TY  - JOUR
A1  - Strekalova, Tatyana
A1  - Pavlov, Dmitrii
A1  - Trofimov, Alexander
A1  - Anthony, Daniel C.
A1  - Svistunov, Andrei
A1  - Proshin, Andrey
A1  - Umriukhin, Aleksei
A1  - Lyundup, Alexei
A1  - Lesch, Klaus-Peter
A1  - Cespuglio, Raymond
T1  - Hippocampal over-expression of cyclooxygenase-2 (COX-2) is associated with susceptibility to stress-induced anhedonia in mice
JF  - International Journal of Molecular Sciences
N2  - The phenomenon of individual variability in susceptibility/resilience to stress and depression, in which the hippocampus plays a pivotal role, is attracting increasing attention. We investigated the potential role of hippocampal cyclooxygenase-2 (COX-2), which regulates plasticity, neuroimmune function, and stress responses that are all linked to this risk dichotomy. We used a four-week-long chronic mild stress (CMS) paradigm, in which mice could be stratified according to their susceptibility/resilience to anhedonia, a key feature of depression, to investigate hippocampal expression of COX-2, a marker of microglial activation Iba-1, and the proliferation marker Ki67. Rat exposure, social defeat, restraints, and tail suspension were used as stressors. We compared the effects of treatment with either the selective COX-2 inhibitor celecoxib (30 mg/kg/day) or citalopram (15 mg/kg/day). For the celecoxib and vehicle-treated mice, the Porsolt test was used. Anhedonic (susceptible) but not non-anhedonic (resilient) animals exhibited elevated COX-2 mRNA levels, increased numbers of COX-2 and Iba-1-positive cells in the dentate gyrus and the CA1 area, and decreased numbers of Ki67-positive cells in the subgranular zone of the hippocampus. Drug treatment decreased the percentage of anhedonic mice, normalized swimming activity, reduced behavioral despair, and improved conditioned fear memory. Hippocampal over-expression of COX-2 is associated with susceptibility to stress-induced anhedonia, and its pharmacological inhibition with celecoxib has antidepressant effects that are similar in size to those of citalopram.
KW  - major depression
KW  - inducible cyclooxygenase-2 (COX-2)
KW  - hippocampus
KW  - anhedonia
KW  - chronic stress
KW  - stress resilience
KW  - fear conditioning
KW  - celecoxib
KW  - citalopram
KW  - mouse
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284056
SN  - 1422-0067
VL  - 23
IS  - 4
ER  - 
TY  - JOUR
A1  - Cline, Brandon H.
A1  - Costa-Nunes, Joao P.
A1  - Cespuglio, Raymond
A1  - Markova, Natalyia
A1  - Santos, Ana I.
A1  - Bukhman, Yury V.
A1  - Kubatiev, Aslan
A1  - Steinbusch, Harry W. M.
A1  - Lesch, Klaus-Peter
A1  - Strekalova, Tatyana
T1  - Dicholine succinate, the neuronal insulin sensitizer, normalizes behavior, REM sleep, hippocampal pGSK3 beta and mRNAs of NMDA receptor subunits in mouse models of depression
JF  - Frontiers in Behavioral Neuroscience
N2  - Central insulin receptor-mediated signaling is attracting the growing attention of researchers because of rapidly accumulating evidence implicating it in the mechanisms of plasticity, stress response, and neuropsychiatric disorders including depression. Dicholine succinate (DS), a mitochondrial complex II substrate, was shown to enhance insulin-receptor mediated signaling in neurons and is regarded as a sensitizer of the neuronal insulin receptor. Compounds enhancing neuronal insulin receptor-mediated transmission exert an antidepressant-like effect in several pre-clinical paradigms of depression; similarly, such properties for DS were found with a stress-induced anhedonia model. Here, we additionally studied the effects of DS on several variables which were ameliorated by other insulin receptor sensitizers in mice. Pre-treatment with DS of chronically stressed C57BL6 mice rescued normal contextual fear conditioning, hippocampal gene expression of NMDA receptor subunit NR2A, the NR2A/NR2B ratio and increased REM sleep rebound after acute predation. In 18-month-old C57BL6 mice, a model of elderly depression, DS restored normal sucrose preference and activated the expression of neural plasticity factors in the hippocampus as shown by Illumina microarray. Finally, young naive DS-treated C57BL6 mice had reduced depressive- and anxiety-like behaviors and, similarly to imipramine-treated mice, preserved hippocampal levels of the phosphorylated (inactive) form of GSK3 beta that was lowered by forced swimming in pharmacologically naive animals. Thus, DS can ameliorate behavioral and molecular outcomes under a variety of stress- and depression-related conditions. This further highlights neuronal insulin signaling as a new factor of pathogenesis and a potential pharmacotherapy of affective pathologies.
KW  - phosphorylated glycogen synthase kinase-3beta (pGSK-3beta)
KW  - hippocampal plasticity
KW  - sleep EEG
KW  - aging
KW  - NMDA receptor subunits NR2A and NR2B
KW  - dicholine succinate
KW  - insulin receptor
KW  - chronic stress
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143992
VL  - 9
IS  - 37
ER  -