Cholecystokinin activates area postrema neurons in rat brain slices

1997 ◽  
Vol 272 (5) ◽  
pp. R1625-R1630 ◽  
Author(s):  
K. Sun ◽  
A. V. Ferguson
Keyword(s):  
Food Intake ◽  
Receptor Antagonist ◽  
Area Postrema ◽  
Brain Slices ◽  
In Vivo Studies ◽  
Unit Recording ◽  
Dose Dependent ◽  
Cckb Receptor

Peripheral cholecystokinin (CCK) reduces food intake and triggers the secretion of both oxytocin and corticotropin-releasing hormone. These responses are partially initiated by activation of receptors in the peripheral endings of the vagus nerve. However, in vivo studies showing that after vagotomy systemic CCK induces fos activation of neurons in the area postrema (AP) suggest that circulating CCK may directly influence the activity of neurons in this structure. The present study was therefore designed to investigate the responsiveness of AP neurons to CCK using in vitro extracellular single-unit recording techniques. Bath application of 100 nM CCK for 200 s resulted in excitatory responses in 41% and inhibitory effects in 6% of 143 AP neurons tested. Application of multiple doses of CCK (1-100 nM) to single neurons demonstrated that CCK effects were dose dependent. The firing rate of tested neurons increased by 48 +/- 15% in response to 1 nM, by 89 +/- 22% in response to 10 nM, and by 242 +/- 77% in response to 100 nM CCK. After we blockaded synaptic transmission with a low-Ca2+/high-Mg2+ artificial cerebrospinal fluid, the excitatory effects of CCK remained in all nine neurons tested. The CCK-receptor antagonist L-364,718 had no significant effect on the responses to CCK (P > 0.1, n = 4), whereas, after perfusion of slices with the CCKB-receptor antagonist L-365,260, mean responses to CCK were significantly reduced to 12.6 +/- 4.7% of the control value (P < 0.001, n = 4). These results demonstrate a direct and dose-dependent excitatory action of CCK on AP neurons that is abolished by CCKB-receptor antagonists. These data emphasize the potential role of AP in processing afferent information derived from circulating peptide concentrations that could be involved in the regulation of food intake.

scholarly journals Effects of Bacterial CLPB Protein Fragments on Food Intake and PYY Secretion

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2223
Author(s):  
Manon Dominique ◽  
Nicolas Lucas ◽  
Romain Legrand ◽  
Illona-Marie Bouleté ◽  
Christine Bôle-Feysot ◽  
...  
Keyword(s):  
Food Intake ◽  
Peptide Yy ◽  
Molecular Mimicry ◽  
Potential Effect ◽  
In Vivo Studies ◽  
Sprague Dawley ◽  
E Coli ◽  
In Vivo Effects

CLPB (Caseinolytic peptidase B) protein is a conformational mimetic of α-MSH, an anorectic hormone. Previous in vivo studies have already shown the potential effect of CLPB protein on food intake and on the production of peptide YY (PYY) by injection of E. coli wild type (WT) or E. coli ΔClpB. However, until now, no study has shown its direct effect on food intake. Furthermore, this protein can fragment naturally. Therefore, the aim of this study was (i) to evaluate the in vitro effects of CLPB fragments on PYY production; and (ii) to test the in vivo effects of a CLPB fragment sharing molecular mimicry with α-MSH (CLPB25) compared to natural fragments of the CLPB protein (CLPB96). To do that, a primary culture of intestinal mucosal cells from male Sprague–Dawley rats was incubated with proteins extracted from E. coli WT and ΔCLPB after fragmentation with trypsin or after a heat treatment of the CLPB protein. PYY secretion was measured by ELISA. CLPB fragments were analyzed by Western Blot using anti-α-MSH antibodies. In vivo effects of the CLPB protein on food intake were evaluated by intraperitoneal injections in male C57Bl/6 and ob/ob mice using the BioDAQ® system. The natural CLPB96 fragmentation increased PYY production in vitro and significantly decreased cumulative food intake from 2 h in C57Bl/6 and ob/ob mice on the contrary to CLPB25. Therefore, the anorexigenic effect of CLPB is likely the consequence of enhanced PYY secretion.

scholarly journals Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 386
Author(s):  
Tung-Hu Tsai ◽  
Yu-Jen Chen ◽  
Li-Ying Wang ◽  
Chen-Hsi Hsieh
Keyword(s):  
Stereotactic Body Radiation Therapy ◽  
In Vivo Studies ◽  
Control Group ◽  
High Dose ◽  
Dependent Manner ◽  
Hep G2 ◽  
Time Curve ◽  
Dose Dependent

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).

Antinociceptive properties of shikonin: in vitro and in vivo studies

2016 ◽  
Vol 94 (7) ◽  
pp. 788-796 ◽  
Author(s):  
Bhawana Gupta ◽  
Sabyasachi Chakraborty ◽  
Soumya Saha ◽  
Sunita Gulabsingh Chandel ◽  
Atul Kumar Baranwal ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Inhibitory Effect ◽  
Pain Modulation ◽  
In Vivo Studies ◽  
Channel Modulation ◽  
Pain Models ◽  
A Cell ◽  
Dose Dependent

Shikonin possess a diverse spectrum of pharmacological properties in multiple therapeutic areas. However, the nociceptive effect of shikonin is not largely known. To investigate the antinociceptive potential of shikonin, panel of GPCRs, ion channels, and enzymes involved in pain pathogenesis were studied. To evaluate the translation of shikonin efficacy in vivo, it was tested in 3 established rat pain models. Our study reveals that shikonin has significant inhibitory effect on pan sodium channel/N1E115 and NaV1.7 channel with half maximal inhibitory concentration (IC50) value of 7.6 μmol/L and 6.4 μmol/L, respectively, in a cell-based assay. Shikonin exerted significant dose dependent antinociceptive activity at doses of 0.08%, 0.05%, and 0.02% w/v in pinch pain model. In mechanical hyperalgesia model, dose of 10 and 3 mg/kg (intraperitoneal) produced dose-dependent analgesia and showed 67% and 35% reversal of hyperalgesia respectively at 0.5 h. Following oral administration, it showed 39% reversal at 30 mg/kg dose. When tested in first phase of formalin induced pain, shikonin at 10 mg/kg dose inhibited paw flinching by ∼71%. In all studied preclinical models, analgesic effect was similar or better than standard analgesic drugs. The present study unveils the mechanistic role of shikonin on pain modulation, predominantly via sodium channel modulation, suggesting that shikonin could be developed as a potential pain blocker.

scholarly journals Hyperoxia, reactive oxygen species, and hyperventilation: oxygen sensitivity of brain stem neurons

2004 ◽  
Vol 96 (2) ◽  
pp. 784-791 ◽  
Author(s):  
Jay B. Dean ◽  
Daniel K. Mulkey ◽  
Richard A. Henderson ◽  
Stephanie J. Potter ◽  
Robert W. Putnam
Keyword(s):  
Oxidative Stress ◽  
Brain Stem ◽  
Brain Slices ◽  
Respiratory Control ◽  
In Vivo Studies ◽  
Future Research ◽  
Direct Effects ◽  
Underlying Assumption

Hyperoxia is a popular model of oxidative stress. However, hyperoxic gas mixtures are routinely used for chemical denervation of peripheral O2 receptors in in vivo studies of respiratory control. The underlying assumption whenever using hyperoxia is that there are no direct effects of molecular O2 and reactive O2 species (ROS) on brain stem function. In addition, control superfusates used routinely for in vitro studies of neurons in brain slices are, in fact, hyperoxic. Again, the assumption is that there are no direct effects of O2 and ROS on neuronal activity. Research contradicts this assumption by demonstrating that O2 has central effects on the brain stem respiratory centers and several effects on neurons in respiratory control areas; these need to be considered whenever hyperoxia is used. This mini-review summarizes the long-recognized, but seldom acknowledged, paradox of respiratory control known as hyperoxic hyperventilation. Several proposed mechanisms are discussed, including the recent hypothesis that hyperoxic hyperventilation is initiated by increased production of ROS during hyperoxia, which directly stimulates central CO2 chemoreceptors in the solitary complex. Hyperoxic hyperventilation may provide clues into the fundamental role of redox signaling and ROS in central control of breathing; moreover, oxidative stress may play a role in respiratory control dysfunction. The practical implications of brain stem O2 and ROS sensitivity are also considered relative to the present uses of hyperoxia in respiratory control research in humans, animals, and brain stem tissues. Recommendations for future research are also proposed.

Kinetic Studies of Dose-Dependent Metabolism of Alprenolol: In Vitro and In Vivo Studies in Different Species

2009 ◽  
Vol 44 (1) ◽  
pp. 28-35 ◽  
Author(s):  
Inger Skånberg ◽  
Karl Olof Borg ◽  
Erik Fellenius ◽  
Kurt-Jürgen Hoffmann ◽  
Christer Bahr ◽  
...  
Keyword(s):  
Kinetic Studies ◽  
In Vivo Studies ◽  
Dose Dependent

Ethanol enhances leukocyte-endothelial cell interactions in mesenteric venules

1990 ◽  
Vol 259 (4) ◽  
pp. G578-G583 ◽  
Author(s):  
P. R. Kvietys ◽  
M. A. Perry ◽  
T. S. Gaginella ◽  
D. N. Granger
Keyword(s):  
Endothelial Cell ◽  
Receptor Antagonist ◽  
Alcohol Intoxication ◽  
Leukotriene B4 ◽  
Cell Interactions ◽  
In Vivo Studies ◽  
Rolling Velocity ◽  
Neutrophil Adherence

In vivo studies have implicated neutrophils in the gastric mucosal injury produced by intraluminal administration of ethanol. However, in vitro studies indicate that ethanol inhibits various neutrophil functions such as adherence, chemotaxis, and degranulation. The aim of the present study was to assess whether ethanol, at clinically relevant concentrations, is proinflammatory in vivo. Ethanol (0.2, 1.0, 2.0, and 4.0%) was applied to the surface of the cat mesentery, and neutrophil adherence to venules (30 microns diam) and extravasation into the interstitium were quantitated using intravital microscopy. Hemodynamic parameters were also measured (venular diameter, red blood cell velocity, and leukocyte rolling velocity) or calculated (venular blood flow and wall shear stress). In this model ethanol produced a dose-dependent increase in neutrophil adherence and extravasation. The increase in leukocyte-endothelial cell interactions could not be attributed to alterations in hemodynamic factors. Pretreatment of animals with a monoclonal antibody (MoAb IB4) directed to the neutrophil CD11/CD18 adherence complex completely prevented the ethanol-induced neutrophil adherence and extravasation. Pretreatment with a leukotriene B4 (LTB4)-receptor antagonist (SC 41930) or a platelet-activating factor (PAF)-receptor antagonist (WEB 2170) did not alter the ethanol-induced neutrophil-endothelial interactions. We conclude that ethanol is proinflammatory at concentrations which may be achieved in the mucosal interstitium during acute alcohol intoxication. The ethanol-induced leukocyte adherence and extravasation is dependent on the expression of adhesive glycoproteins. The inflammatory mediators, PAF and LTB4, do not appear to play an important role in the leukocyte-endothelial cell interactions initiated by ethanol.

Dopamine Modulates Excitability of Basolateral Amygdala Neurons In Vitro

2005 ◽  
Vol 93 (3) ◽  
pp. 1598-1610 ◽  
Author(s):  
Sven Kröner ◽  
J. Amiel Rosenkranz ◽  
Anthony A. Grace ◽  
German Barrionuevo
Keyword(s):  
Basolateral Amygdala ◽  
Neuronal Response ◽  
Brain Slices ◽  
Receptor Activation ◽  
D1 Receptor ◽  
In Vivo Studies ◽  
Projection Neurons ◽  
Direct Effects

The amygdala plays a role in affective behaviors, which are modulated by the dopamine (DA) innervation of the basolateral amygdala complex (BLA). Although in vivo studies indicate that activation of DA receptors alters BLA neuronal activity, it is unclear whether DA exerts direct effects on BLA neurons or whether it acts via indirect effects on BLA afferents. Using whole cell patch-clamp recordings in rat brain slices, we investigated the site and mechanisms through which DA regulates the excitability of BLA neurons. Dopamine enhanced the excitability of BLA projection neurons in response to somatic current injections via a postsynaptic effect. Dopamine D1 receptor activation increased excitability and evoked firing, whereas D2 receptor activation increased input resistance. Current- and voltage-clamp experiments in projection neurons showed that D1 receptor activation enhanced excitability by modulating a 4-aminopyridine- and α-dendrotoxin-sensitive, slowly inactivating K+ current. Furthermore, DA and D1 receptor activation increased evoked firing in fast-spiking BLA interneurons. Consistent with a postsynaptic modulation of interneuron excitability, DA also increased the frequency of spontaneous inhibitory postsynaptic currents recorded in projection neurons without changing release of GABA. These data demonstrate that DA exerts direct effects on BLA projection neurons and indirect actions via modulation of interneurons that may work in concert to enhance the neuronal response to large, suprathreshold inputs, while suppressing weaker inputs.

scholarly journals Characterizing concentration-dependent neural dynamics of 4-aminopyridine-induced epileptiform activity

2018 ◽  
Author(s):  
Timothy L Myers ◽  
Oscar C González ◽  
Jacob B Stein ◽  
Maxim Bazhenov
Keyword(s):  
Epileptiform Activity ◽  
Brain Slices ◽  
Population Level ◽  
Frequency Component ◽  
Pharmacological Agents ◽  
Spatio Temporal ◽  
Dose Dependent ◽  
Array Recordings

AbstractEpilepsy remains one of the most common neurological disorders. In patients, it is characterized by unprovoked, spontaneous, and recurring seizures or ictal events. Typically, inter-ictal events or large bouts of population level activity can be measured between seizures and are generally asymptomatic. Decades of research has focused on understanding the mechanisms leading to the development of seizure-like activity using various proconvulsive pharmacological agents, including 4-aimnopyridine (4AP). However, the lack of consistency in the concentrations used for studying 4AP-induced epileptiform activity in animal models may give rise to differences in the results and interpretation thereof. Indeed, the range of 4AP concentration in both in vivo and in vitro studies varies from 3μM to 40mM. Here, we explored the effects of various 4AP concentrations on the development and characteristics of hippocampal epileptiform activity in acute mouse brain slices of either sex. Using multielectrode array recordings, we show that 4AP induces hippocampal epileptiform activity for broad range of concentrations. The frequency component and the spatio-temporal patterns of the epileptiform activity revealed a dose-dependent response. Finally, in the presence of 4AP, reduction of KCC2 co-transporter activity by KCC2 antagonist VU0240551 prevented the manifestation of the frequency component differences between different concentrations of 4AP. Overall, the study predicts that different concentrations of 4AP can result in the different mechanisms behind hippocampal epileptiform activity, of which some are dependent on the KCC2 co-transporter function.

scholarly journals Platelet-Derived Biomaterials Inhibit Nicotine-Induced Intervertebral Disc Degeneration Through Regulating IGF-1/AKT/IRS-1 Signaling Axis

2021 ◽  
Vol 30 ◽  
pp. 096368972110453
Author(s):  
Wen-Cheng Lo ◽  
Chi-Sheng Chiou ◽  
Feng-Chou Tsai ◽  
Chun-Hao Chan ◽  
Samantha Mao ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
In Vivo Studies ◽  
Nicotine Treatment ◽  
Physiological Processes ◽  
Signaling Axis ◽  
Cellular Apoptosis ◽  
Ivd Degeneration ◽  
Dose Dependent

Apart from aging process, adult intervertebral disc (IVD) undergoes various degenerative processes. However, the nicotine has not been well identified as a contributing etiology. According to a few studies, nicotine ingestion through smoking, air or clothing may significantly accumulate in active as well as passive smokers. Since nicotine has been demonstrated to adversely impact various physiological processes, such as sympathetic nervous system, leading to impaired vasculature and cellular apoptosis, we aimed to investigate whether nicotine could induce IVD degeneration. In particular, we evaluated dose-dependent impact of nicotine in vitro to simulate its chronic accumulation, which was later treated by platelet-derived biomaterials (PDB). Further, during in vivo studies, mice were subcutaneously administered with nicotine to examine IVD-associated pathologic changes. The results revealed that nicotine could significantly reduce chondrocytes and chondrogenic indicators (Sox, Col II and aggrecan). Mice with nicotine treatment also exhibited malformed IVD structure with decreased Col II as well as proteoglycans, which was significantly increased after PDB administration for 4 weeks. Mechanistically, PDB significantly restored the levels of IGF-1 signaling proteins, particularly pIGF-1 R, pAKT, and IRS-1, modulating ECM synthesis by chondrocytes. Conclusively, the PDB impart reparative and tissue regenerative processes by inhibiting nicotine-initiated IVD degeneration, through regulating IGF-1/AKT/IRS-1 signaling axis.

scholarly journals Cytotoxic effect of Montivipera bornmuelleri’s venom on cancer cell lines: in vitro and in vivo studies

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9909
Author(s):  
Carol Haddoub ◽  
Mohamad Rima ◽  
Sandrine Heurtebise ◽  
Myriam Lawand ◽  
Dania Jundi ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cell Lines ◽  
Cytotoxic Effect ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
In Vivo Testing ◽  
Murine Fibrosarcoma ◽  
Dose Dependent

Background Montivipera bornmuelleri’s venom has shown immunomodulation of cytokines release in mice and selective cytotoxicity on cancer cells in a dose-dependent manner, highlighting an anticancer potential. Here, we extend these findings by elucidating the sensitivity of murine B16 skin melanoma and 3-MCA-induced murine fibrosarcoma cell lines to M. bornmuelleri’s venom and its effect on tumor growth in vivo. Methods The toxicity of the venom on B16 and MCA cells was assessed using flow cytometry and xCELLigence assays. For in vivo testing, tumor growth was followed in mice after intratumoral venom injection. Results The venom toxicity showed a dose-dependent cell death on both B16 and MCA cells. Interestingly, overexpression of ovalbumin increased the sensitivity of the cells to the venom. However, the venom was not able to eradicate induced-tumor growth when injected at 100 µg/kg. Our study demonstrates a cytotoxic effect of M. bornmuelleri’s venom in vitro which, however, does not translate to an anticancer action in vivo.

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