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  1. Article ; Online: Facilitation of TRKB Activation by the Angiotensin II Receptor Type-2 (AT2R) Agonist C21

    Liina Laukkanen / Cassiano R. A. F. Diniz / Sebastien Foulquier / Jos Prickaerts / Eero Castrén / Plinio C. Casarotto

    Pharmaceuticals, Vol 14, Iss 773, p

    2021  Volume 773

    Abstract: Blockers of angiotensin II type 1 receptor (AT1R) exert antidepressant-like effects by indirectly facilitating the activation of the angiotensin II type 2 receptor (AT2R), which leads to increased surface expression and transactivation of tropomyosin- ... ...

    Abstract Blockers of angiotensin II type 1 receptor (AT1R) exert antidepressant-like effects by indirectly facilitating the activation of the angiotensin II type 2 receptor (AT2R), which leads to increased surface expression and transactivation of tropomyosin-related kinase B receptors (TRKB). Compound 21 (C21) is a non-peptide AT2R agonist that produces neuroprotective effects. However, the behavioral effects of C21 and its involvement with the brain-derived neurotrophic factor (BDNF)-TRKB system still need further investigation. The aim of the present study was to assess the effect of C21 on the activation of TRKB and its consequences on conditioned fear. The administration of C21 (0.1–10 μM/15 min) increased the surface levels of TRKB but was not sufficient to increase the levels of phosphorylated TRKB (pTRKB) in cultured cortical neurons from rat embryos. Consistent with increased TRKB surface expression, C21 (10 μM/15 min or 3 days) facilitated the effect of BDNF (0.1 ng/mL/15 min) on pTRKB in these cells. In contextual fear conditioning, the freezing time of C21-treated (administered intranasally) wild-type mice was decreased compared to the vehicle-treated group, but no effect of C21 was observed in BDNF.het animals. We observed no effect of C21 in the elevated plus-maze test for anxiety. Taken together, our results indicate that C21 facilitated BDNF effect by increasing the levels of TRKB on the cell surface and reduced the freezing time of mice in a BDNF-dependent manner, but not through a general anxiolytic-like effect.
    Keywords compound 21 ; angiotensin 2 type 2 receptor (AT2R) ; neurotrophin receptor type 2 (NTRK2) ; renin-angiotensin system (RAS) ; fear conditioning ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
    Subject code 571
    Language English
    Publishing date 2021-08-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Reduced P2X receptor levels are associated with antidepressant effect in the learned helplessness model

    Deidiane Elisa Ribeiro / Plinio C. Casarotto / Laura Staquini / Maria Augusta Pinto e Silva / Caroline Biojone / Gregers Wegener / Samia Joca

    PeerJ, Vol 7, p e

    2019  Volume 7834

    Abstract: Purinergic receptors, especially P2RX, are associated to the severity of symptoms in patients suffering from depressive and bipolar disorders, and genetic deletion or pharmacological blockade of P2RX7 induces antidepressant-like effect in preclinical ... ...

    Abstract Purinergic receptors, especially P2RX, are associated to the severity of symptoms in patients suffering from depressive and bipolar disorders, and genetic deletion or pharmacological blockade of P2RX7 induces antidepressant-like effect in preclinical models. However, there is scarce evidence about the alterations in P2RX7 or P2RX4 levels and in behavioral consequences induced by previous exposure to stress, a major risk factor for depression in humans. In the present study, we evaluated the effect of imipramine (IMI) on P2RX7 and P2RX4 levels in dorsal and ventral hippocampus as well as in the frontal cortex of rats submitted to the pretest session of learned helplessness (LH) paradigm. Repeated, but not acute administration of IMI (15 mg/kg ip) reduced the levels of both P2RX7 and P2RX4 in the ventral, but not in dorsal hippocampus or frontal cortex. In addition, we tested the effect of P2RX7/P2RX4 antagonist brilliant blue G (BBG: 25 or 50 mg/kg ip) on the LH paradigm. We observed that repeated (7 days) but not acute (1 day) treatment with BBG (50 mg) reduced the number of failures to escape the shocks in the test session, a parameter mimicked by the same regimen of IMI treatment. Taken together, our data indicates that pharmacological blockade or decrease in the expression of P2RX7 is associated to the antidepressant-like behavior observed in the LH paradigm after repeated drug administration.
    Keywords P2X7 receptor ; P2X4 receptor ; Learned helplessness ; Brilliant blue G ; Imipramine ; Medicine ; R ; Biology (General) ; QH301-705.5
    Subject code 150
    Language English
    Publishing date 2019-10-01T00:00:00Z
    Publisher PeerJ Inc.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Inducible nitric oxide synthase (NOS2) knockout mice as a model of trichotillomania

    Plinio C. Casarotto / Caroline Biojone / Karina Montezuma / Fernando Q. Cunha / Samia R.L. Joca / Eero Castren / Francisco S. Guimaraes

    PeerJ, Vol 6, p e

    2018  Volume 4635

    Abstract: Background Trichotillomania (TTM) is an impulse control disorder characterized by repetitive hair pulling/trimming. Barbering behavior (BB) observed in laboratory animals is proposed as a model of TTM. The neurobiological basis of TTM is unclear, but ... ...

    Abstract Background Trichotillomania (TTM) is an impulse control disorder characterized by repetitive hair pulling/trimming. Barbering behavior (BB) observed in laboratory animals is proposed as a model of TTM. The neurobiological basis of TTM is unclear, but involves striatal hyperactivity and hypoactivation of the prefrontal cortex. Methods In this study, we evaluated the BB in knockout mice for the inducible isoform of nitric oxide synthase (NOS2KO) and the consequences of silencing this enzyme in PC12 cell differentiation. Results NOS2KO exhibit exacerbated BB, starting four weeks of age, and increased repetitive movements compared to wild-type mice (WT). The expression of BB was attenuated by repeated treatment with clomipramine, a clinically approved drug to treat TTM in humans, or memantine, an antagonist of NMDA receptors, as well as partial rescue of NOS2 expression in haploinsufficient animals. The silencing of NOS2 expression reduced the MAP2 (microtubule-associated protein 2) levels in activity-induced differentiated PC12 cells. Discussion Our data led us to propose that NOS2 is putatively involved in the neuronal maturation of the inhibitory afferent pathways during neurodevelopment, and such inadequate inhibition of motor programs might be associated to the observed phenotype.
    Keywords Trichotillomania ; Barbering ; NOS2 ; Memantine ; Clomipramine ; Medicine ; R ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2018-04-01T00:00:00Z
    Publisher PeerJ Inc.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Dual mechanism of TRKB activation by anandamide through CB1 and TRPV1 receptors

    Cassiano R.A.F. Diniz / Caroline Biojone / Samia R.L. Joca / Tomi Rantamäki / Eero Castrén / Francisco S. Guimarães / Plinio C. Casarotto

    PeerJ, Vol 7, p e

    2019  Volume 6493

    Abstract: Background Administration of anandamide (AEA) or 2-arachidonoylglycerol (2AG) induces CB1 coupling and activation of TRKB receptors, regulating the neuronal migration and maturation in the developing cortex. However, at higher concentrations AEA also ... ...

    Abstract Background Administration of anandamide (AEA) or 2-arachidonoylglycerol (2AG) induces CB1 coupling and activation of TRKB receptors, regulating the neuronal migration and maturation in the developing cortex. However, at higher concentrations AEA also engages vanilloid receptor TRPV1, usually with opposed consequences on behavior. Methods and Results Using primary cell cultures from the cortex of rat embryos (E18) we determined the effects of AEA on phosphorylated TRKB (pTRK). We observed that AEA (at 100 and 200 nM) induced a significant increase in pTRK levels. Such effect of AEA at 100 nM was blocked by pretreatment with the CB1 antagonist AM251 (200 nM) and, at the higher concentration of 200 nM by the TRPV1 antagonist capsazepine (200 nM), but mildly attenuated by AM251. Interestingly, the effect of AEA or capsaicin (a TRPV1 agonist, also at 200 nM) on pTRK was blocked by TRKB.Fc (a soluble form of TRKB able to bind BDNF) or capsazepine, suggesting a mechanism dependent on BDNF release. Using the marble-burying test (MBT) in mice, we observed that the local administration of ACEA (a CB1 agonist) into the prelimbic region of prefrontal cortex (PL-PFC) was sufficient to reduce the burying behavior, while capsaicin or BDNF exerted the opposite effect, increasing the number of buried marbles. In addition, both ACEA and capsaicin effects were blocked by previous administration of k252a (an antagonist of TRK receptors) into PL-PFC. The effect of systemically injected CB1 agonist WIN55,212-2 was blocked by previous administration of k252a. We also observed a partial colocalization of CB1/TRPV1/TRKB in the PL-PFC, and the localization of TRPV1 in CaMK2+ cells. Conclusion Taken together, our data indicate that anandamide engages a coordinated activation of TRKB, via CB1 and TRPV1. Thus, acting upon CB1 and TRPV1, AEA could regulate the TRKB-dependent plasticity in both pre- and postsynaptic compartments.
    Keywords TRPV1 ; CB1 ; BDNF ; Marble-burying ; Medicine ; R ; Biology (General) ; QH301-705.5
    Subject code 500
    Language English
    Publishing date 2019-02-01T00:00:00Z
    Publisher PeerJ Inc.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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    Inter-library loan at ZB MED

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