus ; Receptors, Glutamate ; CX3C Chemokine Receptor 1/genetics*

Abnormal brain-gut interaction is considered the core pathological mechanism behind the disorders of gut-brain interaction (DGBI), in which the intestinal microbiota plays an important role. Microglia are the "sentinels" of the central nervous system (CNS), which participate in tissue damage caused by traumatic brain injury, resist central infection and participate in neurogenesis, and are involved in the occurrence of various neurological diseases. With in-depth research on DGBI, we could find an interaction between the intestinal microbiota and microglia and that they are jointly involved in the occurrence of DGBI, especially in individuals with comorbidities of mental disorders, such as irritable bowel syndrome (IBS). This bidirectional regulation of microbiota and microglia provides a new direction for the treatment of DGBI. In this review, we focus on the role and underlying mechanism of the interaction between gut microbiota and microglia in DGBI, especially IBS, and the corresponding clinical application prospects and highlight its potential to treat DGBI in individuals with psychiatric comorbidities.
Humans ; Gastrointestinal Microbiome ; Irritable Bowel Syndrome/therapy* ; Microglia ; Brain Diseases ; Brain

Objective:To analyze the clinical diagnosis, treatment ，and surgical timing of otogenic intracranial complications. Methods:The clinical data of 11 patients with intracranial complications with ear symptoms as the first manifestation in Department of Otorhinolaryngology Head and Neck Surgery, Qilu Hospital of Shandong University（Qingdao） from December 2014 to June 2022 were collected, including 8 males and 3 females, aged from 4 to 69 years. All patients had complete otoendoscopy, audiology, imaging and etiology examination, and the diagnosis and treatment plan was jointly developed through multidisciplinary consultation according to the critical degree of clinical symptoms and imaging changes. Among the 11 patients, 5 cases were treated with intracranial lesions first in neurosurgery department and middle ear lesions later in otolaryngology, 3 cases of meningitis, were treated with middle ear surgery after intracranial infection control, 1 case was treated with middle ear lesions and intracranial infection simultaneously, and 2 cases were treated with sigmoid sinus and transverse sinus thrombosis conservatively. They were followed up for 1-6 years. Descriptive statistical methods were used for analysis. Results:All the 11 patients had ear varying symptoms, including ear pain, pus discharge and hearing loss, etc, and then fever appeared, headache, disturbance of consciousness, facial paralysis and other intracranial complication. Otoendoscopy showed perforation of the relaxation of the tympanic membrane in 5 cases, major perforation of the tension in 3 cases, neoplasia in the ear canal in 1 case, bulging of the tympanic membrane in 1 case, and turbidity of the tympanic membrane in 1 case. There were 4 cases of conductive hearing loss, 4 cases of mixed hearing loss and 3 cases of total deafness. Imaging examination showed cholesteatoma of the middle ear complicated with temporal lobe brain abscess in 4 cases, cerebellar abscess in 2 cases, cholesteatoma of the middle ear complicated with intracranial infection in 3 cases, and sigmoid sinus thrombophlebitis in 2 cases. In the etiological examination, 2 cases of Streptococcus pneumoniae were cultured in the pus of brain abscess and cerebrospinal fluid, and 1 case was cultured in streptococcus vestibularis, Bacteroides uniformis and Proteus mirabilis respectively. During the follow-up, 1 patient died of cardiovascular disease 3 years after discharge, and the remaining 10 patients survived. There was no recurrence of intracranial and middle ear lesions. Sigmoid sinus and transverse sinus thrombosis were significantly improved. Conclusion:Brain abscess, intracranial infection and thrombophlebitis are the most common otogenic intracranial complications, and cholesteatoma of middle ear is the most common primary disease. Timely diagnosis, multidisciplinary collaboration, accurate grasp of the timing in the treatment of primary focal and complications have improved the cure rate of the disease.
Female ; Humans ; Male ; Brain Abscess/therapy* ; Cholesteatoma ; Deafness/etiology* ; Hearing Loss/etiology* ; Lateral Sinus Thrombosis/therapy* ; Retrospective Studies ; Thrombophlebitis/therapy* ; Child, Preschool ; Child ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Aged ; Cholesteatoma, Middle Ear/therapy* ; Central Nervous System Infections/therapy* ; Sinus Thrombosis, Intracranial/therapy* ; Ear Diseases/therapy*