Antiseizure effects of Lilii Bulbus on pentylenetetrazol kindling-induced seizures in mice: Involvement of Reelin, Netrin-1, and semaphorin.

Lilii Bulbus (Lilium lancifolium Thunberg) has a proneurogenic effect on the hippocampus. However, its effects on epilepsy and associated pathological features remain unknown. In this study, we investigated the antiseizure effects of a water extract of Lilii Bulbus (WELB) in mouse model of pentylenetetrazol (PTZ)-induced seizure. Mice were injected with PTZ once every 48 h until full kindling was achieved. WELB (100 and 500 mg/kg) was orally administered once daily before PTZ administration and during the kindling process. We found that WELB treatment protected against PTZ-induced low seizure thresholds and high seizure severity. Further, WELB-treated mice showed attenuated PTZ kindling-induced anxiety and memory impairment. Immunostaining and immunoblots showed that hyperactivation and ectopic migration of dentate granule cells (DGCs) were significantly reduced by WELB treatment in PTZ kindling-induced seizure mice. Staining for mossy fiber sprouting (MFS) using Timm staining and ZnT3 showed that WELB treatment significantly decreased PTZ kindling-induced MFS. Furthermore, the increased or decreased expression of proteins related to ectopic DGCs (Reelin and Dab-1), MFS (Netrin-1, Sema3A, and Sema3F), and their downstream effectors (ERK, AKT, and CREB) in the hippocampus of PTZ kindling mice was significantly restored by WELB treatment. Overall, our findings suggest that WELB is a potential antiseizure drug that acts by reducing ectopic DGCs and MFS and modulating epileptogenesis-related signaling in the hippocampus.

Electroacupuncture modulates glutamate neurotransmission to alleviate PTSD-like behaviors in a PTSD animal model.

Post-traumatic stress disorder (PTSD) is a mental disorder that develops after exposure to a traumatic event. Owing to the relatively low rates of response and remission with selective serotonin reuptake inhibitors as the primary treatment for PTSD, there is a recognized need for alternative strategies to effectively address the symptoms of PTSD. Dysregulation of glutamatergic neurotransmission plays a critical role in various disorders, including anxiety, depression, PTSD, and Alzheimer's disease. Therefore, the regulation of glutamate levels holds great promise as a therapeutic target for the treatment of mental disorders. Electroacupuncture (EA) has become increasingly popular as a complementary and alternative medicine approach. It maintains the homeostasis of central nervous system (CNS) function and alleviates symptoms associated with anxiety, depression, and insomnia. This study investigated the effects of EA at the GV29 (Yintang) acupoint three times per week for 2 weeks in an animal model of PTSD. PTSD was induced using single prolonged stress/shock (SPSS) in mice, that is, SPS with additional foot shock stimulation. EA treatment significantly reduced PTSD-like behavior and effectively regulated serum corticosterone and serotonin levels in the PTSD model. Additionally, EA treatment decreased glutamate levels and glutamate neurotransmission-related proteins (pNR1 and NR2B) in the hippocampus of a PTSD model. In addition, neuronal activity and the number of Golgi-impregnated dendritic spines were significantly lower in the EA treatment group than in the SPSS group. Notably, EA treatment effectively reduced glutamate-induced excitotoxicity (caspase-3, Bax, and pJNK). These findings suggest that EA treatment at the GV29 acupoint holds promise as a potential therapeutic approach for PTSD, possibly through the regulation of NR2B receptor-mediated glutamate neurotransmission to reduce PTSD-like behaviors.

Novel Psychopharmacological Herbs Relieve Behavioral Abnormalities and Hippocampal Dysfunctions in an Animal Model of Post-Traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) is an anxiety disorder caused by traumatic or frightening events, with intensified anxiety, fear memories, and cognitive impairment caused by a dysfunctional hippocampus. Owing to its complex phenotype, currently prescribed treatments for PTSD are limited. This study investigated the psychopharmacological effects of novel COMBINATION herbal medicines on the hippocampus of a PTSD murine model induced by combining single prolonged stress (SPS) and foot shock (FS). We designed a novel herbal formula extract (HFE) from Chaenomeles sinensis, Glycyrrhiza uralensis, and Atractylodes macrocephala. SPS+FS mice were administered HFE (500 and 1000 mg/kg) once daily for 14 days. The effects of HFE of HFE on the hippocampus were analyzed using behavioral tests, immunostaining, Golgi staining, and Western blotting. HFE alleviated anxiety-like behavior and fear response, improved short-term memory, and restored hippocampal dysfunction, including hippocampal neurogenesis alteration and aberrant migration and hyperactivation of dentate granule cells in SPS+FS mice. HFE increased phosphorylation of the Kv4.2 potassium channel, extracellular signal-regulated kinase, and cAMP response element-binding protein, which were reduced in the hippocampus of SPS+FS mice. Therefore, our study suggests HFE as a potential therapeutic drug for PTSD by improving behavioral impairment and hippocampal dysfunction and regulating Kv4.2 potassium channel-related pathways in the hippocampus.

Underwater image illumination estimation via an evolving extreme learning machine by an improved salp swarm algorithm.

Underwater images have chromatic aberrations under different light sources and complex underwater scenes, which can lead to the wrong choice when using an underwater robot. To solve this problem, this paper proposes an underwater image illumination estimation model, which we call the modified salp swarm algorithm (SSA) extreme learning machine (MSSA-ELM). It uses the Harris hawks optimization algorithm to generate a high-quality SSA population, and uses a multiverse optimizer algorithm to improve the follower position that makes an individual salp carry out global and local searches with a different scope. Then, the improved SSA is used to iteratively optimize the input weights and hidden layer bias of ELM to form a stable MSSA-ELM illumination estimation model. The experimental results of our underwater image illumination estimations and predictions show that the average accuracy of the MSSA-ELM model is 0.9209. Compared to similar models, the MSSA-ELM model has the best accuracy for underwater image illumination estimation. The analysis results show that the MSSA-ELM model also has high stability and is significantly different from other models.

Gleditsia sinensis Lam. aqueous extract attenuates nasal inflammation in allergic rhinitis by inhibiting MUC5AC production through suppression of the STAT3/STAT6 pathway.

Allergic rhinitis (AR), a chronic respiratory inflammatory disease, is among the most common chronic diseases reported worldwide. Mucus hypersecretion is a critical feature of AR pathogenesis. Although the Gleditsia sinensis extract has several beneficial effects on human health, its effects on allergic inflammation have not yet been investigated. In this study, we examined the effects of G. sinensis aqueous extract (GSAE) on nasal inflammation in an ovalbumin (OVA)-induced AR mouse model. GSAE was administered orally for 1 week and then the clinical nasal symptoms were evaluated. The levels of histamine, OVA-specific immunoglobulin (Ig) E, and interleukin (IL)-13 were measured in the serum using an enzyme-linked immunosorbent assay (ELISA). Inflammatory cells were then counted in the nasal lavage fluid (NALF) and histopathology in the nasal epithelium was evaluated. STAT3/STAT6 phosphorylation was examined in primary human nasal epithelial cells (HNEpCs) using western blot analysis. Oral administration of GSAE to OVA-induced AR mice alleviated nasal clinical symptoms and reduced OVA-specific immunoglobulin E, interleukin (IL)-13, and histamine levels. The accumulation of eosinophils in nasal lavage fluid, nasal mucosa, mast cells, goblet cells, and mucin 5AC (MUC5AC) in the nasal epithelium was also inhibited by GSAE. Treatment with GSAE inhibited the production of MUC5AC in IL-4/IL-13-stimulated primary human nasal epithelial cells through the signal transducer and activator of transcription (STAT)3/STAT6 signaling pathway. These results indicated that GSAE reduces nasal inflammation suggesting that it is a potential treatment option for AR.

Nutraceutical Interventions for Post-Traumatic Stress Disorder in Animal Models: A Focus on the Hypothalamic-Pituitary-Adrenal Axis.

Post-traumatic stress disorder (PTSD) occurs after exposure to traumatic events and is characterized by overwhelming fear and anxiety. Disturbances in the hypothalamic-pituitary-adrenal (HPA) axis are involved in the pathogenesis of mood disorders, including anxiety, PTSD, and major depressive disorders. Studies have demonstrated the relationship between the HPA axis response and stress vulnerability, indicating that the HPA axis regulates the immune system, fear memory, and neurotransmission. The selective serotonin reuptake inhibitors (SSRIs), sertraline and paroxetine, are the only drugs that have been approved by the United States Food and Drug Administration for the treatment of PTSD. However, SSRIs require long treatment times and are associated with lower response and remission rates; therefore, additional pharmacological interventions are required. Complementary and alternative medicine therapies ameliorate HPA axis disturbances through regulation of gut dysbiosis, insomnia, chronic stress, and depression. We have described the cellular and molecular mechanisms through which the HPA axis is involved in PTSD pathogenesis and have evaluated the potential of herbal medicines for PTSD treatment. Herbal medicines could comprise a good therapeutic strategy for HPA axis regulation and can simultaneously improve PTSD-related symptoms. Finally, herbal medicines may lead to novel biologically driven approaches for the treatment and prevention of PTSD.

Treatment with Herbal Formula Extract in the hSOD1G93A Mouse Model Attenuates Muscle and Spinal Cord Dysfunction via Anti-Inflammation.

Amyotrophic lateral sclerosis (ALS), a multicomplex neurodegenerative disease, has multiple underlying pathological factors and can induce other neuromuscular diseases, leading to muscle atrophy and respiratory failure. Currently, there is no effective drug for treating patients with ALS. Herbal medicine, used to treat various diseases, has multitarget effects and does not usually induce side effects. Each bioactive component in such herbal combinations can exert a mechanism of action to increase therapeutic efficacy. Herein, we investigated the efficacy of an herbal formula, comprising Achyranthes bidentata Blume, Eucommia ulmoides Oliver, and Paeonia lactiflora Pallas, in suppressing the pathological mechanism of ALS in male hSOD1G93A mice. Herbal formula extract (HFE) (1 mg/g) were orally administered once daily for six weeks, starting at eight weeks of age, in hSOD1G93A transgenic mice. To evaluate the effects of HFE, we performed footprint behavioral tests, western blotting, and immunohistochemistry to detect protein expression and quantitative PCR to detect mRNA levels in the muscles and spinal cord of hSOD1G93A mice. HFE-treated hSOD1G93A mice showed increased anti-inflammation, antioxidation, and regulation of autophagy in the muscles and spinal cord. Thus, HEF can be therapeutic candidates for inhibiting disease progression in patients with ALS. This study has some limitations. Although this experiment was performed only in male hSOD1G93A mice, studies that investigate the efficacy of HEF in various ALS models including female mice, such as mice modeling TAR DNA-binding protein 43 (TDP43) and ORF 72 on chromosome 9 (C9orf72) ALS, are required before it can be established that HEF are therapeutic candidates for patients with ALS.

Neurogenic Interventions for Fear Memory via Modulation of the Hippocampal Function and Neural Circuits.

Fear memory helps animals and humans avoid harm from certain stimuli and coordinate adaptive behavior. However, excessive consolidation of fear memory, caused by the dysfunction of cellular mechanisms and neural circuits in the brain, is responsible for post-traumatic stress disorder and anxiety-related disorders. Dysregulation of specific brain regions and neural circuits, particularly the hippocampus, amygdala, and medial prefrontal cortex, have been demonstrated in patients with these disorders. These regions are involved in learning, memory, consolidation, and extinction. These are also the brain regions where new neurons are generated and are crucial for memory formation and integration. Therefore, these three brain regions and neural circuits have contributed greatly to studies on neural plasticity and structural remodeling in patients with psychiatric disorders. In this review, we provide an understanding of fear memory and its underlying cellular mechanisms and describe how neural circuits are involved in fear memory. Additionally, we discuss therapeutic interventions for these disorders based on their proneurogenic efficacy and the neural circuits involved in fear memory.

Combined Treatment with Bojungikgi-Tang and Riluzole Regulates Muscle Metabolism and Dysfunction in the hSOD1G93A Mouse Model.

The progressive neurodegenerative disease, amyotrophic lateral sclerosis (ALS), is characterized by muscle weakness and atrophy owing to selective motoneuron degeneration. The anti-glutamatergic drug, riluzole (RZ), is the standard-of-care treatment for ALS. Bojungikgi-tang (BJIGT), a traditional herbal formula, improves motor function and prolongs the survival of mice with ALS. As ALS is a multicomplex disease, effective therapies must target multiple mechanisms. Here, we evaluated the efficacy of a BJIGT/RZ combination (5-week treatment) in 2-month-old hSOD1G93A mice with ALS. We performed quantitative polymerase chain reaction, Western blotting, immunohistochemistry, and enzyme activity assays. BJIGT/RZ significantly attenuated inflammation, autophagy, and metabolic and mitochondrial dysfunctions in the gastrocnemius (GC) compared with the control. It reduced the mRNA and protein levels of muscle denervation-related proteins and creatine kinase levels. The total creatine level was significantly higher in the BJIGT/RZ-treated GC. Moreover, after BJIGT/RZ treatment, the number of Nissl-stained motoneurons and choline acetyl transferase-positive neurons in the spinal cord significantly increased via the regulation of proinflammatory cytokines. Collectively, the BJIGT/RZ treatment was superior to single-drug treatments in alleviating multiple ALS-related pathological mechanisms in the ALS mouse model. Overall, BJIGT can serve as a dietary supplement and be combined with RZ to achieve superior therapeutic effects against ALS.

Anti-inflammatory Effects of a Novel Herbal Extract in the Muscle and Spinal Cord of an Amyotrophic Lateral Sclerosis Animal Model.

Amyotrophic lateral sclerosis (ALS) is a complex disease characterized by motor neuron loss and muscle atrophy. There is no prominent treatment for ALS as the pathogenic process in the skeletal muscle and spinal cord is complex and multifactorial. Therefore, we investigated the effects of a herbal formula on the multi-target effects in the skeletal muscle and spinal cord in hSOD1G93A transgenic mice. We prepared a herbal extract (HE) from Glycyrrhiza uralensis, Atractylodes macrocephala Koidzumi, Panax ginseng, and Astragalus membranaceus. Control and HE-treated mice underwent rotarod and footprint tests. We also performed immunohistochemical and Western blotting analyses to assess expression of inflammation-related and oxidative stress-related proteins in the muscle and spinal cord tissues. We found that the HE increased motor activity and reduced motor neuron loss in hSOD1G93A mice. In addition, the HE significantly reduced the levels of inflammatory proteins and oxidative stress-related proteins in the skeletal muscles and spinal cord of hSOD1G93A mice. Furthermore, we demonstrated that the HE regulated autophagy function and augmented neuromuscular junction in the muscle of hSOD1G93A mice. Based on these results, we propose that the HE formula may be a potential therapeutic strategy for multi-target treatment in complex and multifactorial pathological diseases.

Moxibustion for cognitive impairment: a systematic review and meta-analysis of animal studies.

BACKGROUND: Cognitive impairment is an age-dependent chronic disorder that exponentially worsens with age; however, its treatment is mostly symptomatic. Moxibustion is widely accepted in East Asia as a treatment for cognitive impairment. This systematic review aimed to verify the efficacy and underlying mechanism of moxibustion in treating cognitive impairment. METHODS: Sixteen trials involving 324 animals obtained from MEDLINE (PubMed), EMBASE, the Cochrane library, the Chinese National Knowledge Infrastructure, Wan-Fang, Cqvip, the Korean Studies Information Service System, and the Oriental Medicine Advanced Searching Integrated System met the inclusion criteria. We extracted the results of behavioral tests and immunohistochemical biomarkers from the included articles and evaluated the risk of bias and reporting quality. RESULTS: The moxibustion group showed significantly decreased escape latency, increased crossing times, and prolonged dwelling times in the Morris water maze test. There was a significantly enhanced latency period and reduced error time in the step-down test and nerve behavior score. The effects of moxibustion were found to be mediated by suppression of oxidative stress and apoptosis, modulation of inflammation and Aß genesis activation of vascular endothelial growth factor, and adjustment of metabolites in the tricarboxylic acid cycle and fatty acid metabolism. CONCLUSION: Our results demonstrated the therapeutic efficacy of moxibustion on cognitive impairment and suggested the putative mechanism. However, considering the small number of included studies, high bias risk, low reporting quality, and the limitations of animal experimentation, our results need to be confirmed by more detailed studies.

Effect of Combined Electroacupuncture and Selegiline Treatment in Alzheimer's Disease: An Animal Model.

The complexity of pathological mechanisms in Alzheimer's disease (AD) poses significant challenges to the development of corresponding drugs. Symptom-specific pharmacological interventions and alternative treatments provide promising treatment possibilities. Therefore, we considered a combination of selegiline (SEL) and electroacupuncture (EA). We used an animal model with AD to investigate the effect of a combination of these treatments on cognitive function. 5XFAD mice received a week of SEL treatment and 2 weeks of EA. Novel object recognition and Y-maze tests were subsequently performed to assess their cognitive functions. To determine the molecular action of the combination treatment, Western blots, Aß1-42 enzyme-linked immunosorbent assays (ELISA), and micro-positron-emission tomography were also performed to assess pathological markers and processes. The results were assessed based on the difference between untreated transgenic, SEL-treated, and SEL- and EA-treated groups of mice. Mice in the combined treatment group demonstrated significantly better cognitive functions, and lesser neuroinflammation than the comparative groups. In addition, mice treated with a combination of SEL and EA did not demonstrate a direct modulation of insoluble Aß but demonstrated greater glucose metabolism. Our findings demonstrated that SEL combined with EA treatment was associated with better cognitive functioning due to inhibition of neuroinflammation and increased glucose metabolism relative to the comparative groups in a mouse model with AD.

The effect of fecal microbiota transplantation on autistic-like behaviors in Fmr1 KO mice.

The importance of alterations in bidirectional communication between gut and brain has become obvious in neuropsychiatric disorders. Gastrointestinal (GI) disturbances are very common in autism spectrum disorders (ASD), and the GI microbiota profiles in children with ASD are significantly different from those in the general population. Fragile X syndrome (FXS) is an inheritable developmental disability in humans, and patients with FXS exhibit autistic behaviors such as mental retardation and impaired social communication or interaction. We hypothesized that an increase in specific gut microbiota by fecal microbiota transplantation (FMT) would mitigate autistic-like behaviors. To test this hypothesis, we measured the effects of FMT from normal mice to Fmr1 KO mice on autistic-like behaviors using several behavioral tests. Because the amounts of A. muciniphila in Fmr1 KO mice was very low, we assessed A. muciniphila population, tested the expression of MUC2, and analyzed goblet cells in the gut after the FMT. We found that FMT ameliorated autistic-like behaviors, especially memory deficits and social withdrawal, and we observed that the levels of A. muciniphila were normalized to wild-type levels. In addition, FMT attenuated the increased levels of TNFα and Iba1 in the brains of Fmr1 KO mice. These results suggest that FMT could be a useful tool for the treatments of cognitive deficits and social withdrawal symptoms observed in FXS or ASD because it increases the population of A. muciniphila and decreases TNFα and Iba1 levels.

Green tea extract containing enhanced levels of epimerized catechins attenuates scopolamine-induced memory impairment in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Green tea has been used as a traditional medicine to control brain function and digestion. Recent works suggest that drinking green tea could prevent cognitive function impairment. During tea manufacturing processes, such as brewing and sterilization, green tea catechins are epimerized. However, the effects of heat-epimerized catechins on cognitive function are still unknown. To take this advantage, we developed a new green tea extract, high temperature processed-green tea extract (HTP-GTE), which has a similar catechin composition to green tea beverages. AIM OF THE STUDY: This study aimed to investigate the effect of HTP-GTE on scopolamine-induced cognitive dysfunction and neuronal differentiation, and to elucidate its underlying mechanisms of action. MATERIALS AND METHODS: The neuronal differentiation promoting effects of HTP-GTE in SH-SY5Y cells was assessed by evaluating neurite length and the expression level of synaptophysin. The DNA methylation status at the synaptophysin promoter was determined in differentiated SH-SY5Y cells and in the hippocampi of mice. HTP-GTE was administered for 10 days at doses of 30, 100 and 300 mg/kg (p.o.) to mice, and its effects on cognitive functions were measured by Y-maze and passive avoidance tests under scopolamine-induced cholinergic blockade state. RESULTS: HTP-GTE induced neuronal differentiation and neurite outgrowth via the upregulation of synaptophysin gene expression. These beneficial effects of HTP-GTE resulted from reducing DNA methylation levels at the synaptophysin promoter via the suppression of DNMT1 activity. The administration of HTP-GTE ameliorated cognitive impairments in a scopolamine-treated mouse model. CONCLUSIONS: These results suggest that HTP-GTE could alleviate cognitive impairment by regulating synaptophysin expression and DNA methylation levels. Taken together, HTP-GTE would be a promising treatment for the cognitive impairment observed in dysfunction of the cholinergic neurotransmitter system.

The effect of maslinic acid on cognitive dysfunction induced by cholinergic blockade in mice.

BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is the most prevalent disease associated with cognitive dysfunction. Current AD therapeutic agents have several gastrointestinal or psychological adverse effects and therefore, novel therapeutic agents with fewer adverse effects must be developed. Previously, we demonstrated that oleanolic acid, which is similar in chemical structure to maslinic acid, ameliorates cognitive impairment through the activation of tropomyosin receptor kinase (TrkB)-ERK-cAMP response element-binding protein (CREB) phosphorylation and increased levels of brain-derived neurotrophic factor (BDNF). In the present study, we investigate the effect of maslinic acid on cholinergic blockade-induced memory impairment in mice. METHODS AND KEY RESULTS: Maslinic acid reversed scopolamine-induced memory impairment, as determined by the Y-maze, passive avoidance and Morris water maze tests. In addition, we also observed that ERK-CREB, PI3K and PKB (Akt) phosphorylation levels were increased by maslinic acid administration in the mouse hippocampus. Moreover, we determined that the effects of maslinic acid on scopolamine-induced memory impairment in the passive avoidance test were abolished by a specific TrkB receptor antagonist (ANA-12). Additionally, we observed similar temporal changes in the expression levels between BDNF and tissue plasminogen activator in the hippocampus. CONCLUSION AND IMPLICATIONS: These findings suggest that maslinic acid enhances cognitive function through the activation of BDNF and its downstream pathway signalling in the hippocampus and that it might be a potential therapeutic agent for cognitive decline, such as that observed in AD.

A botanical drug composed of three herbal materials attenuates the sensorimotor gating deficit and cognitive impairment induced by MK-801 in mice.

OBJECTIVES: A botanical drug derived from the ethanolic extract composed of Clematis chinensis Osbeck (Ranunculaceae), Trichosanthes kirilowii Maximowicz (Cucurbitaceae) and Prunella vulgaris Linné (Lamiaceae) has been used to ameliorate rheumatoid arthritis as an ethical drug in Korea. In our study, we investigated the effect of this herbal complex extract (HCE) on schizophrenia-like behaviours induced by MK-801. METHODS: HCE (30, 100 or 300 mg/kg, p.o) was orally administered to male ICR mice to a schizophrenia-like animal model induced by MK-801. We conducted an acoustic startle response task, an open-field task, a novel object recognition task and a social novelty preference task. KEY FINDINGS: We found that a single administration of HCE (100 or 300 mg/kg) ameliorated MK-801-induced abnormal behaviours including sensorimotor gating deficits and social or object recognition memory deficits. In addition, MK-801-induced increases in phosphorylated Akt and GSK-3ß expression levels in the prefrontal cortex were reversed by HCE (30, 100 or 300 mg/kg). CONCLUSIONS: These results imply that HCE ameliorates MK-801-induced dysfunctions in prepulse inhibition, social interactions and cognitive function, partly by regulating the Akt and GSK-3ß signalling pathways.

Spinosin Attenuates Alzheimer's Disease-Associated Synaptic Dysfunction via Regulation of Plasmin Activity.

Hippocampal synaptic dysfunction is a hallmark of Alzheimer's disease (AD). Many agents regulating hippocampal synaptic plasticity show an ameliorative effect on AD pathology, making them potential candidates for AD therapy. In the present study, we investigated spinosin as a regulating agent of synaptic plasticity in AD. Spinosin attenuated amyloid ß (Aß)-induced long-term potentiation (LTP) impairment, and improved plasmin activity and protein level in the hippocampi of 5XFAD mice, a transgenic AD mouse model. Moreover, the effect of spinosin on hippocampal LTP in 5XFAD mice was prevented by 6-aminocaproic acid, a plasmin inhibitor. These results suggest that spinosin improves synaptic function in the AD hippocampus by regulating plasmin activity.

Electroacupuncture attenuates cognition impairment via anti-neuroinflammation in an Alzheimer's disease animal model.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive loss of cognitive abilities and memory leading to dementia. Electroacupuncture (EA) is a complementary alternative medicine approach, applying an electrical current to acupuncture points. In clinical and animal studies, EA causes cognitive improvements in AD and vascular dementia. However, EA-induced changes in cognition and microglia-mediated amyloid ß (Aß) degradation have not been determined yet in AD animals. Therefore, this study investigated the EA-induced molecular mechanisms causing cognitive improvement and anti-inflammatory activity in five familial mutation (5XFAD) mice, an animal model of AD. METHODS: 5XFAD mice were bilaterally treated with EA at the Taegye (KI3) acupoints three times per week for 2 weeks. To evaluate the effects of EA treatment on cognitive functions, novel object recognition and Y-maze tests were performed with non-Tg, 5XFAD (Tg), and EA-treated 5XFAD (Tg + KI3) mice. To examine the molecular mechanisms underlying EA effects, western blots, immunohistochemistry, and micro-positron emission tomography scans were performed. Furthermore, we studied synapse ultrastructures with transmission electron microscopy and used electrophysiology to investigate EA effects on synaptic plasticity in 5XFAD mice. RESULTS: EA treatment significantly improved working memory and synaptic plasticity, alleviated neuroinflammation, and reduced ultrastructural degradation of synapses via upregulation of synaptophysin and postsynaptic density-95 protein in 5XFAD mice. Furthermore, microglia-mediated Aß deposition was reduced after EA treatment and coincided with a reduction in amyloid precursor protein. CONCLUSIONS: Our findings demonstrate that EA treatment ameliorates cognitive impairment via inhibition of synaptic degeneration and neuroinflammation in a mouse model of AD.

Complementary and alternative medicine for treating amyotrophic lateral sclerosis: A narrative review.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that is characterized by selective motor neuron cell death in the motor cortex, brainstem, and spinal cord. Two drugs for ALS, riluzole and edaravone, have been approved by FDA for the treatment of ALS patients. However, they have many side effects, and riluzole extends the patient's life by only 2-3 months. Therefore, ALS patients seek an effective therapy for treating the symptoms or delaying the progression of ALS. Based on this, we review the effects of complementary and alternative medicine (CAM) in ALS animals or patients to verify the efficacy of CAM in incurable diseases. For this review, we searched published papers focusing on the effect of CAM in pre-clinical and clinical study in ALS. METHODS: The search keywords included amyotrophic lateral sclerosis, acupuncture, herbal medicine, Traditional Chinese medicine, CAM, animals, and clinical study through electronic databases PubMed and Google Scholar from their inception until March 2019. RESULTS: In the ALS animal model, CAM modulated the immune system to increase motor function by reducing the expression levels of neuroinflammatory proteins in the spinal cord. Besides this, ALS patients treated with herbal medicine showed improved disease symptoms, but clinical trials with larger sample sizes are needed to develop a treatment with this herbal medicine. CONCLUSION: This review shows that CAM may be useful for ALS treatment, but more evidence regarding the efficacy and molecular mechanisms is required to establish CAM as a good therapy for the treatment of ALS patients.

Hochu-Ekki-To Improves Motor Function in an Amyotrophic Lateral Sclerosis Animal Model.

Hochu-ekki-to (Bojungikgi-Tang (BJIGT) in Korea; Bu-Zhong-Yi-Qi Tang in Chinese), a traditional herbal prescription, has been widely used in Asia. Hochu-ekki-to (HET) is used to enhance the immune system in respiratory disorders, improve the nutritional status associated with chronic diseases, enhance the mucosal immune system, and improve learning and memory. Amyotrophic lateral sclerosis (ALS) is pathologically characterized by motor neuron cell death and muscle paralysis, and is an adult-onset motor neuron disease. Several pathological mechanisms of ALS have been reported by clinical and in vitro/in vivo studies using ALS models. However, the underlying mechanisms remain elusive, and the critical pathological target needs to be identified before effective drugs can be developed for patients with ALS. Since ALS is a disease involving both motor neuron death and skeletal muscle paralysis, suitable therapy with optimal treatment effects would involve a motor neuron target combined with a skeletal muscle target. Herbal medicine is effective for complex diseases because it consists of multiple components for multiple targets. Therefore, we investigated the effect of the herbal medicine HET on motor function and survival in hSOD1G93A transgenic mice. HET was orally administered once a day for 6 weeks from the age of 2 months (the pre-symptomatic stage) of hSOD1G93A transgenic mice. We used the rota-rod test and foot printing test to examine motor activity, and Western blotting and H&E staining for evaluation of the effects of HET in the gastrocnemius muscle and lumbar (L4-5) spinal cord of mice. We found that HET treatment dramatically inhibited inflammation and oxidative stress both in the spinal cord and gastrocnemius of hSOD1G93A transgenic mice. Furthermore, HET treatment improved motor function and extended the survival of hSOD1G93A transgenic mice. Our findings suggest that HET treatment may modulate the immune reaction in muscles and neurons to delay disease progression in a model of ALS.