acetylcholine chloride [keywords]
- Does environmental exposure to the greenhouse gas, N2O, contribute to etiological factors in neurodevelopmental disorders? A mini-review of the evidence. [REVIEW, JOURNAL ARTICLE]
- Environ Toxicol Pharmacol 2016 Aug 18.:6-18.
Neurodevelopmental disorders are increasing in prevalence worldwide. Previous work suggests that exposure to the environmental air pollutant and greenhouse gas - nitrous oxide (N2O) - may be an etiological factor in neurodevelopmental disorders through the targeting of several neural correlates.While a number of recent systematic reviews have addressed the role of general anesthesia in the surgical setting and neurodevelopmental outcomes, a narrative mini-review was conducted to first define and characterize the relevant variables (i.e., N2O, attention-deficit hyperactivity disorder [ADHD] and autism spectrum disorders [ASD]) and their potential interactions into a coherent, hypothesis-generating work. The narrative mini-review merges basic principles in environmental science, anesthesiology, and psychiatry to more fully develop the novel hypotheses that neurodevelopmental impairment found in conditions like ADHD and ASD may be due to exposure to the increasing air pollutant, N2O.The results of the present mini-review indicate that exposure to N2O, even at non-toxic doses, may modulate central neurotransmission and target many neural substrates directly implicated in neurodevelopmental disorders, including the glutamatergic, opioidergic, cholinergic, and dopaminergic systems. Epidemiological studies also indicate that early and repeated exposure to general anesthesia, including N2O, may contribute to later adverse neurodevelopmental outcomes in children.The current evidence and subsequent hypotheses suggest that a renewed interest be taken in the toxicological assessment of environmental N2O exposure using validated biomarkers and psychiatric endpoints. Given the relevance of N2O as a greenhouse gas, societies may also wish to engage in a more robust monitoring and reporting of N2O levels in the environment for climactic benefit as well.
- Tannoid principles of Emblica officinalis attenuated aluminium chloride induced apoptosis by suppressing oxidative stress and tau pathology via Akt/GSK-3βsignaling pathway. [JOURNAL ARTICLE]
- J Ethnopharmacol 2016 Aug 23.
Fruits of Phyllanthus emblica Linn. or Emblica officinalis Gaertn. (Phyllanthaceae) are used in Ayurveda, Siddha, Unani, Arabic, Tibetan and various other folk medicinal systems to promote intelligence and memory. Recent study from our lab indicated the neuroprotective effect of tannoids principles of Emblica officinalis (EoT) against memory loss caused by aluminium chloride (AlCl3) intoxication through attenuating acetylcholine esterase activity and the expression of amyloid β protein biosynthesis related markers. However the molecular mechanism of EoT has not yet been fully elucidated.The aim of the present study was to further investigate the neuroprotective mechanisms of EoT against AlCl3-induced cognitive deficits, tau hyperphosphorylation, oxidative stress and apoptosis.Rats were treated with AlCl3 for 60 days to induce biochemical and physiological abnormalities similar to AD patients. AD rats were treated with EoT (100mg/kg., bw. oral) for 60 days. For the examination of neuroprotective effect of EoT, behavior analysis, biochemical estimations and western blot were performed in the hippocampus and cortex of control, EoT treated and untreated AD rats.Intraperitoneal injections of AlCl3 (100mg/kg., b.w.) for 60 days enhanced the learning and memory deficits, levels of TBARS and diminished the levels of reduced glutathione and activities of enzymatic antioxidants as compared to control group. Moreover toxicity of AlCl3 is accompanied by the enhanced expressions of Bax, caspases-3, -9, cytosolic cytochrome c (cyto c), and pTau along with diminished expressions of Bcl-2, mitochondrial cyto c, pGSK-3β and pAkt. Coadministration of EoT nullified the cognitive deficits, biochemical abnormalities and apoptosis induced by AlCl3 treatment. Moreover EoT prevents tau hyperphosphorylation by targeting the GSK-3β/Akt signaling pathway.This study confirms that EoT would be used as a potential drug candidate for AD and other tau pathology-related neuronal degenerative diseases.
- The effects of suplatast tosilate on acutely dissociated sensory and paratracheal ganglia neurons. [JOURNAL ARTICLE]
- Am J Physiol Lung Cell Mol Physiol 2016 Aug 26.:ajplung.00451.2016.
In this study, we investigated the effects of suplatast on acutely dissociated single neurons of sensory and paratracheal ganglia using a patch-clamp technique. Suplatast had little effect on various responses caused by capsaicin, acid, bradykinin, serotonin and adenosine 5'-triphosphate in rat sensory neurons. Suplatast, even at 10-3 M, also did not induce any current at various membrane potentials in rat and guinea pig paratracheal ganglia neurons. Further, acetylcholine- and bradykinin-induced depolarizations were not affected by suplatast. On the other hand, in rat paratracheal ganglia neurons, 10-5 M nicotine-induced current were inhibited by suplatast in a concentration-dependent manner with a 50% inhibitory concentration of 9.86x10-5 M. The effect was noncompetitive and voltage-dependent. Furthermore, the effect was use-independent and not affected by the pretreatment time of suplatast. The results suggested that suplatast may inhibit neurotransmission at the paratracheal ganglia via the inhibition of nicotinic current. Thus, suplatast may attenuate cough production through the improvement of pathological conditions of the lower airway via suppressed acetylcholine release from the postganglionic nerve terminal.
- A spatial covariance (123)I-5IA-85380 SPECT study of α4β2 nicotinic receptors in Alzheimer's disease. [JOURNAL ARTICLE]
- Neurobiol Aging 2016 Jul 30.:83-90.
Alzheimer's disease (AD) is characterized by widespread degeneration of cholinergic neurons, particularly in the basal forebrain. However, the pattern of these deficits and relationship with known brain networks is unknown. In this study, we sought to clarify this and used (123)I-5-iodo-3-[2(S)-2-azetidinylmethoxy] pyridine ((123)5IA-85380) single photon emission computed tomography to investigate spatial covariance of α4β2 nicotinic acetylcholine receptors in AD and healthy controls. Thirteen AD and 16 controls underwent (123)5IA-85380 and regional cerebral blood flow ((99m)Tc-exametazime) single photon emission computed tomography scanning. We applied voxel principal component (PC) analysis, generating series of principal component images representing common intercorrelated voxels across subjects. Linear regression generated specific α4β2 and regional cerebral blood flow covariance patterns that differentiated AD from controls. The α4β2 pattern showed relative decreased uptake in numerous brain regions implicating several networks including default mode, salience, and Papez hubs. Thus, as well as basal forebrain and brainstem cholinergic system dysfunction, cholinergic deficits mediated through nicotinic acetylcholine receptors could be evident within key networks in AD. These findings may be important for the pathophysiology of AD and its associated cognitive and behavioral phenotypes.
- Involvement of oxidative stress, cholinergic and adenosinergic systems on renal damage caused by Trypanosoma evansi infection: Relationship with lipid peroxidation. [JOURNAL ARTICLE]
- Microb Pathog 2016 Aug 23.
The aim of this study was to evaluate the oxidative stress variables, and enzymes of cholinergic (acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)) and adenosinergic (adenosine deaminase (ADA)) systems in renal tissue, as well the relationship between these systems and lipid peroxidation. The animals were divided into two groups with six animals each: uninfected (negative control) and infected (positive control). On day 4 post-infection (PI), animals were euthanized and the kidney were collected. Thiobarbituric acid reactive species (TBARS) and lipid peroxidation (FOX) levels increased, while the catalase (CAT), AChE, BChE and ADA activities decreased in kidney tissue on day 4 PI. A negative correlation between AChE and TBARS (r = -0.750), AChE and FOX (r = -0.650), as well as ADA and TBARS (r = -0.345) and ADA and FOX (r = -0.540) were observed (p < 0.05). In summary, the T. evansi infection cause lipid peroxidation in the renal tissue, altering the antioxidant-oxidant status, alterations compatible to oxidative stress and oxidative damage. Also, the T. evansi decrease the activities of AChE, BChE and ADA in order to reduce the oxidative damage increasing the levels of ACh, BCh and adenosine. These alterations in the kidney may be contribute do pathophysiology of T. evansi infection.
- Neuromodulation of olfactory transformations. [REVIEW, JOURNAL ARTICLE]
- Curr Opin Neurobiol 2016 Aug 23.:170-177.
The olfactory bulb and piriform cortex are the best studied structures of the mammalian olfactory system and are heavily innervated by extrinsic neuromodulatory inputs. The state-dependent release of acetylcholine, norepinephrine, serotonin, and other neuromodulators into these olfactory structures alters a constellation of physiological parameters in neurons and synapses that together modify the computations performed on sensory signals. These modifications affect the specificity, detectability, discriminability, and other properties of odor representations and thereby govern perceptual performance. Whereas different neuromodulators have distinct cellular effects, and tend to be associated with nominally different functions, it also is clear that these purported functions overlap substantially, and that ad hoc hypotheses regarding the roles of particular neuromodulators may have reached the limits of their usefulness.
- The Dinoflagellate Toxin 20-Methyl Spirolide-G Potently Blocks Skeletal Muscle and Neuronal Nicotinic Acetylcholine Receptors. [Journal Article]
- Toxins (Basel) 2016; 8(9)
The cyclic imine toxin 20-methyl spirolide G (20-meSPX-G), produced by the toxigenic dinoflagellate Alexandrium ostenfeldii/Alexandrium peruvianum, has been previously reported to contaminate shellfish in various European coastal locations, as revealed by mouse toxicity bioassay. The aim of the present study was to determine its toxicological profile and its molecular target selectivity. 20-meSPX-G blocked nerve-evoked isometric contractions in isolated mouse neuromuscular preparations, while it had no action on contractions elicited by direct electrical stimulation, and reduced reversibly nerve-evoked compound muscle action potential amplitudes in anesthetized mice. Voltage-clamp recordings in Xenopus oocytes revealed that 20-meSPX-G potently inhibited currents evoked by ACh on Torpedo muscle-type and human α7 nicotinic acetylcholine receptors (nAChR), whereas lower potency was observed in human α4β2 nAChR. Competition-binding assays showed that 20-meSPX-G fully displaced [³H]epibatidine binding to HEK-293 cells expressing the human α3β2 (Ki = 0.040 nM), whereas a 90-fold lower affinity was detected in human α4β2 nAChR. The spirolide displaced [(125)I]α-bungarotoxin binding to Torpedo membranes (Ki = 0.028 nM) and in HEK-293 cells expressing chick chimeric α7-5HT₃ nAChR (Ki = 0.11 nM). In conclusion, this is the first study to demonstrate that 20-meSPX-G is a potent antagonist of nAChRs, and its subtype selectivity is discussed on the basis of molecular docking models.
- Neuroprotective Effects of a Standardized Flavonoid Extract from Safflower against a Rotenone-Induced Rat Model of Parkinson's Disease. [Journal Article]
- Molecules 2016; 21(9)
Parkinson's disease (PD) is a major age-related neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra par compacta (SNpc). Rotenone is a neurotoxin that is routinely used to model PD to aid in understanding the mechanisms of neuronal death. Safflower (Carthamus tinctorius. L.) has long been used to treat cerebrovascular diseases in China. This plant contains flavonoids, which have been reported to be effective in models of neurodegenerative disease. We previously reported that kaempferol derivatives from safflower could bind DJ-1, a protein associated with PD, and that a flavonoid extract from safflower exhibited neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of PD. In this study, a standardized safflower flavonoid extract (SAFE) was isolated from safflower and found to primarily contain flavonoids. The aim of the current study was to confirm the neuroprotective effects of SAFE in rotenone-induced Parkinson rats. The results showed that SAFE treatment increased body weight and improved rearing behavior and grip strength. SAFE (35 or 70 mg/kg/day) treatment reversed the decreased protein expression of tyrosine hydroxylase, dopamine transporter and DJ-1 and increased the levels of dopamine and its metabolite. In contrast, acetylcholine levels were decreased. SAFE treatment also led to partial inhibition of PD-associated changes in extracellular space diffusion parameters. These changes were detected using a magnetic resonance imaging (MRI) tracer-based method, which provides novel information regarding neuronal loss and astrocyte activation. Thus, our results indicate that SAFE represents a potential therapeutic herbal treatment for PD.
- Imaging α4β2 Nicotinic Acetylcholine Receptors (nAChRs) in Baboons with [(18)F]XTRA, a Radioligand with Improved Specific Binding in Extra-Thalamic Regions. [JOURNAL ARTICLE]
- Mol Imaging Biol 2016 Aug 26.
Currently available positron-emitting radiotracers for imaging of the α4β2 subtype of nicotinic acetylcholine receptors (nAChRs) exhibit high and moderate specific binding in the thalamus and extra-thalamic brain regions, respectively. In many neuropsychiatric disorders, α4β2-nAChRs are altered in the extra-thalamic brain regions, but not necessarily in the thalamus. The purpose of this study was to evaluate [(18)F]XTRA, a new α4β2-nAChR positron emission tomography (PET) radioligand with improved specific binding in extra-thalamic brain regions, in non-human primates.The regional distribution of [(18)F]XTRA in the brain of Papio anubis baboons was evaluated in baseline and blocking experiments. Various PET modeling procedures were used for determination of volume of distribution (V T), binding potential (BPND), and receptor occupancy. Radiation dosimetry for [(18)F]XTRA was studied in male CD-1 mice and extrapolated to human dosimetry estimates using OLINDA/EXM software.[(18)F]XTRA was synthesized using an automated radiochemistry module with 25 % decay-corrected radiochemical yield. [(18)F]XTRA readily enters the baboon brain and specifically labels α4β2-nAChRs. Mathematical modeling demonstrates high binding potential values (BPND = 7 and 1.3 in the thalamus and frontal cortex, respectively). A PET scanning time of 90-120 min was sufficient to obtain stable V T values in the extra-thalamic regions. The extrapolated human effective dose was 0.041 mSv/MBq (0.15 Rem/mCi).[(18)F]XTRA exhibits improved specific binding in the baboon brain including extra-thalamic regions and it is considered radiologically acceptable for human studies. Further evaluations of [(18)F]XTRA in human subjects are under way.
- Endothelium-dependent vasodilatory signalling modulates α1 -adrenergic vasoconstriction in contracting skeletal muscle of humans. [JOURNAL ARTICLE]
- J Physiol 2016 Aug 26.
Stimulation of α-adrenoceptors elicits vasoconstriction in resting skeletal muscle that is blunted during exercise in an intensity-dependent manner. In humans, the underlying mechanisms remain unclear. We tested the hypothesis that stimulating endothelium-dependent vasodilatory signalling will enhance the ability of contracting skeletal muscle to blunt α1 -adrenergic vasoconstriction. Changes in forearm vascular conductance (FVC; Doppler Ultrasound, brachial intra-arterial pressure via catheter) to local intra-arterial infusion of phenylephrine (PE; α1 -adrenoceptor agonist) were calculated during (1) infusion of the endothelium-dependent vasodilators acetylcholine (ACh) and adenosine triphosphate (ATP), the endothelium-independent vasodilator (sodium nitroprusside, SNP), or potassium chloride (KCl) at rest; (2) mild or moderate intensity handgrip exercise; and (3) combined mild exercise + ACh, ATP, SNP, or KCl infusions in healthy adults. Robust vasoconstriction to PE was observed during vasodilator infusion alone and mild exercise, and this was blunted during moderate intensity exercise (ΔFVC:-34 ± 4 and -34 ± 3 vs. -13 ± 2% respectively, P < 0.05). Infusion of ACh or ATP during mild exercise significantly attenuated PE vasoconstriction similar to levels observed during moderate exercise (ACh:-3 ± 4; ATP:-18 ± 4%). In contrast, infusion SNP or KCl during mild exercise did not attenuate PE-mediated vasoconstriction (-32 ± 5 and -46 ± 3%). To further study the role of endothelium-dependent hyperpolarization (EDH), ACh trials were repeated with combined nitric oxide synthase and cyclooxygenase inhibition. Here, PE-mediated vasoconstriction was blunted at rest (blockade: -20 ± 5 vs.-31 ± 3% vs.; P < 0.05) and remained blunted during exercise (blockade: -15 ± 5 vs.-14 ± 5%). We conclude that stimulation of EDH-like vasodilatation can blunt α1 -adrenergic vasoconstriction in contracting skeletal muscle of humans. This article is protected by copyright. All rights reserved.