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- Black henbane and its toxicity - a descriptive review. [Journal Article, Review]
- Avicenna J Phytomed 2014 Sep; 4(5):297-311.
Black henbane (BH) or Hyoscyamus niger, has been used as a medicine since last centuries and has been described in all traditional medicines. It applies as a herbal medicine, but may induce intoxication accidentally or intentionally. All part of BH including leaves, seeds and roots contain some alkaloids such as Hyoscyamine, Atropine, Tropane and Scopolamine. BH has pharmacological effects like bronchodilating, antisecretory, urinary bladder relaxant, spasmolytic, hypnotic, hallucinogenic, pupil dilating, sedative and anti-diarrheal properties. Clinical manifestations of acute BH poisoning are very wide which include mydriasis, tachycardia, arrhythmia, agitation, convulsion and coma, dry mouth, thirst, slurred speech, difficulty speaking, dysphagia, warm flushed skin, pyrexia, nausea, vomiting, headache, blurred vision and photophobia, urinary retention, distension of the bladder, drowsiness, hyper reflexia, auditory, visual or tactile hallucinations, confusion, disorientation, delirium, aggressiveness, and combative behavior. The main treatment of BH intoxicated patients is supportive therapies including gastric emptying (not by Ipecac), administration of activated charcoal and benzodiazepines. Health care providers and physicians particularly emergency physicians and clinical toxicologists should know the nature, medical uses, clinical features, diagnosis and management of BH poisoning.
- Acetylcholinesterase (AChE) inhibition aggravates fasting-induced triglyceride accumulation in the mouse liver. [Journal Article]
- FEBS Open Bio 2014.:905-14.
Although fasting induces hepatic triglyceride (TG) accumulation in both rodents and humans, little is known about the underlying mechanism. Because parasympathetic nervous system activity tends to attenuate the secretion of very-low-density-lipoprotein-triglyceride (VLDL-TG) and increase TG stores in the liver, and serum cholinesterase activity is elevated in fatty liver disease, the inhibition of the parasympathetic neurotransmitter acetylcholinesterase (AChE) may have some influence on hepatic lipid metabolism. To assess the influence of AChE inhibition on lipid metabolism, the effect of physostigmine, an AChE inhibitor, on fasting-induced increase in liver TG was investigated in mice. In comparison with ad libitum-fed mice, 30 h fasting increased liver TG accumulation accompanied by a downregulation of sterol regulatory element-binding protein 1 (SREBP-1) and liver-fatty acid binding-protein (L-FABP). Physostigmine promoted the 30 h fasting-induced increase in liver TG levels in a dose-dependent manner, accompanied by a significant fall in plasma insulin levels, without a fall in plasma TG. Furthermore, physostigmine significantly attenuated the fasting-induced decrease of both mRNA and protein levels of SREBP-1 and L-FABP, and increased IRS-2 protein levels in the liver. The muscarinic receptor antagonist atropine blocked these effects of physostigmine on liver TG, serum insulin, and hepatic protein levels of SREBP-1 and L-FABP. These results demonstrate that AChE inhibition facilitated fasting-induced TG accumulation with up regulation of the hepatic L-FABP and SREBP-1 in mice, at least in part via the activation of muscarinic acetylcholine receptors. Our studies highlight the crucial role of parasympathetic regulation in fasting-induced TG accumulation, and may be an important source of information on the mechanism of hepatic disorders of lipid metabolism.
- Physostigmine is the Antidote for Anticholinergic Syndrome. [JOURNAL ARTICLE]
- J Med Toxicol 2014 Oct 23.
- Response: Physostigmine May Not Be the Only Option for Treating Anticholinergic Syndrome. [JOURNAL ARTICLE]
- J Med Toxicol 2014 Oct 21.
- Corticosterone and corticotropin-releasing factor acutely facilitate gamma oscillations in the hippocampus in vitro. [JOURNAL ARTICLE]
- Eur J Neurosci 2014 Oct 13.
Stressful experiences do not only cause peripheral changes in stress hormone levels, but also affect central structures such as the hippocampus, implicated in spatial orientation, stress evaluation, and learning and memory. It has been suggested that formation of memory traces is dependent on hippocampal gamma oscillations observed during alert behaviour and rapid eye movement sleep. Furthermore, during quiescent behaviour, sharp wave-ripple (SW-R) activity emerges. These events provide a temporal window during which reactivation of memory ensembles occur. We hypothesized that stress-responsive modulators, such as corticosterone (CORT), corticotropin-releasing factor (CRF) and the neurosteroid 3α, 21-dihydroxy-5α-pregnan-20-one (THDOC) are able to modulate gamma oscillations and SW-Rs. Using in vitro hippocampal slices, we studied acute and subacute (2 h) impact of these agents on gamma oscillations in area cornu ammonis 3 of the ventral hippocampus induced by acetylcholine (10 μm) combined with physostigmine (2 μm). CORT increased the gamma oscillations in a dose-dependent fashion. This effect was mediated by glucocorticoid receptors. Likewise, CRF augmented gamma oscillations via CRF type 1 receptor. Lastly, THDOC was found to diminish cholinergic gamma oscillations in a dose-dependent manner. Neither CORT, CRF nor THDOC modulated gamma power when pre-applied for 1 h, 2 h before the induction of gamma oscillations. Interestingly, stress-related neuromodulators had rather mild effects on spontaneous SW-R compared with their effects on gamma oscillations. These data suggest that the alteration of hippocampal gamma oscillation strength in vitro by stress-related agents is an acute process, permitting fast adaptation to new attention-requiring situations in vivo.
- Reversible cholinesterase inhibitors as pre-treatment for exposure to organophosphates: assessment using azinphos-methyl. [JOURNAL ARTICLE]
- J Appl Toxicol 2014 Sep 3.
Pre-treatment with reversible acetylcholinesterase (AChE) inhibitors before organophosphorous compound (OPC) exposure can reduce OPC-induced mortality. However, pyridostigmine, the only substance employed for such prophylaxis, is merely efficacious against a limited number of OPCs. In search of more efficacious and broad-range alternatives, we have compared in vivo the ability of five reversible AChE inhibitors (pyridostigmine, physostigmine, ranitidine, tacrine and K-27) to reduce mortality induced by the OPC azinphos-methyl. Protection was quantified using Cox analysis by determining the relative risk (RR) of death in rats that were administered these AChE inhibitors in equitoxic dosage (25% of LD01 ) 30 min before azinphos-methyl exposure. Azinphos-methyl-induced mortality was significantly reduced by all five tested compounds as compared with the reference group that was only exposed to azinphos-methyl without prior pre-treatment (RR = 1). The most efficacious prophylactic agents were K-27 (RR = 0.15) and physostigmine (RR = 0.21), being significantly more efficacious than ranitidine (RR = 0.62) and pyridostigmine (RR = 0.37). Pre-treatment with tacrine (RR = 0.29) was significantly more efficacious than pre-treatment with ranitidine, but the difference between tacrine and pyridostigmine was not significant. Our results indicate that prophylactic administration of the oxime K-27 may be a promising alternative in cases of imminent OPC exposure. Copyright © 2014 John Wiley & Sons, Ltd.
- Cyclic acyl guanidines bearing carbamate moieties allow potent and dirigible cholinesterase inhibition of either acetyl- or butyrylcholinesterase. [JOURNAL ARTICLE]
- Bioorg Med Chem 2014 Jun 26.
A series of cyclic acyl guanidine with carbamate moieties have been synthesized and evaluated in vitro for their AChE and BChE inhibitory activities. Structure-activity relationships identified compound 23 as a nanomolar and selective BChE inhibitor, while compound 32 exhibited nanomolar and selective AChE inhibition, selectivity depending on both the structure of the carbamate substituent as well as the position of guanidines-N substitution. The velocity of enzyme carbamoylation was analyzed and showed similar behavior to physostigmine. Phenolic compounds formed after carbamate transfer to the active site of cholinesterases showed additional neuroprotective properties on a hippocampal neuronal cell line (HT-22) after glutamate-induced intracellular reactive oxygen species generation.
- Evaluation of the sensitivity of the novel α4β2* nicotinic acetylcholine receptor PET radioligand (18) F-(-)-NCFHEB to increases in synaptic acetylcholine levels in rhesus monkeys. [JOURNAL ARTICLE]
- Synapse 2014 Jul 17.
Objective: (18) F-(-)-NCFHEB (also known as (18) F-(-)-Flubatine) is a new radioligand to image α4β2* nicotinic acetylcholine receptors in vivo with positron emission tomography (PET), with faster kinetics than previous radioligands such as (18) F-2-F-A85380. The goal of this study was to assess the sensitivity of (18) F-(-)-NCFHEB-PET to increases in synaptic acetylcholine concentration induced by acetylcholinesterase inhibitors. Methods: Two rhesus monkeys were scanned four times each on a Focus 220 scanner: first at baseline, then during two bolus plus infusions of physostigmine (0.06-0.28 mg/kg), and finally following a bolus injection of donepezil (0.25 mg/kg). The arterial input function and the plasma free fraction fP were measured. (18) F-(-)-NCFHEB volume of distribution VT was estimated using the multilinear analysis MA1 and then normalized by plasma free fraction fP . Results: (18) F-(-)-NCFHEB fP was 0.89±0.04. At baseline, (18) F-(-)-NCFHEB VT /fP ranged from 7.9±1.3 mL plasma/cm(3) tissue in the cerebellum to 34.3±8.4 mL plasma/cm(3) tissue in the thalamus. Physostigmine induced a dose-dependent reduction of (18) F-(-)-NCFHEB VT /fP of 34±9% in the putamen, 32±8% in the thalamus, 25±8% in the cortex, and 23±10% in the hippocampus. With donepezil, (18) F-(-)-NCFHEB VT /fP was reduced by 24±2%, 14+3% and 14±5%, 10±6% in the same regions. Conclusion: (18) F-(-)-NCFHEB can be used to detect changes in synaptic acetylcholine concentration and is a promising tracer to study acetylcholine dynamics with shorter scan durations than previous radioligands. Synapse, 2014. © 2014 Wiley Periodicals, Inc.
- Investigation into the role of the cholinergic system in radiation-induced damage in the rat liver and ileum. [JOURNAL ARTICLE]
- J Radiat Res 2014 Jun 8.
It has been previously shown that acetylcholine (ACh) may affect pro-inflammatory and anti-inflammatory cytokines. The role of the cholinergic system in radiation-induced inflammatory responses and tissue damage remains unclear. Therefore, the present study was designed to determine the radio-protective properties of the cholinergic system in the ileum and the liver of rats. Rats were exposed to 8-Gy single-fraction whole-abdominal irradiation and were then decapitated at either 36 h or 10 d post-irradiation. The rats were treated either with intraperitoneal physiological saline (1 ml/kg), physostigmine (80 µg/kg) or atropine (50 μg/kg) twice daily for 36 h or 10 d. Cardiac blood samples and liver and ileal tissues were obtained in which TNF-α, IL-1β and IL-10 levels were assayed using ELISA. In the liver and ileal homogenates, caspase-3 immunoblots were performed and myeloperoxidase (MPO) activity was analyzed. Plasma levels of IL-1β and TNF-α increased significantly following radiation (P < 0.01 and P < 0.001, respectively) as compared with non-irradiated controls, and physostigmine treatment prevented the increase in the pro-inflammatory cytokines (P < 0.01 and P < 0.001, respectively). Plasma IL-10 levels were not found to be significantly changed following radiation, whereas physostigmine augmented IL-10 levels during the late phase (P < 0.01). In the liver and ileum homogenates, IL-1β and TNF-α levels were also elevated following radiation, and this effect was inhibited by physostigmine treatment but not by atropine. Similarly, physostigmine also reversed the changes in MPO activity and in the caspase-3 levels in the liver and ileum. Histological examination revealed related changes. Physostigmine experiments suggested that ACh has a radio-protective effect not involving the muscarinic receptors.
- Surgery-induced changes in rat IL1β and acetylcholine metabolism: role of physostigmine. [JOURNAL ARTICLE]
- Clin Exp Pharmacol Physiol 2014 May 29.
Pharmacological enhancement of cholinergic activities by administering physostigmine is known to induce protective effects. It is unclear, however, whether the impact of physostigmine on inflammation and acetylcholine metabolism is related to different types of surgical intervention or to anesthesia alone. To determine this, rats were subjected to partial liver resection (PLR) or sham surgery. A control group only received anesthesia. Half of each treatment group received a single intraoperative dose of physostigmine; the others received placebo. Acetylcholine esterase (ACHE) activity and IL1β and acetylcholine (ACH) concentrations were determined. Both PLR and sham operation induced a time-dependent increase in plasma concentration of IL1β (3.9 and 4.8-fold) as compared to rats that received anesthesia alone. In rat brain, IL1β had increased by about twofold after surgery as compared to controls. Blood ACHE was transiently decreased after surgery. Brain ACHE activity increased 1.3-fold (p=0.014) only after PLR; consequently, the cerebral ACH concentration was significantly reduced. Physostigmine administration significantly reduced IL1β and ACHE levels. Cerebral ACH concentration was markedly increased from 543.9±121.5 (placebo) to 653.5±93.3 ng mg(-1) protein (p<0.001) after administering physostigmine. We conclude that a single dose of physostigmine intraoperatively had a sustained anti-inflammatory effect up to 120 min after injection that was especially pronounced under the conditions of PLR surgery. In addition to its protective peripheral action, physostigmine exerts neuroprotective action by increasing levels of the neurotransmitter ACH. This article is protected by copyright. All rights reserved.