scholarly journals Antidepressive effect of an inward rectifier K+ channel blocker peptide, tertiapin-RQ

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0233815
Author(s):  
Masayoshi Okada ◽  
Ikkou Kozaki ◽  
Hiroyuki Honda
Keyword(s):  
Disulfide Bonds ◽  
Wheel Running ◽  
Lateral Septum ◽  
K Channel ◽  
Antidepressive Effect ◽  
Whole Cell Patch Clamp ◽  
Circular Structure ◽  
Plus Maze ◽  
Motor Activities ◽  
The Central Nervous System

Renal outer medullary K+ channel, ROMK (Kir1.1, kcnj1) is expressed in the kidney and brain, but its role in the central nervous system remains unknown. Recent studies suggested an involvement of the ROMK channel in mental diseases. Tertiapin (TPN) is a European honey bee venom peptide and is reported to selectively block the ROMK channel. Here, we have chemically synthesized a series of mutated TPN peptides, including TPN-I8R and -M13Q (TPN-RQ), reported previously, and examined their blocking activity on the ROMK channel. Among 71 peptides tested, TPN-RQ was found to block the ROMK channel most effectively. Whole-cell patch-clamp recordings showed the essential roles of two disulfide bonds and the circular structure for the blockade activity. To examine the central role, we injected TPN-RQ intracerebroventricularly and examined the effects on depression- and anxiety-like behaviors in mice. TPN-RQ showed an antidepressive effect in tail-suspension and forced swim tests. The injection of TPN-RQ also enhanced the anxiety-like behavior in the elevated plus-maze and light/dark box tests and impaired spontaneous motor activities in balance beam and wheel running tests. Administration of TPM-RQ suppressed the anti-c-Fos immunoreactivity in the lateral septum, without affecting immunoreactivity in antidepressant-related nuclei, e.g. the dorsal raphe nucleus and locus coeruleus. TPN-RQ may exert its antidepressive effects through a different mechanism from current drugs.

Neuropharmacological Characterization of Dioclea altissima Seed Lectin (DAL) in Mice: Evidence of Anxiolytic-like Effect Mediated by Serotonergic, GABAergic Receptors and NO Pathway

2020 ◽  
Vol 26 (31) ◽  
pp. 3895-3904
Author(s):  
João R.C. Araújo ◽  
Adriana R. Campos ◽  
Marina de Barros M.V. Damasceno ◽  
Sacha A.A.R. Santos ◽  
Maria K.A. Ferreira ◽  
...  
Keyword(s):  
Structural Integrity ◽  
Elevated Plus Maze ◽  
Biological Activities ◽  
Plant Lectins ◽  
Plus Maze ◽  
Marble Burying ◽  
Gabaergic Receptors ◽  
The Central Nervous System ◽  
Hole Board

Background: Plant lectins have shown promising biological activities in the central nervous system (CNS). Objective: This study evaluated the effect of DAL, a lectin isolated from the seeds of the Dioclea altissima species, having binding affinity to D-glucose or D-mannose residues, on mice behavior. Methods: Mice (n=6/group) were treated (i.p.) with DAL (0.25, 0.5 or 1 mg/kg) or vehicle and subjected to several tests (open field/OFT, marble-burying/MBT, hole-board/HBT, elevated plus maze/PMT, tail suspension/ TST, forced swimming/FST or rotarod/RRT). Pizotifen, cyproheptadine, flumazenil, L-NAME, 7-NI, Larginine or yohimbine were administered 15 min before DAL (0.5 mg/kg) and the animals were evaluated on PMT. It was also verified whether the DAL effect depended on its structural integrity and ability to interact with carbohydrates. Results: The results showed there were no neurobehavioral changes in the mice at the RRT, FST and locomotion in the OFT. DAL (0.25, 0.5 or 1 mg/kg) increased the behavior of grooming and rearing in the OFT, head dips in the HBT, pedalling in the TST and decreased the number of marbles hidden in the MBT. In the PMT, DAL (0.25, 0.5 and 1 mg/kg) and Diazepam increased the frequency of entries in the open arms and the time of permanence in the open arms without affecting the locomotor activity. The effect of DAL was dependent on carbohydrate interaction and protein structure integrity and it prevented by pizotifen, cyproheptadine, flumazenil, L-NAME and 7-NI, but not by L-arginine or yohimbine. Conclusion: DAL was found to have an anxiolytic-like effect mediated by the 5-HT and GABAergic receptors and NO pathway.

Neuropharmacological Screening of Chiral and Non-chiral Phthalimide- Containing Compounds in Mice: in vivo and in silico Experiments

2019 ◽  
Vol 15 (1) ◽  
pp. 102-118 ◽  
Author(s):  
Carolina Campos-Rodríguez ◽  
José G. Trujillo-Ferrara ◽  
Ameyali Alvarez-Guerra ◽  
Irán M. Cumbres Vargas ◽  
Roberto I. Cuevas-Hernández ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
In Silico ◽  
Biological Properties ◽  
Chiral Molecules ◽  
Chiral Compounds ◽  
Plus Maze ◽  
In Silico Studies ◽  
The Central Nervous System

Background: Thalidomide, the first synthesized phthalimide, has demonstrated sedative- hypnotic and antiepileptic effects on the central nervous system. N-substituted phthalimides have an interesting chemical structure that confers important biological properties. Objective: Non-chiral (ortho and para bis-isoindoline-1,3-dione, phthaloylglycine) and chiral phthalimides (N-substituted with aspartate or glutamate) were synthesized and the sedative, anxiolytic and anticonvulsant effects were tested. Method: Homology modeling and molecular docking were employed to predict recognition of the analogues by hNMDA and mGlu receptors. The neuropharmacological activity was tested with the open field test and elevated plus maze (EPM). The compounds were tested in mouse models of acute convulsions induced either by pentylenetetrazol (PTZ; 90 mg/kg) or 4-aminopyridine (4-AP; 10 mg/kg). Results: The ortho and para non-chiral compounds at 562.3 and 316 mg/kg, respectively, decreased locomotor activity. Contrarily, the chiral compounds produced excitatory effects. Increased locomotor activity was found with S-TGLU and R-TGLU at 100, 316 and 562.3 mg/kg, and S-TASP at 316 and 562.3 mg/kg. These molecules showed no activity in the EPM test or PTZ model. In the 4-AP model, however, S-TGLU (237.1, 316 and 421.7 mg/kg) as well as S-TASP and R-TASP (316 mg/kg) lowered the convulsive and death rate. Conclusion: The chiral compounds exhibited a non-competitive NMDAR antagonist profile and the non-chiral molecules possessed selective sedative properties. The NMDAR exhibited stereoselectivity for S-TGLU while it is not a preference for the aspartic derivatives. The results appear to be supported by the in silico studies, which evidenced a high affinity of phthalimides for the hNMDAR and mGluR type 1.

Gq/11 and PLC-beta 1 mediate the substance P-induced inhibition of an inward rectifier K+ channel in brain neurons

1996 ◽  
Vol 76 (3) ◽  
pp. 2131-2136 ◽  
Author(s):  
K. Takano ◽  
J. Yasufuku-Takano ◽  
T. Kozasa ◽  
W. D. Singer ◽  
S. Nakajima ◽  
...  
Keyword(s):  
Substance P ◽  
Single Channel ◽  
Cholinergic Neurons ◽  
Nucleus Basalis ◽  
Alpha Subunit ◽  
K Channel ◽  
Whole Cell Patch Clamp ◽  
K Current ◽  
Beta 2 ◽  
G Protein Alpha Subunit

1. Substance P (SP) induces a slow neuronal excitation in cholinergic neurons from the nucleus basalis by suppressing an inwardly rectifying K+ current (Kir). We have determined which G protein alpha-subunit mediates this SP effect. 2. After intracellularly injecting antibody against each alpha-subunit of G proteins (Gq alpha/11 alpha, G12 alpha, and G13 alpha) with an Eppendorf microinjector, we examined, by using the whole cell patch-clamp and the ON-cell mode of single-channel recording, the effect of SP on Kir in cultured neurons of the nucleus basalis. The effect of SP on Kir was substantially reduced in neurons injected with antibodies to Gq alpha/11 alpha but not with antibodies to G12 alpha or G13 alpha. 3. The effects of antibodies against three isozymes of phospholipase C (PLC-beta 1, PLC-beta 2, and PLC-beta 3) were tested. The SP-induced suppression of Kir was reduced by antibody against PLC-beta 1 but not by antibodies against PLC-beta 2 or PLC-beta 3. 4. We conclude that the SP-induced inhibition of Kir in nucleus basalis neurons is mediated by Gq/11 and PLC-beta 1.

scholarly journals Influences of Morphine on the Spontaneous and Evoked Excitatory Postsynaptic Currents in Lateral Amygdala of Rats

2016 ◽  
pp. 165-169 ◽  
Author(s):  
J.-J. ZHANG ◽  
X.-D. LIU ◽  
L.-C. YU
Keyword(s):  
Synaptic Transmission ◽  
Excitatory Synaptic Transmission ◽  
Morphine Treatment ◽  
Lateral Amygdala ◽  
Excitatory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Whole Cell Patch Clamp ◽  
The Central Nervous System ◽  
Underlying Mechanisms

Acute morphine exposure induces antinociceptive activity, but the underlying mechanisms in the central nervous system are unclear. Using whole-cell patch clamp recordings, we explore the role of morphine in the modulation of excitatory synaptic transmission in lateral amygdala neurons of rats. The results demonstrate that perfusion of 10 μM of morphine to the lateral amygdala inhibits the discharge frequency significantly. We further find that there are no significant influences of morphine on the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). Interestingly, morphine shows no marked influence on the evoked excitatory postsynaptic currents (eEPSCs) in the lateral amygdala neurons. These results indicate that acute morphine treatment plays an important role in the modulation on the excitatory synaptic transmission in lateral amygdala neurons of rats.

Kainate receptor-mediated synaptic transmissions in the adult rodent insular cortex

2012 ◽  
Vol 108 (7) ◽  
pp. 1988-1998 ◽  
Author(s):  
Kohei Koga ◽  
Su-Eon Sim ◽  
Tao Chen ◽  
Long-Jun Wu ◽  
Bong-Kiun Kaang ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Receptor Antagonist ◽  
Ampa Receptor ◽  
Time Course ◽  
Insular Cortex ◽  
Nmda Receptor Antagonist ◽  
Functional Roles ◽  
Adult Rat ◽  
Whole Cell Patch Clamp ◽  
The Central Nervous System

Kainate (KA) receptors are expressed widely in the central nervous system and regulate both excitatory and inhibitory synaptic transmission. KA receptors play important roles in fear memory, anxiety, and pain. However, little is known about their function in synaptic transmission in the insular cortex (IC), a critical region for taste, memory, and pain. Using whole cell patch-clamp recordings, we have shown that KA receptors contribute to fast synaptic transmission in neurons in all layers of the IC. In the presence of the GABAA receptor antagonist picrotoxin, the NMDA receptor antagonist AP-5, and the selective AMPA receptor antagonist GYKI 53655, KA receptor-mediated excitatory postsynaptic currents (KA EPSCs) were revealed. We found that KA EPSCs are ∼5–10% of AMPA/KA EPSCs in all layers of the adult mouse IC. Similar results were found in adult rat IC. KA EPSCs had a significantly slower rise time course and decay time constant compared with AMPA receptor-mediated EPSCs. High-frequency repetitive stimulations at 200 Hz significantly facilitated the summation of KA EPSCs. In addition, genetic deletion of GluK1 or GluK2 subunit partially reduced postsynaptic KA EPSCs, and exposure of GluK2 knockout mice to the selective GluK1 antagonist UBP 302 could significantly reduce the KA EPSCs. These data suggest that both GluK1 and GluK2 play functional roles in the IC. Our study may provide the synaptic basis for the physiology and pathology of KA receptors in the IC-related functions.

scholarly journals Absence of sibutramine effect on spontaneous anxiety in rats

2010 ◽  
Vol 54 (4) ◽  
pp. 375-380 ◽  
Author(s):  
Silvana S. Frassetto ◽  
Isis O. Alves ◽  
Marislane M. Santos ◽  
Ana E. S. Schmidt ◽  
Janaína J. Lopes ◽  
...  
Keyword(s):  
Chronic Treatment ◽  
Elevated Plus Maze ◽  
Anxiolytic Effect ◽  
Chronic Administration ◽  
Positive Control ◽  
Maximum Effect ◽  
Plus Maze ◽  
The Central Nervous System ◽  
Treatment Of Obesity ◽  
Acute And Chronic Treatments

INTRODUSTION: Sibutramine has been described as a drug recommended for treatment of obesity, since it has the ability to inhibit the reuptake of serotonin and noradrenaline in the central nervous system, thereby increasing energy expenditure. OBJECTIVE: Investigate the anxiogenic and anxiolytic effects of acute and chronic treatment with sibutramine in rats submitted to the task of the elevated plus-maze. METHODS: Diazepam was used as a positive control for the anxiolytic effect, and the task of the elevated plus-maze showed sensitivity to detect the effect. In the chronic treatment, sibutramine was ingested for a period of two months. RESULTS: The acute and chronic treatments at the studied dose, which is described to produce a maximum effect of anti-obesity in rats, did not interfere with anxiety. CONCLUSIONS: The acute and chronic administration of sibutramine is not related to anxiolytic or anxiogenic effects.

scholarly journals Heterotrimeric G Proteins of the Gq/11 Family Are Crucial for the Induction of Maternal Behavior in Mice

2004 ◽  
Vol 24 (18) ◽  
pp. 8048-8054 ◽  
Author(s):  
Nina Wettschureck ◽  
Alexandra Moers ◽  
Tuula Hamalainen ◽  
Thomas Lemberger ◽  
Günther Schütz ◽  
...  
Keyword(s):  
G Proteins ◽  
Maternal Behavior ◽  
Motor Behavior ◽  
Oxytocin Receptor ◽  
Lateral Septum ◽  
Heterotrimeric G Proteins ◽  
Bed Nucleus ◽  
The Central Nervous System ◽  
Gland Function

ABSTRACT Heterotrimeric G proteins of the Gq/11 family transduce signals from a variety of neurotransmitter receptors and have therefore been implicated in several functions of the central nervous system. To investigate the potential role of Gq/11 signaling in behavior, we generated mice which lack the α-subunits of the two main members of the Gq/11 family, Gαq and Gα11, selectively in the forebrain. We show here that forebrain Gαq/11-deficient females do not display any maternal behavior such as nest building, pup retrieving, crouching, or nursing. However, olfaction, motor behavior and mammary gland function are normal in forebrain Gαq/11-deficient females. We used c-fos immunohistochemistry to investigate pup-induced neuronal activation in different forebrain regions and found a significant reduction in the medial preoptic area, the bed nucleus of stria terminalis, and the lateral septum both in postpartum females and in virgin females after foster pup exposure. Pituitary function, especially prolactin release, was normal in forebrain Gαq/11-deficient females, and activation of oxytocin receptor-positive neurons in the hypothalamus did not differ between genotypes. Our findings show that Gq/11 signaling is indispensable to the neuronal circuit that connects the perception of pup-related stimuli to the initiation of maternal behavior and that this defect cannot be attributed to either reduced systemic prolactin levels or impaired activation of oxytocin receptor-positive neurons of the hypothalamus.

scholarly journals 4-aminopyridine – the new old drug for the treatment of neurodegenerative diseases

Pharmacia ◽  
2019 ◽  
Vol 66 (2) ◽  
pp. 67-74
Author(s):  
Ivanka Kostadinova ◽  
Nikolai Danchev
Keyword(s):  
Multiple Sclerosis ◽  
Channel Blocker ◽  
K Channel ◽  
Chemical Agent ◽  
Channel Blockade ◽  
Reversal Agent ◽  
Trade Name ◽  
Pharmacological Data ◽  
The Usa ◽  
The Central Nervous System

In this review are described the preclinical and clinical pharmacological data as well as new therapeutic indications for the use of 4-aminopyridine. 4-aminopyridine is a potassium (K+) channel blocker that has a long history and various application areas. It is a chemical agent developed in 1963 as a bird poison. The first approval for clinical application of 4-aminopyridine was in 70’s in Bulgaria, since anesthetists in that country have confirmed its effect as reversal agent for nondepolarizing myorelaxants. The Bulgarian pharmaceutical company Sopharma commersialized 4-aminopyridine under the trade name Pymadin. Since then 4-aminopyridine was extensively studied and in 2010 is approved in the USA for the treatment of walking disabilities in patients with multiple sclerosis. In recent years, data from clinical trials indicated that K-channel blockade may prove to be an appropriate strategy to overcome disturbances in nerve impulses conduction associated with demyelination of the central nervous system.

scholarly journals Characterization of α3 Glycine Receptors with Ginkgolide B and Picrotoxin

2018 ◽  
Author(s):  
Sampurna Chakrabarti ◽  
Anil Neelakantan ◽  
Malcolm M. Slaughter
Keyword(s):  
Beta Subunits ◽  
Ginkgolide B ◽  
Glycine Receptors ◽  
Hek 293 ◽  
Whole Cell Patch Clamp ◽  
293 Cells ◽  
Voltage Dependent ◽  
The Central Nervous System ◽  
Subunit Isoforms

AbstractGinkgolide B (GB) and picrotoxin (PTX) are antagonists of the major inhibitory receptors of the central nervous system: GABA and glycine receptors (GlyRs). GlyRs contain one or more of the four alpha subunit isoforms of which α1 and α2 have been extensively studied. This report compares GB and PTX block of α3 GlyRs expressed in HEK 293 cells, using whole-cell patch clamp techniques. In CNS, α3 exists as a heteropentamer in conjunction with beta subunits in a 2α:3β ratio. Thus, the nature of block was also tested in α3β heteromeric glycine receptors. GB and PTX blocked α3 GlyRs both in the presence (liganded state) and absence of glycine (unliganded state). This property is unique to α3 subunits; α1 and α2 subunits are only blocked in the liganded state. The GB block of α3 GlyRs is voltage-dependent (more effective when the cell is depolarized) and non-competitive, while the PTX block is competitive and not voltage-dependent. The heteromeric and homomeric α3 GlyRs recovered significantly faster from unliganded GB block compared to liganded GB block, but no such distinction was found for PTX block suggesting more than one binding site for GB. This study sheds light on features of the α3 GlyR that distinguish it from the more widely studied α1 and α2 subunits. Understanding these properties can help decipher the physiological functioning of GlyRs in the CNS and may permit development of subunit specific drugs.

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