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Article ; Online: From Ketamine to Drugs Targeting Subtype-Selective Benzodiazepine Site-Containing Gamma-Aminobutyric Acid A Receptors as Novel Rapid-Acting Antidepressants.

Carreno, Flavia Regina

2022 Volume 92, Issue 3, Page(s) 175–176

MeSH term(s)	Antidepressive Agents/pharmacology ; Benzodiazepines ; Ketamine/pharmacology ; Receptors, GABA-A ; gamma-Aminobutyric Acid
Chemical Substances	Antidepressive Agents ; Receptors, GABA-A ; Benzodiazepines (12794-10-4) ; gamma-Aminobutyric Acid (56-12-2) ; Ketamine (690G0D6V8H)
Language	English
Publishing date	2022-07-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Comment
ZDB-ID	209434-4
ISSN	1873-2402 ; 0006-3223
ISSN (online)	1873-2402
ISSN	0006-3223
DOI	10.1016/j.biopsych.2022.05.018
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Article ; Online: Mechanisms associated with the antidepressant-like effects of L-655,708.

Bugay, Vladislav / McCoy, Alexandra Maxine / Lodge, Daniel James / Brenner, Robert / Frazer, Alan / Carreno, Flavia Regina

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2020 Volume 45, Issue 13, Page(s) 2289–2298

Abstract: Previous research has demonstrated that selective modulation of hippocampal transmission by systemic administration of an α5- ... ...

Abstract	Previous research has demonstrated that selective modulation of hippocampal transmission by systemic administration of an α5-GABA
MeSH term(s)	Animals ; Antidepressive Agents/pharmacology ; Hippocampus ; Imidazoles ; Ketamine/pharmacology ; Rats
Chemical Substances	Antidepressive Agents ; Imidazoles ; L 655,708 ; Ketamine (690G0D6V8H)
Language	English
Publishing date	2020-07-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	639471-1
ISSN	1740-634X ; 0893-133X
ISSN (online)	1740-634X
ISSN	0893-133X
DOI	10.1038/s41386-020-0772-2
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Article ; Online: Activation of signaling pathways downstream of the brain-derived neurotrophic factor receptor, TrkB, in the rat brain by vagal nerve stimulation and antidepressant drugs.

Carreno, Flavia Regina / Frazer, Alan

The international journal of neuropsychopharmacology

2014 Volume 17, Issue 2, Page(s) 247–258

Abstract: Vagal nerve stimulation (VNS) has been approved for treatment resistant depression (TRD) by the Food and Drug Administration (FDA) since 2005. However, the cellular and molecular targets responsible for its effects are still not characterized. Previously, ...

Abstract	Vagal nerve stimulation (VNS) has been approved for treatment resistant depression (TRD) by the Food and Drug Administration (FDA) since 2005. However, the cellular and molecular targets responsible for its effects are still not characterized. Previously, chronic administration of VNS to rats was found to phosphorylate tyrosine 515 on TrkB, the neurotrophin receptor, whereas traditional antidepressants did not do this. In the present study, Western blot analysis was used to characterize activation due to phosphorylation in the hippocampus of down-stream pathways linked to specific key tyrosine residues on TrkB (namely Y816 and Y515) after either acute or chronic administration of VNS and traditional antidepressant drugs. Chronic administration of VNS caused phosphorylation of effectors linked to Y 515; namely Akt, ERK and p70S6 kinase, but this was not produced by either desipramine or sertraline. All the treatments, when given chronically, caused phosphorylation of the transcription factor, CREB. Acute administration of all the treatments also caused phosphorylation of PLCγ1 but this was not maintained with chronic treatment. Further research is required to determine what role, if any, activation of down-stream targets of Y515 plays in the behavioural effects of VNS.
MeSH term(s)	Animals ; Antidepressive Agents/pharmacology ; Brain/drug effects ; Brain/metabolism ; Electrodes, Implanted ; Male ; Phosphorylation/physiology ; Rats ; Rats, Sprague-Dawley ; Receptor, trkB/metabolism ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Vagus Nerve Stimulation/methods
Chemical Substances	Antidepressive Agents ; Receptor, trkB (EC 2.7.10.1)
Language	English
Publishing date	2014-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1440129-0
ISSN	1469-5111 ; 1461-1457
ISSN (online)	1469-5111
ISSN	1461-1457
DOI	10.1017/S1461145713000977
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Article ; Online: Intracerebroventricular losartan infusion modulates angiotensin II type 1 receptor expression in the subfornical organ and drinking behaviour in bile-duct-ligated rats.

Walch, Joseph D / Carreño, Flávia Regina / Cunningham, J Thomas

Experimental physiology

2012 Volume 98, Issue 4, Page(s) 922–933

Abstract: Bile duct ligation (BDL) causes congestive liver failure that initiates haemodynamic changes, including peripheral vasodilatation and generalized oedema. Peripheral vasodilatation is hypothesized to activate compensatory mechanisms, including increased ... ...

Abstract	Bile duct ligation (BDL) causes congestive liver failure that initiates haemodynamic changes, including peripheral vasodilatation and generalized oedema. Peripheral vasodilatation is hypothesized to activate compensatory mechanisms, including increased drinking behaviour and neurohumoral activation. This study tested the hypothesis that changes in the expression of angiotensin II type 1 receptor (AT(1)R) mRNA and protein in the lamina terminalis are associated with BDL-induced hyposmolality in the rat. All rats received either BDL or sham-ligation surgery. The rats were housed in metabolic chambers for measurement of fluid and food intake and urine output. Expression of AT(1)R in the lamina terminalis was assessed by Western blot and quantitative real-time PCR (RT-qPCR). Average baseline water intake increased significantly in BDL rats compared with sham-operated rats, and upregulation of AT(1)R protein and AT(1a)R mRNA were observed in the subfornical organ of BDL rats. Separate groups of BDL and sham-ligated rats were instrumented with minipumps filled with either losartan (2.0 μg μl(-1)) or 0.9% saline for chronic intracerebroventricular or chronic subcutaneous infusion. Chronic intracerebroventricular losartan infusion attenuated the increased drinking behaviour and prevented the increased abundance of AT(1)R protein in the subfornical organ in BDL rats. Chronic subcutaneous infusion did not affect water intake or AT(1)R abundance in the subfornical organ. The data presented here indicate a possible role of increased central AT(1)R expression in the regulation of drinking behaviour during congestive cirrhosis.
MeSH term(s)	Animals ; Bile Ducts/surgery ; Disease Models, Animal ; Drinking/physiology ; Drinking Behavior/drug effects ; Infusions, Intraventricular ; Ligation/methods ; Liver Cirrhosis/surgery ; Losartan/administration & dosage ; Losartan/pharmacology ; Male ; Rats ; Rats, Sprague-Dawley ; Receptor, Angiotensin, Type 1/metabolism ; Subfornical Organ/drug effects
Chemical Substances	Receptor, Angiotensin, Type 1 ; Losartan (JMS50MPO89)
Language	English
Publishing date	2012-12-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1016295-1
ISSN	1469-445X ; 0958-0670
ISSN (online)	1469-445X
ISSN	0958-0670
DOI	10.1113/expphysiol.2012.068593
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Article: Therapeutic modalities for treatment resistant depression: focus on vagal nerve stimulation and ketamine.

Shah, Aparna / Carreno, Flavia Regina / Frazer, Alan

Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology

2014 Volume 12, Issue 2, Page(s) 83–93

Abstract: Treatment resistant depression (TRD) is a global health concern affecting a large proportion of depressed patients who then require novel therapeutic options. One such treatment option that has received some attention in the past several years is vagal ... ...

Abstract	Treatment resistant depression (TRD) is a global health concern affecting a large proportion of depressed patients who then require novel therapeutic options. One such treatment option that has received some attention in the past several years is vagal nerve stimulation (VNS). The present review briefly describes the relevance of this treatment in the light of other existing pharmacological and non-pharmacological options. It then summarizes clinical findings with respect to the efficacy of VNS. The anatomical rationale for its efficacy and other potential mechanisms of its antidepressant effects as compared to those employed by classical antidepressant drugs are discussed. VNS has been approved in some countries and has been used for patients with TRD for quite some time. A newer, fast-acting, non-invasive pharmacological option called ketamine is currently in the limelight with reference to TRD. This drug is currently in the investigational phase but shows promise. The clinical and preclinical findings related to ketamine have also been summarized and compared with those for VNS. The role of neurotrophin factors, specifically brain derived neurotrophic factor and its receptor, in the beneficial effects of both VNS and ketamine have been highlighted. It can be concluded that both these therapeutic modalities, while effective, need further research that can reveal specific targets for intervention by novel drugs and address concerns related to side-effects, especially those seen with ketamine.
Language	English
Publishing date	2014-08-12
Publishing country	Korea (South)
Document type	Journal Article ; Review
ZDB-ID	2211550-X
ISSN	1738-1088
ISSN	1738-1088
DOI	10.9758/cpn.2014.12.2.83
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Zs.A 6227: Show issues

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Article ; Online: Vagal nerve stimulation rapidly activates brain-derived neurotrophic factor receptor TrkB in rat brain.

Furmaga, Havan / Carreno, Flavia Regina / Frazer, Alan

PloS one

2012 Volume 7, Issue 5, Page(s) e34844

Abstract: Background: Vagal nerve stimulation (VNS) has been approved for treatment-resistant depression. Many antidepressants increase expression of brain-derived neurotrophic factor (BDNF) in brain or activate, via phosphorylation, its receptor, TrkB. There ... ...

Abstract	Background: Vagal nerve stimulation (VNS) has been approved for treatment-resistant depression. Many antidepressants increase expression of brain-derived neurotrophic factor (BDNF) in brain or activate, via phosphorylation, its receptor, TrkB. There have been no studies yet of whether VNS would also cause phosphorylation of TrkB. Methods: Western blot analysis was used to evaluate the phosphorylation status of TrkB in the hippocampus of rats administered VNS either acutely or chronically. Acute effects of VNS were compared with those caused by fluoxetine or desipramine (DMI) whereas its chronic effects were compared with those of sertraline or DMI. Results: All treatments, given either acutely or chronically, significantly elevated phosphorylation of tyrosines 705 and 816 on TrkB in the hippocampus. However, only VNS increased the phosphorylation of tyrosine 515, with both acute and chronic administration causing this effect. Pretreatment with K252a, a nonspecific tyrosine kinase inhibitor, blocked the phosphorylation caused by acute VNS at all three tyrosines. Downstream effectors of Y515, namely Akt and ERK, were also phosphorylated after acute treatment with VNS, whereas DMI did not cause this effect. Conclusion: VNS rapidly activates TrkB phosphorylation and this effect persists over time. VNS-induced phosphorylation of tyrosine 515 is distinct from the effect of standard antidepressant drugs.
MeSH term(s)	Adrenergic Uptake Inhibitors/pharmacology ; Animals ; Blotting, Western ; Brain/drug effects ; Brain/metabolism ; Carbazoles/pharmacology ; Desipramine/pharmacology ; Enzyme Inhibitors/pharmacology ; Fluoxetine/pharmacology ; Hippocampus/drug effects ; Hippocampus/metabolism ; Indole Alkaloids/pharmacology ; Male ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor, trkB/metabolism ; Serotonin Uptake Inhibitors/pharmacology ; Time Factors ; Tyrosine/metabolism ; Vagus Nerve/drug effects ; Vagus Nerve/physiology ; Vagus Nerve Stimulation/methods
Chemical Substances	Adrenergic Uptake Inhibitors ; Carbazoles ; Enzyme Inhibitors ; Indole Alkaloids ; Serotonin Uptake Inhibitors ; Fluoxetine (01K63SUP8D) ; Tyrosine (42HK56048U) ; staurosporine aglycone (97161-97-2) ; Receptor, trkB (EC 2.7.10.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Desipramine (TG537D343B)
Language	English
Publishing date	2012-05-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0034844
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Article: Altered central TRPV4 expression and lipid raft association related to inappropriate vasopressin secretion in cirrhotic rats.

Carreño, Flávia Regina / Ji, Lisa L / Cunningham, J Thomas

American journal of physiology. Regulatory, integrative and comparative physiology

2008 Volume 296, Issue 2, Page(s) R454–66

Abstract: Inappropriate vasopressin (AVP) release causes dilutional hyponatremia in many pathophysiological states such as cirrhosis. The central molecular mechanisms that mediate inappropriate AVP release are unknown. We tested the hypothesis that changes in the ... ...

Abstract	Inappropriate vasopressin (AVP) release causes dilutional hyponatremia in many pathophysiological states such as cirrhosis. The central molecular mechanisms that mediate inappropriate AVP release are unknown. We tested the hypothesis that changes in the expression or trafficking of TRPV4 in the central nervous system may contribute to inappropriate AVP release in the bile duct ligation (BDL) model of cirrhosis in the rat. Four weeks after surgery, BDL rats demonstrated significantly increased plasma vasopressin and plasma renin activity (PRA), hypervolemia, and decreased plasma osmolality. These effects were blocked by providing BDL rats with 2% saline to drink for 15 days. TRPV4 protein expression was significantly increased in brain punches from BDL rats containing the supraoptic nucleus (SON) of the hypothalamus (100% +/- 11 to 157% +/- 4.8), and this effect was blocked in BDL rats given saline. Immunohistochemistry demonstrated a significant increase in TRPV4-positive cells and the percentage of AVP neurons that also were TRPV4-positive in the SON of BDL rats. In the hypothalamus of BDL rats, TRPV4 lipid raft association increased compared with sham (from 100% +/- 2.1 to 326.1% +/- 16). This effect was significantly attenuated in BDL rats given 2% saline to drink (174% +/- 11). In the brain stem, TRPV4 lipid raft association was reduced by BDL and inversely related to plasma AVP and PRA. We speculate that changes in TRPV4 expression and compartmentalization within lipid rafts could contribute to a feed-forward mechanism related to AVP release in cirrhosis.
MeSH term(s)	Animals ; Arginine Vasopressin/blood ; Arginine Vasopressin/metabolism ; Blotting, Western ; Brain/metabolism ; Brain/physiopathology ; Brain Stem/metabolism ; Common Bile Duct/surgery ; Disease Models, Animal ; Drinking ; Hematocrit ; Immunohistochemistry ; Inappropriate ADH Syndrome/blood ; Inappropriate ADH Syndrome/metabolism ; Inappropriate ADH Syndrome/physiopathology ; Ligation ; Liver Cirrhosis, Experimental/blood ; Liver Cirrhosis, Experimental/metabolism ; Liver Cirrhosis, Experimental/physiopathology ; Male ; Membrane Microdomains/metabolism ; Neurons/metabolism ; Osmolar Concentration ; Rats ; Rats, Sprague-Dawley ; Renin/blood ; Supraoptic Nucleus/metabolism ; TRPV Cation Channels/metabolism ; Water-Electrolyte Balance
Chemical Substances	TRPV Cation Channels ; Trpv4 protein, rat ; Arginine Vasopressin (113-79-1) ; Renin (EC 3.4.23.15)
Language	English
Publishing date	2008-12-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	603839-6
ISSN	1522-1490 ; 0363-6119
ISSN (online)	1522-1490
ISSN	0363-6119
DOI	10.1152/ajpregu.90460.2008
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Article ; Online: Vagal nerve stimulation rapidly activates brain-derived neurotrophic factor receptor TrkB in rat brain.

Havan Furmaga / Flavia Regina Carreno / Alan Frazer

PLoS ONE, Vol 7, Iss 5, p e

2012 Volume 34844

Abstract: Vagal nerve stimulation (VNS) has been approved for treatment-resistant depression. Many antidepressants increase expression of brain-derived neurotrophic factor (BDNF) in brain or activate, via phosphorylation, its receptor, TrkB. There have been no ... ...

Abstract	Vagal nerve stimulation (VNS) has been approved for treatment-resistant depression. Many antidepressants increase expression of brain-derived neurotrophic factor (BDNF) in brain or activate, via phosphorylation, its receptor, TrkB. There have been no studies yet of whether VNS would also cause phosphorylation of TrkB.Western blot analysis was used to evaluate the phosphorylation status of TrkB in the hippocampus of rats administered VNS either acutely or chronically. Acute effects of VNS were compared with those caused by fluoxetine or desipramine (DMI) whereas its chronic effects were compared with those of sertraline or DMI.All treatments, given either acutely or chronically, significantly elevated phosphorylation of tyrosines 705 and 816 on TrkB in the hippocampus. However, only VNS increased the phosphorylation of tyrosine 515, with both acute and chronic administration causing this effect. Pretreatment with K252a, a nonspecific tyrosine kinase inhibitor, blocked the phosphorylation caused by acute VNS at all three tyrosines. Downstream effectors of Y515, namely Akt and ERK, were also phosphorylated after acute treatment with VNS, whereas DMI did not cause this effect.VNS rapidly activates TrkB phosphorylation and this effect persists over time. VNS-induced phosphorylation of tyrosine 515 is distinct from the effect of standard antidepressant drugs.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article: Cell junctions in the germinal epithelium may play an important role in spermatogenesis of the catfish P. fasciatum (Pisces, Siluriformes).

Batlouni, Sergio Ricardo / Carreño, Flávia Regina / Romagosa, Elizabeth / Borella, Maria Inês

Journal of molecular histology

2005 Volume 36, Issue 1-2, Page(s) 97–110

Abstract: We identified adhesive junctions and gap junctions between Sertoli cells, between Sertoli and germ cells and between germ cells in the testis of P. fasciatum, a catfish of commercial relevance. To investigate the role of these junctions in ... ...

Abstract	We identified adhesive junctions and gap junctions between Sertoli cells, between Sertoli and germ cells and between germ cells in the testis of P. fasciatum, a catfish of commercial relevance. To investigate the role of these junctions in spermatogenesis, as well as the molecular composition of the junctions, we performed an immunohistochemistry light microscopy as well as an immunogold labelling electron microscopy study with antibodies to adhesive and gap junctions proteins. Testes that were at different stages of spermatogenesis were used. Based on our morphological studies we speculate that Sertoli-germ and germ-germ cell adhesive junctions are important for maintaining the three-dimensional structure of the germinal cysts and an organized arrangement of the germ cells inside the cysts. Connexin 32 was identified in the germ cells and in the cysts walls. Our observations also suggest that Sertoli-germ and germ-germ cells gap junctions may be involved in the mechanism of synchronous development of germ cells.
MeSH term(s)	Adherens Junctions/chemistry ; Adherens Junctions/ultrastructure ; Animals ; Catfishes/anatomy & histology ; Catfishes/physiology ; Cell Adhesion Molecules/analysis ; Connexins/analysis ; Cytoskeletal Proteins/analysis ; Epithelium/ultrastructure ; Gap Junctions/chemistry ; Gap Junctions/ultrastructure ; Male ; Sertoli Cells/chemistry ; Sertoli Cells/cytology ; Sertoli Cells/ultrastructure ; Spermatogenesis ; Testis/cytology
Chemical Substances	Cell Adhesion Molecules ; Connexins ; Cytoskeletal Proteins
Language	English
Publishing date	2005-02
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2144021-9
ISSN	1567-2379
ISSN	1567-2379
DOI	10.1007/s10735-004-4115-0
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Article: Cloning and expression of calglandulin, a new EF-hand protein from the venom glands of Bothrops insularis snake in E. coli.

Junqueira-de-Azevedo, Inácio de L M / Pertinhez, Thelma / Spisni, Alberto / Carreño, Flávia Regina / Farah, Chuck S / Ho, Paulo Lee

Biochimica et biophysica acta

2003 Volume 1648, Issue 1-2, Page(s) 90–98

Abstract: The EF-hand protein family is comprised of many proteins with conserved Ca(2+)-binding motifs with important biological roles in intracellular communication. During the generation of Expressed Sequence Tags (ESTs) from the venom glands of the Viperidae ... ...

Abstract	The EF-hand protein family is comprised of many proteins with conserved Ca(2+)-binding motifs with important biological roles in intracellular communication. During the generation of Expressed Sequence Tags (ESTs) from the venom glands of the Viperidae snake Bothrops insularis, we identified a cDNA coding for a putative Ca(2+) binding protein with four EF-hand motifs, named here calglandulin. The deduced amino acid sequence displayed the greatest sequence similarity with calmodulin (59%), followed by troponin-C (52%). The encoded polypeptide was first expressed in Escherichia coli as a 6XHis-tagged fusion protein. The expressed protein was purified by Ni(2+)-charged affinity chromatography and circular dichroism (CD) spectroscopy confirmed the prevalence of alpha-helix as observed in calmodulin/calmodulin-like proteins. A polyclonal antiserum was generated in mice using this recombinant calglandulin. To investigate the tissue-specific biological occurrence of this protein, this antiserum was used in Western blot experiments, which revealed an immunoreactive band in samples of venom gland extracts from different snakes, but not in the crude venom or in brain, heart and other tissues. This exclusive occurrence suggests a specialized function of calglandulin in snake venom glands.
MeSH term(s)	Amino Acid Sequence ; Animals ; Base Sequence ; Bothrops/genetics ; Bothrops/metabolism ; Cloning, Molecular ; Crotalid Venoms/chemistry ; Crotalid Venoms/genetics ; Crotalid Venoms/metabolism ; Escherichia coli ; Molecular Sequence Data ; Organ Specificity ; Phylogeny ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Recombinant Proteins/biosynthesis ; Recombinant Proteins/genetics ; Sequence Alignment
Chemical Substances	Crotalid Venoms ; Recombinant Proteins ; calglandulin, Bothrops insularis
Language	English
Publishing date	2003-05-14
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/s1570-9639(03)00111-0
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