Application and advantages of zebrafish model in the study of neurovascular unit.

The concept of "Neurovascular Unit" (NVU) was put forward, so that the research goal of Central Nervous System (CNS) diseases gradually transitioned from a single neuron to the structural and functional integrity of the NVU. Zebrafish has the advantages of high homology with human genes, strong reproductive capacity and visualization of neural circuits, so it has become an emerging model organism for NVU research and has been applied to a variety of CNS diseases. Based on CNKI (https://www.cnki.net/) and PubMed (https://pubmed.ncbi.nlm.nih.gov/about/) databases, the author of this article sorted out the relevant literature, analyzed the construction of a zebrafish model of various CNS diseases，and the use of diagrams showed the application of zebrafish in the NVU, revealed its relationship, which would provide new methods and references for the treatment and research of CNS diseases.

Neurotensins and their therapeutic potential: research field study.

The natural tridecapeptide neurotensin has been emerged as a promising therapeutic scaffold for the treatment of neurological diseases and cancer. In this work, we aimed to identify the top 100 most cited original research papers as well as recent key studies related to neurotensins. The Web of Science Core Collection database was searched and the retrieved research articles were analyzed by using the VOSviewer software. The most cited original articles were published between 1973 and 2013. The top-cited article was by Carraway and Leeman reporting the discovery of neurotensin in 1973. The highly cited terms were associated with hypotension and angiotensin-converting-enzyme. The conducted analysis reveals the therapeutic potentials of neurotensin, and further impactful research toward its clinical development is warrantied.

Uncaria rhynchophylla and its Major Constituents on Central Nervous System: A Review on Their Pharmacological Actions.

BACKGROUND: Uncaria rhynchophylla (Miq.) Jacks (Rubinaceae), a common herbal medicine known as Gou-teng in Chinese, is commonly used in Chinese medicine practice for the treatment of convulsions, hypertension, epilepsy, eclampsia and other cerebral diseases. The major active components of U. rhynchophylla are alkaloids, terpenoids and flavonoids. The protective effects of U. rhynchophylla and its major components on central nervous system (CNS) have become a focus of research in recent decades. OBJECTIVE: The study aimed to systematically summarize the pharmacological activities of U. rhynchophylla and its major components on the CNS. METHODS: This review summarized the experimental findings from our laboratories, together with other literature data obtained through a comprehensive search of databases including the Pubmed and the Web of Science. RESULTS: U. rhynchophylla and its major components such as rhynchophylline and isorhynchophylline have been shown to have neuroprotective effects on Alzheimer's disease, Parkinson's disease, depression, cerebral ischaemia through a number of mechanisms including anti-oxidant, anti-inflammatory actions and regulation on neurotransmitters. CONCLUSION: U. rhynchophylla and its major components have multiple beneficial pharmacological effects on CNS. Further studies on U. rhynchophylla and its major components are warranted to fully illustrate the underlying molecular mechanisms, pharmacokinetics, and toxicological profiles of these naturally occurring compounds and their potential for clinical application.

Ginsenoside Rg1 attenuates chronic unpredictable mild stress-induced depressive-like effect via regulating NF-κB/NLRP3 pathway in rats.

Ginsenoside (GS Rg1), which has neuroprotection and anti-inflammation activities, is the main active ingredient of Radix Ginseng. However, its antidepressant-like effect in rats remains unclear. Our study was conducted to investigate whether GS Rg1 confers an antidepressant effect in rats exposed to a chronic unpredictable mild stress model of depression and to explore its possible mechanisms. Our results revealed that GS Rg1 treatments for 3 weeks alleviated the depression-related behaviors of chronic unpredictable mild stress-exposed rats, as indicated by increasing sucrose preference, improving locomotor activity and shortening immobile time in both the forced swimming tests and tail suspension tests. And these ameliorative effects of GS Rg1 treatment were involved with regulating chronic unpredictable mild stress-induced pro-inflammatory cytokine interleukin beta (IL-1ß) related neuro-inflammation. In addition, we further found that GS Rg1 reversed chronic unpredictable mild stress-induced IL-1ß elevation, possibly by inhibiting nuclear factor kappa B pathway activation and regulating nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 inflammasome expression. In short, our results suggested that GS Rg1 exerted a potential antidepressant-like effect in chronic unpredictable mild stress rat model of depression, which may provide an insight into the potential of GS Rg1 in therapeutic implications for depression.

Enhancing the Utility of Preclinical Research in Neuropsychiatry Drug Development.

Most large pharmaceutical companies have downscaled or closed their clinical neuroscience research programs in response to the low clinical success rate for drugs that showed tremendous promise in animal experiments intended to model psychiatric pathophysiology. These failures have raised serious concerns about the role of preclinical research in the identification and evaluation of new pharmacotherapies for psychiatry. In the absence of a comprehensive understanding of the neurobiology of psychiatric disorders, the task of developing "animal models" seems elusive. The purpose of this review is to highlight emerging strategies to enhance the utility of preclinical research in the drug development process. We address this issue by reviewing how advances in neuroscience, coupled with new conceptual approaches, have recently revolutionized the way we can diagnose and treat common psychiatric conditions. We discuss the implications of these new tools for modeling psychiatric conditions in animals and advocate for the use of systematic reviews of preclinical work as a prerequisite for conducting psychiatric clinical trials. We believe that work in animals is essential for elucidating human psychopathology and that improving the predictive validity of animal models is necessary for developing more effective interventions for mental illness.

The core pattern of Chinese herbal formulae and drug-herb concurrent usage in patients with dementia.

More than 40% dementia patients received traditional Chinese Medicine treatment. However, the prescription pattern of Chinese herbal formulae (CHF) for treating neurocognitive or behavioral disorders in patients with dementia has not been elucidated. This large-scale survey aimed is to evaluate core patterns of CHF and drug-herb concurrent use in patients with dementia.We analyzed patients with a diagnosis of dementia from one million cohorts of the Longitudinal Health Insurance Database in the National Health Insurance Research Database, between 1997 and 2008. Of 18,141 newly diagnosed dementia patients, 3471 patients received CHF for mental and nervous system diseases. There were 13,254 outpatient visits, with 60,968 formulae prescriptions. We calculate the frequency and proportion of combined use, identify drug-herb concurrent usage, and determine core prescription patterns. Also, we drew network graphs of co-prescription pairs which occurred more than 200 times.Chinese medicine prescription patterns changed as dementia progressed.During the first 3 years after the diagnosis of dementia, Jia-Wei-Xiao-Yao-San, Gan-Mai-Da-Zao-Tang, and Ban-Xia-Bai-Zhu-Tian-Ma-Tang were the core CHF prescribed for mental and nervous system disorders. However, during the later stages of dementia, Suan-Zao-Ren-Tang, Gui-Pi-Tang, Jia-Wei-Xiao-Yao-San, and Wen-Dan-Tang were the core CHF prescribed. Benzodiazepines were the most common sedative drugs combined with traditional Chinese formulae.The results of this study suggest that TCM prescription were different in various stages of dementia, and indicated the frequently combined use of the TCM formulae and Benzodiazepines in dementia care.

Effectiveness and safety of Injinoryung-San-Gagambang (Yinchen Wuling powder) decoction on stroke patients with elevated serum liver enzymes: Three case reports.

RATIONALE: Injinoryung-San-Gagambang (IJORS) effectively improves hepatic dysfunction caused by polypharmacy in stroke patients. PATIENT CONCERNS: We present 3 cases of hepatic dysfunction caused by polypharmacy, one of which was a 51-year-old man with cerebellum infarction and pneumonia as a complication of stroke. He took multiple medications because of baseline diseases. After recurrence of pneumonia, his laboratory tests showed abnormal aminotransferase levels. Another patient was an 81-year-old woman with cerebral infarction at the right-middle cerebral artery. She was also taking >5 medications. Her laboratory tests conducted on admission showed abnormally elevated aminotransferase levels. The last patient was 77-year-old man with cerebral infarction at the left-middle cerebral artery. He also had an abdominal aneurysm, a thoracic aortic aneurysm, and a myocardial infarction. After taking multiple medications including healthy functional foods, his laboratory tests showed abnormally elevated aminotransferase levels. DIAGNOSIS: Diagnosis is conducted with the result of laboratory test including blood count, chemistry test. INTERVENTIONS: All 3 patients received the same herbal treatment (IJORS decoction) for 1 to 3 weeks. OUTCOMES: All 3 patients' abnormal serum aminotransferase level were significantly improved by IJORS decoction treatment while keeping other medicines. LESSONS: IJORS can be considered as an effective treatment for hepatic dysfunction induced by numerous medications in stroke patients.

A systematic review on the neuroprotective perspectives of beta-caryophyllene.

Beta (ß)-caryophyllene (BCAR) is a major sesquiterpene of various plant essential oils reported for several important pharmacological activities, including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, antimicrobial, and immune-modulatory activity. Recent studies suggest that it also possesses neuroprotective effect. This study reviews published reports pertaining to the neuropharmacological activities of BCAR. Databases such as PubMed, Scopus, MedLine Plus, and Google Scholar with keywords "beta (ß)-caryophyllene" and other neurological keywords were searched. Data were extracted by referring to articles with information about the dose or concentration/route of administration, test system, results and discussion, and proposed mechanism of action. A total of 545 research articles were recorded, and 41 experimental studies were included in this review, after application of exclusion criterion. Search results suggest that BCAR exhibits a protective role in a number of nervous system-related disorders including pain, anxiety, spasm, convulsion, depression, alcoholism, and Alzheimer's disease. Additionally, BCAR has local anesthetic-like activity, which could protect the nervous system from oxidative stress and inflammation and can act as an immunomodulatory agent. Most neurological activities of this natural product have been linked with the cannabinoid receptors (CBRs), especially the CB2R. This review suggests a possible application of BCAR as a neuroprotective agent.

Normalization of disrupted clock gene expression in males with tetraplegia: a crossover randomized placebo-controlled trial of melatonin supplementation.

STUDY DESIGN: Crossover double blind, randomized placebo-controlled trial. OBJECTIVES: Circadian oscillators are located both in the brain and in peripheral organs. Melatonin, the main brain-derived hormone governing circadian variations, is highly associated with daylight patterns. However, in subjects with tetraplegia the melatonin levels are blunted. Here we studied peripheral oscillators in peripheral blood mononuclear cells (PBMCs) in males with tetraplegia by examining how exogenous melatonin may influence the expression of clock gene mRNAs. SETTING: Sunnaas Rehabilitation Hospital, Nesoddtangen, Norway. METHODS: Six males with tetraplegia received 2 mg of melatonin or placebo 4 days before the study period. We also included six able-bodied men sleeping or kept awake during the night. Plasma samples were collected four times during a 24-h period. The mRNA expression levels of the clock genes PER1, PER2, BMAL1, and REV-ERBα were quantified in PBMCs using quantitative RT-PCR. RESULTS: The mRNA expression levels of PER-1 and -2 and REV-ERBα were increased at 04:00 h compared with the able-bodied controls (p < 0.05). Melatonin supplementation changed mRNA peak-time toward the time of supplementation. CONCLUSIONS: Several peripheral clock genes displayed distorted expression levels in tetraplegia. Supplementation with melatonin changed the mRNA expression levels of these genes toward those observed among able-bodied. SPONSORSHIP: Financial support was provided from the Throne Holst Foundation, Sunnaas Rehabilitation hospital and the University of Ferrara (FAR2016).

Research of falls risk of taking central nervous system drugs in oncology inpatients.

This study aimed to analyze the medication use and related falls risk of central nervous system(CNS) drugs in oncology inpatients, explore the association between CNS drugs and falls. In this study, we enrolled inpatients, hospitalized in the oncology department of the Teaching Hospital of Chengdu University of Traditional Chinese Medicine, from March 2013 to October 2015. All inpatients were divided into two groups: taking-CNS drugs group (treatment group) and non CNS drugs group (control group). The falls risk between two groups were being compared and analyzed. Results showed that a total of 768 inpatients were enrolled in this study; 401 of them were males and 367 were females; the average age was 47.9±5.8 year-old. Of them, 129 were taking CNS drugs, while 639 were not. In the treatment group, the number of fall patients was 39, at an incidence rate of 30.23%; of the 39 fall patients, 3 suffered fractures, and 1 suffered an intracranialhemorrhage; while in the control group, the incidence of falls totaled at 45, at an incidence rate of 7.04%; 4 of the patients suffered fractures. The difference of incidence rate between two groups had statistical significance (P＜ 0.01). The incidence rate of falls in the treatment group was 4.29 times that in the control group. By the further analysis of CNS drugs, results implied that hypnotics, sedatives, selective serotonin reuptake inhibitors (no patient taking tricyclic antidepressants in this study), opioids, antiepileptics and antipsychotics had relationship with falls (OR>1). Our finding indicates that oncology inpatients have a higher risk of falls resulting from taking CNS drugs. Therefore, it is necessary to build up a systemic mechanism of nursing safety management on preventing falls of oncology inpatients, to improve nursing quality, and reduce the risk of falls.

Medicinal uses, pharmacology, and phytochemistry of Convolvulaceae plants with central nervous system efficacies: A systematic review.

Central nervous system (CNS) disorders play a major impact on individual lives and place a severe strain on health care resources. Convolvulaceae is a family comprising approximately 1,600-1,700 species grouped in 55-60 genera, and many species are reported to have an effect on CNS functions. A systematic review of the literature studies was carried out to summarize available evidences on Convolvulaceae plants with CNS efficacies. This review is based on various data sources such as Google Scholar, Web of Science, Scopus, PubMed, and Wanfang Data. A total of 200 related articles were included in this review. According to the research result, 54 Convolvulaceae species are suggested to display CNS efficacies historically, and 46 species have been evaluated for their CNS efficacies. In addition, 67 compounds from 16 Convolvulaceae species are recognized to possess CNS efficacies. Despite great progress made through pharmacology and phytochemistry studies on CNS active Convolvulaceae species, more exploratory research is needed to gain a better understanding of the CNS efficacies of this plant family.

Incidence and Risk Factors of Postoperative Delirium following Pancreatic Surgery: Does the Administration of TJ-54 Reduce the Incidence of Delirium.

PURPOSES: To clarify the incidence and risk factors of postoperative delirium in patients following pancreatic surgery, and the impact of yokukansan (TJ-54) administered to reduce delirium. METHODS: Fifty-nine consecutive patients who underwent pancreatic surgery (2012.4-2013.5) were divided into 2 groups: TJ-54 group: patients who received TJ-54 (n = 21) due to insomnia and the No-TJ-54 group: patients who did not receive TJ-54 (n = 38), and the medical records including the delirium rating scale - Japanese version (DRS-J) were retrospectively reviewed. RESULTS: Postoperative delirium occurred in 2 patients (9.5%) in the TJ-54 group and in 4 (10.5%) patients in the No-TJ-54 group (p = 0.90). The DRS-J on 5 days after surgery was lower in the TJ-54 group than in the No-TJ-54 group (rough p = 0.006), however, without any statistically significant differences with the Bonferroni correction. As for the hospital cost, there was no difference between the TJ-54 and the No-TJ-54 groups (p = 0.78). History of delirium was identified as an independent risk factor of postoperative delirium. CONCLUSION: The patients with preoperative insomnia, who were treated with TJ-54, did not have a higher incidence of postoperative delirium, compared to those without preoperative insomnia. The patients who had a history of delirium have an increased risk of postoperative delirium and should be cared for and treated prophylactically to prevent it.

Use of melatonin versus valproic acid in prophylaxis of migraine patients: A double-blind randomized clinical trial.

BACKGROUND: Melatonin is known to be effective in curing migraine. OBJECTIVE: This study aimed to investigate the therapeutic effect of melatonin versus sodium valproate in the prophylaxis of chronic migraine. METHODS: This randomized, double-blind, placebo-controlled clinical trial included patients with chronic migraine who were divided into three equal sized groups, and baseline therapy with nortriptyline (10-25 mg) and propranolol (20-40 mg) was used. Patients in groups A, B, and C were adjunctively treated daily with 3 mg melatonin, 200 mg sodium valproate, and a placebo, respectively. The patients underwent treatment for 2 months and follow-up was done at baseline (baseline), first (I) and second month (II). Attack frequency (AF), attack duration, attack severity, Migraine Disability Assessment (MIDAS) score (within 3 months in two steps), analgesic intake, and drug side effects between the groups and during follow-up were compared. RESULTS: The mean of monthly AF (melatonin: baseline: 4.2, I: 3.1, II: 2.5, p = 0.018; valproate: baseline: 4.3, I: 3.1, II: 2.3, p = 0.001; placebo: baseline: 4.1, I: 3.8, II: 3.8 p = 0.211), attack duration (hr) (melatonin: baseline: 19.8, I: 10.1, II: 8.7, p < 0.001; valproate: baseline: 19.5, I: 10.2, II: 8.8, p < 0.001; placebo: baseline: 19.6, I: 15.4, II: 14.1, p = 0.271), attack severity (melatonin: baseline: 7.3, I: 5.4, II: 3.5, p < 0.001; valproate: baseline: 7.4, I: 5.3, II: 3.4, p = 0.000; placebo: baseline: 7.3, I: 6.4, II: 6, p = 0.321), and MIDAS score (melatonin: baseline: 15.2, II: 8.9, p = 0.005; valproate: baseline: 16.1, II: 8.3, p = 0.001; placebo: baseline: 16, II: 12.1, p = 0.44), were significantly reduced in the melatonin and sodium valproate groups, but not in the placebo groups. Adverse events were reported in 11 patients (10.47%): 2 (5.71%) during melatonin treatment, 8 (22.85%) during valproate, and 1 (2.85%) during placebo. CONCLUSION: The adjuvant treatment with melatonin was found to be superior to the placebo and had the same clinical efficacy as sodium valproate, but with higher tolerability. Melatonin may prove to be an efficient substitute for sodium valproate, as a chronic migraine prophylaxis.

Rational Design and Multibiological Profiling of Novel Donepezil-Trolox Hybrids against Alzheimer's Disease, with Cholinergic, Antioxidant, Neuroprotective, and Cognition Enhancing Properties.

A novel series of donepezil-trolox hybrids were designed, synthesized, and evaluated as multifunctional ligands against Alzheimer's disease (AD). Biological assays showed that these derivatives possessed moderate to good inhibitory activities against acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) as well as remarkable antioxidant effects. The optimal compound 6d exhibited balanced functions with good inhibition against hAChE (IC50 = 0.54 µM) and hMAO-B (IC50 = 4.3 µM), significant antioxidant activity (41.33 µM IC50 by DPPH method, 1.72 and 1.79 trolox equivalent by ABTS and ORAC methods), excellent copper chelation, and Aß1-42 aggregation inhibition effect. Furthermore, cellular tests indicated that 6d has very low toxicity and is capable of combating oxidative toxin (H2O2, rotenone, and oligomycin-A) induced neurotoxicity. Most importantly, oral administration of 6d demonstrated notable improvements on cognition and spatial memory against scopolamine-induced acute memory deficit as well as d-galactose (d-gal) and AlCl3 induced chronic oxidative stress in a mouse model without acute toxicity and hepatotoxicity. In summary, both in vitro and in vivo results suggested that 6d is a valuable candidate for the development of a safe and effective anti-Alzheimer's drug.

A randomized controlled trial of acupressure as an adjunctive therapy to sodium valproate on the prevention of chronic migraine with aura.

BACKGROUND: The primary objective of the present study was to evaluate the efficacy and safety of using acupressure as an adjunctive therapy to sodium valproate (SV) combined with acupressure (ASV) on the prevention of chronic migraine with aura (CMA). METHODS: A total of 98 patients with CMA were randomly divided into an intervention group and a control group, with 49 patients in each group. The patients in the intervention group received ASV, while the participants in the control group received SV alone. The primary outcome was measured by the numeric rating scale (NRS). The secondary outcomes including frequency of migraine attacks, the times of using analgesics, and quality of life, measured by the short-form 36 Health Survey Scale (SF-36) score. In addition, adverse events (AEs) were also recorded throughout the trial. The outcomes were measured at the end of the 8-week treatment, and 4-week follow-up. RESULTS: After the 8-week treatment and 4-week follow-up, ASV efficacy was not greater than that of SV alone regarding pain relief, as measured using the NRS, and frequency of migraine attacks, consumption of analgesics, and quality of life, as measured using the SF-36. However, ASV can significantly reduce the nausea when compared with SV (P = .04). CONCLUSION: The present results indicate that ASV can decrease migraine-related nausea during treatment, but cannot relieve pain or enhance quality of life in patients with CMA.

Ginsenoside Rg1 attenuates the inflammatory response in DSS-induced mice colitis.

Ginsenoside Rg1 is a major active constituent of Panax ginseng and possesses anti-inflammatory effects. It has been reported to have therapeutic effects on various diseases. In the present study, we investigated the role of ginsenoside Rg1 in dextran sodium sulfate (DSS)-induced mouse colitis. Our results showed that ginsenoside Rg1 markedly reduces proinflammatory cytokines release upon DSS stimulation of mouse dendritic cells, that ginsenoside Rg1 suppresses IL-1ß (Interleukin 1 beta) and TNF-α (Tumor necrosis factor alpha) release via up-regulation of NLRP12 (NACHT, LRR and PYD domains-containing protein 12) expression, and that ginsenoside Rg1 significantly decreases the inflammatory response to DSS-induced mouse colitis, as evidenced by increased body weight, reduced colonic damage scores and disease activity index (DAI), and lowered proinflammatory cytokines levels. These results highlight the potential therapeutic use of ginsenoside Rg1 as an anti-inflammatory agent in the treatment of colitis.

The effects of Chinese medicines on cAMP/PKA signaling in central nervous system dysfunction.

Neuropathological injury in the mammalian adult central nervous system (CNS) may cause axon disruption, neuronal death and lasting neurological deficits. Failure of axon regeneration is one of the major challenges for CNS functional recovery. Recently, the cAMP/PKA signaling pathway has been proven to be a critical regulator for neuronal regeneration, neuroplasticity, learning and memory. Also, previous studies have shown the effects of Chinese medicines on the prevention and treatment of CNS dysfunction mediated in part by cAMP/PKA signaling. In this review, the authors discuss current knowledge of the role of cAMP/PKA signaling pathway in neuronal regeneration and provide an overview of the Chinese medicines that may enable CNS functional recovery via this signaling pathway.