Electroacupuncture Ameliorates Depressive-Like State and Synaptic Deficits Induced by Hyper-Cholinergic Tone During Chronic Stress in Rats.

BACKGROUND Major depressive disorder (MDD) is the leading cause of disability around the world. It is generally agreed that the central cholinergic system plays an important role in emotional regulation. Acetylcholine (ACh) is now a new target for antidepressants. Therefore, the aim of this study was to evaluate the effect of acupuncture on depressive behaviors, cholinergic tones, and synaptic plasticity in the prefrontal cortex (PFC) in chronic unpredictable mild stress (CUMS). MATERIAL AND METHODS We randomly divided 36 male Sprague-Dawley (SD) rats into the Normal group, Stress group, Physostigmine+stress (Phys+stress) group, and Electroacupuncture+physostigmine+stress (EA+Phys+stress) group. Rats underwent CUMS exposure for 42 days. After 28 days of CUMS, rats received physostigmine or EA treatment for 2 weeks. Rats in the Phys+stress and EA+Phys+stress group received an intraperitoneal injection of physostigmine (TOCRIS, UK, 5 mg/kg) daily. Rats in the EA+Phys+stress group also received EA stimulation at GV 20 (Baihui), GV 29 (Yintang), LI 4 (Hegu), and LR 3 (Taichong) daily for 2 weeks. RESULTS We found that EA ameliorated weight loss and the depressive-like behaviors in the sucrose preference test, novelty-suppressed feeding test, and open-field test. There was significantly decreased expression of ACh and increased expression of acetylcholinesterase (AChE) after EA treatment. Consistent with the behavior tests and cholinergic tones, there were increased spine density and expressions of synaptic proteins, including brain-derived neurotrophic factor (BDNF), glutamate receptor 1 (GluR1), glutamate receptor 2 (GluR2), postsynaptic density protein 95 (PSD95), and synapsin I in the PFC. CONCLUSIONS The results suggest that EA can reverse the depressive-like behaviors and synaptic deficits induced by hyper-cholinergic tone during chronic stress via the modulation of hyper-cholinergic tone.

The history of acetylcholinesterase inhibitors in the treatment of myasthenia gravis.

The beneficial effects of acetylcholinesterase inhibitors for the treatment of myasthenia gravis (MG) was a major discovery that came about through one young physician putting together a string of previous observations. To understand how this discovery came to light, we must first go back to earlier times when men hunted by bow-and-arrow to capture their prey. The substance used to poison the prey was eventually was identified as curare. Centuries later, a connection was made between the physiological effects of curare and a disease entity with no known pathological mechanism or treatment, myasthenia gravis. In 1935, house officer Dr. Mary Walker was the first physician to try physostigmine in the treatment of MG, which had previously been used to treat curare poisoning. What she saw was a dramatic improvement in the symptoms experienced in patients with MG, and thus became the first documented case of use of physostigmine, an acetylcholinesterase inhibitor, in the treatment of MG. This article is a summary of the history of the use of acetylcholinesterase inhibitors in the treatment of myasthenia gravis. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.

[Update - intoxications in critical care medicine]. / Update ­ Intoxikationen in der Intensivmedizin.

While monitoring and symptomatic care is sufficient for most intoxicated patients, some develop life threatening symptoms. We present recent changes in the recommendations of the treatment in patients with calcium channel blocker, beta blocker and high dose paracetamol intoxications. Additionally, new insights in the efficacy and safety of the use of physostigmine in anticholinergic patients and beta blockers in cocaine intoxication are discussed as well as the specific considerations in the resuscitation of intoxicated patients.

Datura and Brugmansia plants related antimuscarinic toxicity: an analysis of poisoning cases reported to the Taiwan poison control center.

INTRODUCTION: Datura and Brugmansia plants, especially Datura species, have been used for their hallucinogenic effects in the United States and Europe; whereas Datura plants have been used as a traditional medicine in many Asian countries. This study was conducted to better understand the pattern and outcome of Datura/Brugmansia plant related poisoning in Taiwan. METHODS: This is a retrospective case series study of all cases with Datura/Brugmansia exposure reported to the Taiwan Poison Control Center between 1986 and 2015. Data for patients with relevant poisoning were reviewed and abstracted. Logistic regression analysis was used to identify potential predictors of the severity of poisoning; bivariate analysis was employed to assess the effectiveness of physostigmine in the treatment of Datura/Brugmansia poisoning. RESULTS: A total of 203 cases involving 114 Datura exposures and 89 Brugmansia suaveolens exposures were eligible for analysis. Using Datura/Brugmansia for a medicinal purpose by the patients without consulting Chinese medicine practitioners was the most common reason of poisoning (81.2%); whereas only 2% of the patients were poisoned after medicinal use associated with the prescription from Chinese medicine practitioners. None of the 203 patients had used Datura/Brugmansia plant for recreational purpose. Most frequently observed clinical effect was mydriasis (53.2%), followed by confusion (40%), tachycardia (35.5%), dry mouth (35.5%), dizziness (34%), dry skin (32.5%), and delirium (31%). Seventy-three cases (36%) had severe effects; none of them died. Misidentification of the plants and ingestion of plant parts other than flowers were positively associated with the severity of poisoning. Forty patients (19.7%) received physostigmine therapy and patients receiving physostigmine had an earlier resolution of central nervous system toxicity than those who did not. CONCLUSIONS: Medicinal use without consulting Chinese medicine practitioners is the main reason for Datura/Brugmansia poisoning in Taiwan. Consumption of parts other than flowers and misidentification of the plants predicted the severity of poisoning in this study. Patients who received physostigmine appear to have earlier improvement in the central nervous system effects. No adverse events were reported from physostigmine administration.

An animal model of fetal alcohol spectrum disorder: Trace conditioning as a window to inform memory deficits and intervention tactics.

Animal models of Fetal Alcohol Spectrum Disorders (FASD) afford the unique capacity to precisely control timing of alcohol exposure and alcohol exposure amounts in the developing animal. These models have powerfully informed neurophysiological alterations associated with fetal and perinatal alcohol. In two experiments presented here we expand use of the Pavlovian Trace Conditioning procedure to examine cognitive deficits and intervention strategies in a rat model of FASD. Rat pups were exposed to 5g/kg/day ethanol on postnatal days (PD) 4-9, simulating alcohol exposure in the third trimester in humans. During early adolescence, approximately PD 30, the rats were trained in the trace conditioning task in which a light conditioned stimulus (CS) and shock unconditioned stimulus (US) were paired but separated by a 10-s stimulus free trace interval. Learning was assessed in freezing behavior during shock-free tests. Experiment 1 revealed that neonatal ethanol exposure significantly impaired hippocampus-dependent trace conditioning relative to controls. In Experiment 2 a serial compound conditioning procedure known as 'gap filling' completely reversed the ethanol-induced deficit in trace conditioning. We also discuss prior data regarding the beneficial effects of supplemental choline and novel preliminary data regarding the pharmacological cognitive enhancer physostigmine, both of which mitigate the alcohol-induced cognitive deficit otherwise seen in trace conditioning controls. We suggest trace conditioning as a useful tool for characterizing some of the core cognitive deficits seen in FASD, and as a model for developing effective environmental as well as nutritional and pharmacological interventions.

Chinese herbal medicine-induced anticholinergic poisoning in Hong Kong.

OBJECTIVE: To study the epidemiology, causes, and clinical course of Chinese herbal medicine-induced anticholinergic poisoning in Hong Kong. DESIGN: Case series. SETTING: Hong Kong. PATIENTS: All case histories of Chinese herbal medicine-induced anticholinergic poisoning (with laboratory confirmation) recorded by the Hong Kong Poison Information Centre over a 93-month period were accessed for analysis. RESULTS: During the relevant period, 22 clusters of Chinese herbal medicine-induced anticholinergic poisoning involving 32 patients were retrieved. The commonest clinical features were mydriasis (n=32, 100%) and confusion (n=24, 75%). No gastro-intestinal decontamination was performed. None of these patients underwent intubation, defibrillation, cardioversion, pacing, fluid resuscitation, inotropic support or dialysis. Of the 32 patients, 17 (53%) were treated with physostigmine because of confusion, three of whom had previously received intravenous benzodiazepines. No patient could be effectively treated with benzodiazepines alone. There was no mortality, and all the patients were discharged within 3 days. None of them re-attended the emergency department within 1 week of discharge. The commonest cause was the substitution of flos campsis (Campsis grandiflora) by the flower of the Datura species (7 clusters [32%] in 10 patients). CONCLUSION: Mydriasis and confusion were the commonest clinical features of Chinese herbal medicine-induced anticholinergic poisoning in Hong Kong. Physostigmine was frequently used in the treatment; benzodiazepines appeared ineffective. The commonest cause was the substitution of flos campsis (Campsis grandiflora) by the flower of the Datura species.

Cholinomimetic agents and neurocognitive impairment following head injury: a systematic review.

PRIMARY OBJECTIVE: There has been increasing interest in the role of cholinomimetic agents in the long-term management of cognitive impairment following traumatic brain injury. This paper aims to assess the evidence accumulated thus far. METHODS: Studies are identified by searching MEDLINE, EMBASE and PsychINFO, contacting experts and pharmaceutical companies and hand searching bibliographies. All study designs are included. MAIN OUTCOME AND RESULTS: This study identified 25 papers that studied cholinesterase inhibitors, physostigmine and choline in mild-to-severe traumatic brain injury. The outcome with cholinesterase inhibitors and choline is suggestive but not conclusive while physostigmine appears of little benefit. A lack of rigorous studies and a plethora of outcome measures preclude drawing definitive conclusions. Further randomized controlled trials are urgently required.

Clinical outcomes in children with hyoscyamus niger intoxication not receiving physostigmine therapy.

OBJECTIVE: Diagnosis of hyoscyamus niger intoxication is based on clinical symptomatology and history. Therapy includes stomach lavage, supportive therapy, and physostigmine as a specific antidote. Physostigmine is not available in Turkey. This retrospective study investigated the clinical outcomes in children with hyoscyamus niger intoxication who did not receive physostigmine therapy. METHODS: Twenty-three children whose history and medical records indicated hyoscyamus niger intoxication were included the study. RESULTS: None of the cases had any abnormal laboratory findings. All the patients were performed gastric lavage and provided with supportive therapy. None of the children had any complications, and none required mechanical ventilation or died. All the patients were discharged in good health within 48 h. CONCLUSION: Our findings suggest that hyoscyamus niger intoxication in children is self-terminating and responds to supportive therapy and that routine use of physostigmine is unnecessary in every case with hyoscyamus niger intoxication.

Novel cholinesterase inhibitors as future effective drugs for the treatment of Alzheimer's disease.

Current pharmacotherapy for Alzheimer's disease involves compounds that are aimed at increasing the levels of acetylcholine in the brain by facilitating cholinergic neurotransmission through inhibition of cholinesterase. These drugs, known as acetylcholinesterase inhibitors, have been shown to improve cognition and global functions but have little impact on improving the eventual progression of the disease; however, there is evidence that other cholinesterases such as butyrylcholinesterase can play an important role in cholinergic function in the brain, and the long-suspected non-cholinergic actions of acetylcholinesterase, mainly the interference with the beta-amyloid protein cascade, have recently driven a profound revolution in cholinesterase drug research. Several disease-modifying agents are under development that target these enzymes and have hope of becoming the next generation of effective drugs in the treatment of Alzheimer's disease.

Plants with traditional uses and activities, relevant to the management of Alzheimer's disease and other cognitive disorders.

In traditional practices of medicine, numerous plants have been used to treat cognitive disorders, including neurodegenerative diseases such as Alzheimer's disease (AD) and other memory related disorders. An ethnopharmacological approach has provided leads to identifying potential new drugs from plant sources, including those for memory disorders. There are numerous drugs available in Western medicine that have been directly isolated from plants, or are derived from templates of compounds from plant sources. For example, some alkaloids from plant sources have been investigated for their potential in AD therapy, and are now in clinical use (e.g. galantamine from Galanthus nivalis L. is used in the United Kingdom). Various other plant species have shown favourable effects in AD, or pharmacological activities indicating the potential for use in AD therapy. This article reviews some of the plants and their active constituents that have been used in traditional medicine, including Ayurvedic, Chinese, European and Japanese medicine, for their reputed cognitive-enhancing and antidementia effects. Plants and their constituents with pharmacological activities that may be relevant to the treatment of cognitive disorders, including enhancement of cholinergic function in the central nervous system, anti-cholinesterase (anti-ChE), antiinflammatory, antioxidant and oestrogenic effects, are discussed.

Anticholinergic poisoning from a large dose of Scopolia extract.

Scopolia extract (SE) contains hyoscyamine and scopolamine, which are both anticholinergic. It is usually used as a patent medicine to treat gastrointestinal disorders, to relieve spasmotic discomfort, or to decrease the secretion of gastric acid. Poisoning by SE presents similar symptoms and signs as other types of anticholinergic poisoning. We report a case of severe anticholinergic poisoning after accidentally drinking 8 ml of SE. The patient presented with acute delirium and was successfully treated with physostigmine.

[Etiology of initially unexplained confusion of excitability in deadly nightshade poisoning with suicidal intent. Symptoms, differential diagnosis, toxicology and physostigmine therapy of anticholinergic syndrome]. / Atiologisch zunächst unklare Verwirrtheit und Exzitation im Verlauf einer Tollkirschenvergiftung mit suizidaler Absicht. Symptomatik, Differentialdiagnose, Toxikologie und Physostigmin-Therapie des anticholinergen Syndroms.

HISTORY AND ADMISSION FINDINGS: After a walk in a wood a 55-year-old teacher was admitted to the emergency unit of a university hospital because of somnolence and excitability. Her rectal temperature was 37.8 degrees C, she had sinus tachycardia (rate of 130/min) but no other significant findings. INVESTIGATIONS: With the exception of C-reactive protein (10 mg/dl), MCV (101 fl), MCH (34 pg) and arterial blood gases (pH 7.483, pCO2 35.5 mmHg, base excess 5.1 mmp/l) laboratory tests were within normal limits. Qualitative screening of serum for benzodiazepines, barbiturates and antidepressives was negative. Neurological examination, including lumbar puncture and cranial computed tomography were noncontributory. TREATMENT AND COURSE: 10 hours after admission the patient developed signs of an anticholinergic syndrome with mydriasis, dry mouth, tachycardia, hot skin and an atonic bladder. Physostigmine 2 mg completely reversed the neurological and mental symptoms. After gas chromatography, mass-spectrometry of a urine sample showed an atropine molecular fragment with a molecular weight of 271. At intervals of 3 to 5 hours the recurrence of confusion and excitability required 4 further i.v. injection of physostigmine. The patient subsequently became accessible to psychiatric examination and reported that during the walk she had swallowed 8-10 berries of deadly nightshade with suicidal intent. CONCLUSION: In case of excitability and confusion as well as somnolence or coma of uncertain aetiology an anticholinergic syndrome caused by ingestion of atropine-containing plants or psychoactive drugs (phenothiazines, butyrophenones, tri- or tetracyclic antidepressants) should be included in the differential diagnosis. If there are suggestive clinical findings (tachycardia, somnolence, coma or threatened respiratory arrest, physostigmine should be given if there are no contraindications.

Poisoning by Datura leaves used as edible wild vegetables.

The causes of Datura intoxication include medication overdose, misuse of edible vegetables, deliberate abuse as a hallucinogen, homicidal or robbery and accidental intoxication from contaminated food. We report an incident of 14 people with Datura intoxication caused by ingesting wild Datura suaveolans for food. The incubation period was 15 to 30 min. The symptoms/signs were dizziness, dry mouth, flushed skin, palpitation, nausea, drowsiness, tachycardia, blurred vision, mydriasis, hyperthermia, disorientation, vomiting, agitation, delirium, urine retention, hypertension and coma. Three patients were hospitalized for 2-3 days. Thirteen persons received supportive fluid therapy. One patient did not receive medical therapy, he induced vomiting and drank a lot of water. Four patients presented with delirium/coma and 3 received physostigmine therapy with good response. One patient was intubated because of coma and respiratory depression. Three persons needed Foley catheterization for urine retention or coma status. One patient had a complication of urinary tract infection and antibiotic management. All patients recovered with no sequelae.

Mass ingestion of Jimson Weed by eleven teenagers.

Jimson Weed is a naturally occurring plant which is commonly ingested for its hallucinogenic properties. This paper is a case report summarizing 11 cases of patients, ages 13-21 years, who presented to our emergency department following oral ingestion of large quantities of Jimson Weed pods and seeds. Toxicity following ingestion is due to an atropine-containing alkaloid contained throughout the plant and concentrated in the seeds. Signs and symptoms ranged from asymptomatic mydriasis and tachycardia to severe agitation, disorientation, and hallucinations. Nine of the eleven patients were admitted for observation. There were no deaths associated with these ingestions and none of the patients required physostigmine for reversal of severe anticholinergic symptoms. This paper also includes an historical overview of Jimson Weed, its physiologic effects, the epidemiological data, and a treatment summary.

Accidental ingestion of jimsonweed by an adolescent.

Ingestion of jimsonweed can result in hallucinations. Despite this side effect, the differential diagnosis of jimsonweed toxicity can be difficult, in part, because routine drug screens do not detect this agent. Such a delay in diagnosis not only postpones treatment but may also result in the patient's death. Treatment involves gastric lavage, followed by supportive care. Life-threatening cases entail the cautious use of physostigmine salicylate.