Improvement of depressive behaviors by nefiracetam is associated with activation of CaM kinases in olfactory bulbectomized mice.
ABSTRACT 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.
- SourceAvailable from: Hendrikus Hendriksen[Show abstract] [Hide abstract]
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; · 2.68 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Depression induces anorexia, leading to suppressed feeding behaviors and energy intake. Previously, we revealed that chronic social defeat induced a mild suppression of feeding in rats with elevated levels of hypothalamic malonyl-CoA which regulates feeding. Therefore, we attempted to elucidate the effects of chronic mild food restriction on behavior and on hypothalamic malonyl-CoA. The chronic mild food restricted rats were fed a restricted diet approximately 80% to 90% amount of diet compared to the control for 5 weeks. Ratios of restriction were adjusted with feed consumption in the chronic social defeat stressed rats. Chronic mild food restricted rats exhibited a suppression of body weight gain similar to that of the chronic social defeat stressed rats. Also these rats showed increased time spent in the center area of an open field (OF), prolonged immobility time in forced swim, increased phosphorylation of hypothalamic adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase and a decreased concentration of hypothalamic malonyl-CoA. Weight of the adrenal glands, locomotion in an OF, mitogen-activated protein kinase cascade and calcium/calmodulin-dependent protein kinases II in the hippocampus were not affected by chronic mild food restriction. Our findings suggest that chronic mild food restriction activates AMPK following a decreased hypothalamic malonyl-CoA.Animal Science Journal 08/2014; · 1.04 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: This study investigated the effects of alcoholic extract of Bacopa monnieri (L.) Wettst. (BM) on cognitive deficits using olfactory bulbectomized (OBX) mice and the underlying molecular mechanisms of its action. OBX mice were treated daily with BM (50 mg/kg, p.o.) or a reference drug, tacrine (2.5 mg/kg, i.p.), 1 week before and continuously 3 days after OBX. Cognitive performance of the animals was analyzed by the novel object recognition test, modified Y maze test, and fear conditioning test. Brain tissues of OBX animals were used for neurochemical and immunohistochemical studies. OBX impaired non-spatial short-term memory, spatial working memory, and long-term fair memory. BM administration ameliorated these memory disturbances. The effect of BM on short-term memory deficits was abolished by a muscarinic receptor antagonist, scopolamine. OBX downregulated phosphorylation of synaptic plasticity-related signaling proteins: NR1 subunit of N-methyl-D-aspartate receptor, glutamate receptor 1 (GluR1), and calmodulin-dependent kinase II but not cyclic AMP-responsive element binding protein (CREB), and reduced brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus. OBX also reduced choline acetyltransferase in the hippocampus and cholinergic neurons in the medial septum, and enlarged the size of lateral ventricle. BM administration reversed these OBX-induced neurochemical and histological alterations, except the decrease of GluR1 phosphorylation, and enhanced CREB phosphorylation. Moreover, BM treatment inhibited ex vivo activity of acetylcholinesterase in the brain. These results indicate that BM treatment ameliorates OBX-induced cognition dysfunction via a mechanism involving enhancement of synaptic plasticity-related signaling and BDNF transcription and protection of cholinergic systems from OBX-induced neuronal damage.Neurochemical Research 08/2013; · 2.55 Impact Factor