Improvement of depressive behaviors by nefiracetam is associated with activation of CaM kinases in olfactory bulbectomized mice

Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Japan.
Brain research (Impact Factor: 2.84). 03/2009; 1265:205-14. DOI: 10.1016/j.brainres.2009.02.014
Source: PubMed


Olfactory bulbectomized (OBX) mice exhibit depressive-like behaviors as assessed by the tail suspension test (TST) and the forced swim test (FST). Interestingly, chronic intraperitoneal administration (1 mg/kg/day) of nefiracetam (DM-9384), a prototype cognitive enhancer, significantly improved depressive-like behaviors as well as spatial reference memory assessed by Y-maze task. As previously reported (Moriguchi, S., Han, F., Nakagawasai, O., Tadano, T., Fukunaga, K., 2006. Decreased calcium/calmoculin-dependent protein kinase II and protein kinase C activities mediate impairment of hippocampal long-term potentiation in the olfactory bulbectomized mice. J. Neurochem. 97, 22-29), decreased activities of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) in the hippocampal CA1 region and amygdala were observed in OBX mice. Nefiracetam treatment (1 mg/kg/day) significantly elevated CaMKII but not ERK activities in the amygdala, prefrontal cortex and hippocampal CA1 regions. In addition, we found an elevation of cAMP response element-binding protein (CREB) phosphorylation in the amygdala and prefrontal cortex but not in the hippocampal CA1 region. Increased CREB phosphorylation was associated with activation of CaMKI and CaMKIV as well as CaMKII in these regions. Taken together, in addition to CaMKII, CaMKI and CaMKIV activation mediated by nefiracetam treatment might mediate CREB phosphorylation following chronic nefiracetam treatment, thereby eliciting an anti-depressive and cognition-enhancing effect on OBX mice.

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    • "It has been demonstrated that depressive behavior is associated with the downregulation of the PLC/IP3 pathway (Dwivedi et al., 2005). Previous studies suggest that CaMKIIα is not only involved in the synthesis of BDNF (Chen et al., 2012; Yu et al., 2013) but is also modulated by chronic stress (Suenaga et al., 2006; Barbiero et al., 2007; Han et al., 2009). It has also been demonstrated that SKF83959 promotes both striatal and prefrontal BDNF expression through CaMKIIα activation (Rashid et al., 2007b; Hasbi et al., 2009; Perreault et al., 2013). "
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    ABSTRACT: SKF83959 stimulates the phospholipase Cβ (PLCβ)/inositol phosphate 3 (IP3) pathway, resulting in the activation of Ca(2+)/calmodulin-dependent kinase IIα (CaMKIIα) which affects the synthesis of brain-derived neurotrophic factor (BDNF), a neurotrophic factor critical for the pathophysiology of depression. Previous reports showed that SKF83959 elicited antidepressant activity in the forced swim test (FST) and tail suspension test (TST) as a novel triple reuptake inhibitor. However, there are no studies showing the effects of SKF83959 in a chronic stress model of depression, and the role of PLC/IP3/CaMKIIα/BDNF pathway in the SKF83959-mediated antidepressant effects. In this study, SKF83959 was firstly investigated in the chronic social defeat stress (CSDS) model of depression. The change of hippocampal neurogenesis, dendrite spine density, and BDNF signaling pathway after CSDS and SKF83959 treatment were then investigated. Pharmacological inhibitors and siRNA/shRNA methods were further used to explore the antidepressive mechanisms of SKF83959. We found that SKF83959 produced antidepressant effects in the CSDS model, and also restored the CSDS-induced decrease in hippocampal BDNF signaling pathway, dendritic spine density and neurogenesis. By using various inhibitors and siRNA/shRNA methods, we further demonstrated that the hippocampal dopamine D5 receptor, PLC/IP3/CaMKIIα pathway and BDNF system are all necessary for the SKF83959 effects. These results suggest that SKF83959 can be developed as a novel antidepressant, and produces antidepressant effects via the hippocampal D5/PLC/IP3/CaMKIIα/BDNF pathway. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 12/2014; 18(6). DOI:10.1093/ijnp/pyu096 · 4.01 Impact Factor
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    • "peractivity in the open field test was measured first one week after surgery . The hyperactivity of OBX animals in an open field test is a robust effect that has been shown in our lab alone already for more than 20 separate experiments . Also in mice this phenomena is robust and described often ( Possidente et al . , 1996 ; Zueger et al . , 2005 ; Han et al . , 2009 ) . A large number of studies in rat and mouse have shown that OBX induced hyperactivity is normalized after chronic treatment with antidepressants ( Otmakhova et al . , 1992 ; Cryan et al . , 1998 ; Breuer et al . , 2007 ; Jarosik et al . , 2007 ; Roche et al . , 2007 ) . As in humans , the antidepressant treatment is not acutely effec"
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    ABSTRACT: Olfactory bulbectomy (OBX), the surgical removal of the olfactory bulbs, lead, both in mice and rats, to a specific set of behavioral changes in social behavior, cognitive function and activity. The latter is often used as a readout measure to predict antidepressant effects of new compounds. More recently, the model is used to study neurodegeneration and the associated cognitive decline. Although most of the OBX-induced behavioral and neurochemical changes seen in mice and rats are very similar, there are also some remarkable differences. For instance, OBX has different effects on BDNF and the 5-HT2c receptor of these two species. These species differ also in how they respond to certain treatments after OBX. In this review we describe these species-specific differences and discuss what they may mean in terms of translational value. Copyright © 2014. Published by Elsevier B.V.
    European Journal of Pharmacology 11/2014; 753. DOI:10.1016/j.ejphar.2014.10.033 · 2.53 Impact Factor
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    • "Interestingly, OBX animals show sensitivity to antidepressant treatments only after repeated administration, similar to the human condition, a feature that increases the validity of this animal model (Mar et al., 2002; Wang et al., 2007). The OBX surgical procedure consistently induces depression-like behaviors in diverse behavioral tests (Song et al., 1996; Wang et al., 2007; Tasset et al., 2008; Han et al., 2009). However, a comparative analysis of various behavioral tests that measure emotionality in the same cohort of OBX animals remains to be conducted. "
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    ABSTRACT: Disturbances in olfactory circuitry have been associated with depression in humans. The removal of olfactory bulbs (OBX lesion) has been largely used as a model of depression-like behavior in the rat. However, quantitative neuronal rearrangements in key brain regions in this animal model have not been evaluated yet. Accordingly, we investigated changes in hippocampal plasticity as well as behavioral deficits in this animal model. OBX-induced behavioral deficits were studied in a battery of tests, namely the open field test (OFT), forced swim test (FST), and spatial memory disturbances in the Morris Water Maze (MWM). To characterize the neuronal remodelling, neuroanatomical rearrangements were investigated in the CA1 hippocampus and piriform cortex, brain regions receiving inputs from the olfactory bulbs and associated with emotional or olfactory processes. Additionally, cell proliferation and survival of newborn cells in the adult dentate gyrus (DG) of hippocampus were also determined. OBX induced hyperlocomotion and enhanced rearing and grooming in the OFT, increased immobility in the FST as well as required a longer time to find the hidden platform in the MWM. OBX also induced dendritic atrophy in the hippocampus and piriform cortex. In addition, cell proliferation was decreased while the survival remained unchanged in the DG of these animals. These various features are also observed in depressed subjects, adding further support to the validity and usefulness of this model to evaluate potential novel antidepressants.
    Neuroscience 01/2013; 236. DOI:10.1016/j.neuroscience.2013.01.037 · 3.36 Impact Factor
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