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- Synaptic muscarinic response types in hippocampal CA1 interneurons depend on different levels of presynaptic activity and different muscarinic receptor subtypes. [JOURNAL ARTICLE]
- Neuropharmacology 2013 Jun 5.
Depolarizing, hyperpolarizing and biphasic muscarinic responses have been described in hippocampal inhibitory interneurons, but the receptor subtypes and activity patterns required to synaptically activate muscarinic responses in interneurons have not been completely characterized. Using optogenetics combined with whole cell patch clamp recordings in acute slices, we measured muscarinic responses produced by endogenously released acetylcholine (ACh) from cholinergic medial septum/diagonal bands of Broca inputs in hippocampal CA1. We found that depolarizing responses required more cholinergic terminal stimulation than hyperpolarizing ones. Furthermore, elevating extracellular ACh with the acetylcholinesterase inhibitor physostigmine had a larger effect on depolarizing versus hyperpolarizing responses. Another subpopulation of interneurons responded biphasically, and periodic release of ACh entrained some of these interneurons to rhythmically burst. M4 receptors mediated hyperpolarizing responses by activating inwardly rectifying K(+) channels, whereas the depolarizing responses were inhibited by the nonselective muscarinic antagonist atropine but were unaffected by M1, M4 or M5 receptor modulators. In addition, activation of M4 receptors significantly altered biphasic interneuron firing patterns. Anatomically, interneuron soma location appeared predictive of muscarinic response types but response types did not correlate with interneuron morphological subclasses. Together these observations suggest that the hippocampal CA1 interneuron network will be differentially affected by cholinergic input activity levels. Low levels of cholinergic activity will preferentially suppress some interneurons via hyperpolarization and increased activity will recruit other interneurons to depolarize, possibly because of elevated extracellular ACh concentrations. These data provide important information for understanding how cholinergic therapies will affect hippocampal network function in the treatment of some neurodegenerative diseases.
- Physostigmine reverses disturbances of the intestinal microcirculation during experimental endotoxemia. [JOURNAL ARTICLE]
- Clin Hemorheol Microcirc 2013 Jun 4.
Intestinal microcirculatory disturbances play an important role in the pathophysiology of sepsis. A neural anti-inflammatory pathway has been suggested as a potential target for therapy that may dampen systemic inflammation. The aim of this study is to investigate the effects of physostigmine, a cholinesterase inhibitor, on the intestinal microcirculation and vascular contractility in experimental endotoxemia. Endotoxemia was induced in Lewis rats by intravenous lipopolysaccharide (LPS) administration. Animals were treated with either physostigmine or saline (control) following LPS challenge. The intestinal microcirculation, including leukocyte-endothelial interaction, functional capillary density (FCD) and non-perfused capillary density (NCD), was examined by intravital microscopy (IVM) 2 hours after LPS administration. The impact of physostigmine on vascular contractility of rat aortic rings was examined by in vitro myography. Physostigmine significantly reduced the number of adhering leukocytes in intestinal submucosal venules (V1 venules: -61%, V3 venules: -36%) of LPS animals. FCD was significantly increased by physostigmine treatment (circular muscle layer: +180%, longitudinal muscle layer: +162%, mucosa: +149%). Low concentrations of physostigmine produced significant contraction of aortic ring preparations, whereas high concentrations produced relaxation. In conclusion, physostigmine treatment significantly improved the intestinal microcirculation in experimental endotoxemia by reducing leukocyte adhesion and increasing FCD.
- The role of the cholinergic system in the signal attenuation rat model of obsessive-compulsive disorder. [JOURNAL ARTICLE]
- Psychopharmacology (Berl) 2013 May 18.
RATIONALE:In comparison to studies of the involvement of the serotonergic, dopaminergic, and glutamatergic systems in the pathophysiology of obsessive-compulsive disorder (OCD), research on the involvement of the cholinergic system in this disorder has remained sparse.
OBJECTIVES:The aim of this study was to test the role of the cholinergic system in compulsive behavior using the signal attenuation rat model of OCD. In this model, "compulsive" behavior is induced by attenuating a signal indicating that a lever-press response was effective in producing food.
METHODS:The acetylcholinesterase inhibitor physostigmine (0.05, 0.10, and 0.15 mg/kg), the nicotinic agonist nicotine (0.03, 0.06, 0.10, 0.30, 0.60, and 1.00 mg/kg), the nicotinic antagonist mecamylamine (1, 3, 5, and 8 mg/kg), the muscarinic agonist oxotremorine (0.0075, 0.0150, and 0.0300 mg/kg), and the muscarinic antagonist scopolamine (0.15, 0.50, 1.00, and 1.50 mg/kg) were acutely administered to rats just before assessing their lever-press responding following signal attenuation (experiments 1, 3, 5, 7, and 9, respectively). Because the effects of signal attenuation are assessed under extinction conditions, drug doses that were effective in the above experiments were also tested in an extinction session of lever-press responding that was not preceded by signal attenuation (experiments 2, 4, 6, 8, and 10).
RESULTS:Acute systemic administration of the cholinergic agents did not exert a selective anti- or pro-compulsive effect in the signal attenuation model.
CONCLUSIONS:Acetylcholine does not seem to play a role in the signal attenuation rat model of OCD.
- Acetylcholinesterase inhibitors reduce neuroinflammation and -degeneration in the cortex and hippocampus of a surgery stress rat model. [Journal Article]
- PLoS One 2013; 8(5):e62679.
Exogenous stress like tissue damage and pathogen invasion during surgical trauma could lead to a peripheral inflammatory response and induce neuroinflammation, which can result in postoperative cognitive dysfunction (POCD). The cholinergic anti-inflammatory pathway is a neurohumoral mechanism that plays a prominent role by suppressing the inflammatory response. Treatments with acetylcholinesterase inhibitors enhance cholinergic transmission and may therefore act as a potential approach to prevent neuroinflammation. In the presence or absence of acetylcholinesterase inhibitors, adult Wistar rats underwent surgery alone or were additionally treated with lipopolysaccharide (LPS). Physostigmine, which can overcome the blood-brain barrier or neostigmine acting only peripheral, served as acetylcholinesterase inhibitors. The expression of pro- and anti-inflammatory cytokines in the cortex, hippocampus, spleen and plasma was measured after 1 h, 24 h, 3 d and 7 d using Real-Time PCR, western blot analysis or cytometric bead array (CBA). Fluoro-Jade B staining of brain slices was employed to elucidate neurodegeneration. The activity of acetylcholinesterase was estimated using a spectrofluorometric method. Surgery accompanied by LPS-treatment led to increased IL-1beta gene and protein upregulation in the cortex and hippocampus but was significantly reduced by physostigmine and neostigmine. Furthermore, surgery in combination with LPS-treatment caused increased protein expression of IL-1, TNF-alpha and IL-10 in the spleen and plasma. Physostigmine and neostigmine significantly decreased the protein expression of IL-1 and TNF-alpha. Neuronal degeneration and the activity of acetylcholinesterase were elevated after surgery with LPS-treatment and reduced by physostigmine and neostigmine. Along with LPS-treatment, acetylcholinesterase inhibitors reduce the pro-inflammatory response as well as neurodegeneration after surgery in the cortex and hippocampus. This combination may represent a tool to break the pathogenesis of POCD.
- Scopolamine modulates paternal parental retrieval behavior in mice induced by the maternal mate. [JOURNAL ARTICLE]
- Neurosci Lett 2013 May 10.
Appropriate parental care by the father can greatly facilitate healthy human family life. Much less is known from animal studies about the factors leading to paternal parental care than those favoring maternal parent care. Recently, we have reported that sires of the ICR strain of laboratory mice can express maternal-like retrieval behavior when separated from their pups through ultrasound and pheromonal signals from the dam, i.e. mate-dependent parental care. The sire's retrieval behavior was inhibited by prior treatment of scopolamine, a muscarinic cholinergic inhibitor, and recovered by physostigmine. KCNQ K(+)-channel blocking and enhancing drugs, linopiridine and retigabine, were also examined. Linopiridine alone did not enhance care after pairing with the dam, nor change scopolamine-induced inhibition of care. Retigabine totally suppressed parental care, and this effect was partially rescued by co-administration of linopiridine. These results indicate the involvement of cholinergic cellular signaling in the central nervous system in the maternal induction of paternal parental behavior in ICR mice.
- Neonatal alcohol exposure impairs contextual fear conditioning in juvenile rats by disrupting cholinergic function. [Journal Article]
- Behav Brain Res 2013 Jul 1.:114-20.
The context preexposure facilitation effect (CPFE) is a variant of context fear conditioning in which context preexposure facilitates conditioning to immediate foot shock. Learning about context (preexposure), associating the context with shock (training), and expression of context fear (testing) occur in successive phases of the protocol. The CPFE develops postnatally, depends on hippocampal NMDA receptor function, and is highly sensitive to neonatal alcohol exposure during the weanling/juvenile period of development [15,16]. The present study examined some behavioral and pharmacological mechanisms through which neonatal alcohol impairs the CPFE in juvenile rats. We found that a 5-min context preexposure plus five 1-min preexposures greatly increases the levels of conditioned freezing compared to a single 5-min exposure or to five 1-min preexposures (Experiment 1). Increasing conditioned freezing with the multiple- exposure CPFE protocol does not alter the neonatal alcohol-induced deficit in the CPFE (Experiment 2). Finally, systemic administration of 0.01mg/kg physostigmine prior to all three phases of the CPFE reverses this ethanol-induced deficit. These findings show that impairment of the CPFE by neonatal alcohol is not confined to behavioral protocols that produce low levels of conditioned freezing. They also support recent evidence that this impairment reflects a disruption of cholinergic function .
- In vitro acetylcholinesterase activity of peptide derivatives isolated from two species of Leguminosae. [JOURNAL ARTICLE]
- Pharm Biol 2013 Apr 9.
Context:Cratylia mollis Martius ex Benth. and Cenostigma macrophyllum Tul. (Leguminosae) are both endemic Brazilian plants and they are used by the natives as medicinal plants, and the leaves of C. mollis are also employed as forage for cattle during the dry season of region.
Objective:Isolation of the compounds responsible for the acetylcholinesterase (AChE) inhibition from the CHCl3 active extract. Materials and methods: Two peptidic compounds were isolated by chromatographic techniques from the CHCl3 extract of the leaves of C. mollis and C. macrophyllum. They were identified by spectrometric data analysis (MS and NMR) and they were subjected to AChE inhibition employing Ellman's test.
Results:The peptides were identified as N-benzoylphenylalaninoyl-phenlyalaninolacetate (aurentiamide acetate) (1) and N-benzoylphenylalaninyl-N-benzoylphenylalaninate (2). Both peptides 1 and 2 exhibit AChE inhibition, with IC50 values equal to 111.34 µM and 137.6 µM, respectively. Discussion and conclusion: Compound 1 (aurentiamide acetate) has rarely been isolated from the Leguminosae family, and N-benzoylphenylalaninyl-N-benzoylphenylalaninate (2) is a compound that has never previously been isolated from this family. Compound 1 is shown to be a potent inhibitor of AChE, with IC50 values similar to the physostigmine control (141.51 µM).
- In vivo cholinergic modulation of the cellular properties of medial entorhinal cortex neurons. [Journal Article]
- J Physiol 2013 May 15; 591(Pt 10):2611-27.
Abstract Extensive in vitro data and modeling studies suggest that intrinsic properties of medial entorhinal cortex (MEC) neurons contribute to the spiking behaviour of functional cell types of MEC neurons, such as grid cells, recorded in behaving animals. It remains unclear, however, how intrinsic properties of MEC neurons influence cellular dynamics in intact networks in vivo. In order to begin to bridge the gap between electrophysiological data sets from brain slices and behaving animals, in the present study we performed intracellular recordings using sharp electrodes in urethane-anaesthetized rats to elucidate the cellular dynamics of MEC neurons in vivo. We focused on the h-current-dependent sag potential during hyperpolarizing current steps, subthreshold resonance in response to oscillatory frequency sweeps (chirp stimuli), persistent spiking in response to brief depolarizing inputs and the relationship between firing frequency and input (f-I curve), each of which is sensitive to cholinergic modulation in vitro. Consistent with data from in vitro studies, cholinergic activation by systemic application of the acetylcholinesterase inhibitor, physostigmine, resulted in decreased sag amplitude, increased sag time constant and a decrease of the peak resonance frequency. The f-I curve was also modulated by physostigmine in many neurons, but persistent spiking was not observed in any of our recordings, even when picrotoxin, a GABAA blocker, was included in the internal solution of the recording pipette to reduce possible effects of network inhibition. These results suggest that intrinsic oscillatory and rate-coding mechanisms, but not intrinsic bistability, are significantly modulated by acetylcholine in the intact entorhinal network.
- Cholinesterase enzymes inhibitors from the leaves of rauvolfia reflexa and their molecular docking study. [Journal Article, Research Support, Non-U.S. Gov't]
- Molecules 2013; 18(4):3779-88.
Plants of the Apocynaceae family have been traditionally used in the treatment of age-related brain disorders. Rauvolfia reflexa, a member of the family, has been used as an antidote for poisons and to treat malaria. The dichloromethane, ethanol and methanol extracts from the leaves of Rauvolfia reflexa showed potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, with IC50 values in the 8.49 to 52.23 g/mL range. Further cholinesterase inhibitory-guided isolation of these extracts afforded four bioactive compounds, namely: (E)-3-(3,4,5-trimethoxyphenyl)acrylic acid (1), (E)-methyl 3-(4-hydroxy-3,5-dimethoxyphenyl) acrylate (2), 17-methoxycarbonyl-14-heptadecaenyl-4-hydroxy-3-methoxycinnamate (3) and 1,2,3,4-tetrahydro-1-oxo-β-carboline (4). The isolated compounds showed moderate cholinesterase inhibitory activity compared to the reference standard, physostigmine. Compounds 1 and 2 showed the highest inhibitory activity against AChE (IC50 = 60.17 µM) and BChE (IC50 = 61.72 µM), respectively. Despite having similar molecular weight, compounds 1 and 2 were structurally different according to their chemical substitution patterns, leading to their different enzyme inhibition selectivity. Compound 2 was more selective against BChE, whereas compound 1 was a selective inhibitor of AChE. Molecular docking revealed that both compounds 1 and 2 were inserted, but not deeply into the active site of the cholinesterase enzymes.
- TLC-bioautographic evaluation of in vitro anti-tyrosinase and anti-cholinesterase potentials of sandalwood oil. [Journal Article, Research Support, Non-U.S. Gov't]
- Nat Prod Commun 2013 Feb; 8(2):253-6.
Sandalwood oil, rich in sesquiterpenoid alcohols, has been used in traditional medicinal systems as a relaxant and coolant. Besides, sandalwood oil is used as an ingredient in numerous skin fairness enhancing cosmetics. However, there is no available information on biological activities that relate to the above applications. Hence, the anti-tyrosinase and anti-cholinesterase potentials of sandalwood oil were probed by both TLC-bioautographic and colorimetric methods. Results obtained from colorimetric assays indicated that sandalwood oil is a potent inhibitor of tyrosinase (IC50 = 171 microg mL(-1)) and cholinesterases (IC50 = 4.8-58 microg mL(-1)), in comparison with the positive controls used in the assays, kojic acid and physostigmine, respectively. The TLC-bioautographic assays indicated that alpha-santalol, the major constituent of the oil, is a strong inhibitor of both tyrosinase and cholinesterase. These in vitro results indicate that there is a great potential of this essential oil for use in the treatment of Alzheimer's disease, as well as in skin-care.