Molecular and behavioural abnormalities in the FUS‐tg mice mimic frontotemporal lobar degeneration: Effects of old and new anti‐inflammatory therapies

Munter, Johannes de; Babaevskaya, Diana; Wolters, Erik Ch.; Павлов, Д. А.; Lysikova, Ekaterina A.; Kalueff, Allan V.; Gorlova, Anna; Oplatchikova, Margarita; Помыткин, И. А.; Proshin, A. T.; Umriukhin, Aleksei; Lesch, Klaus‐Peter; Strekalova, Tatyana

doi:10.1111/jcmm.15628

Cited by 12 publications

(24 citation statements)

References 17 publications

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“… Alboni et al (2018) found a non-significant tendency of celecoxib to increase the antidepressant effects of fluoxetine when coadministered. de Munter et al (2020) showed that celecoxib did not affect FST-induced despair in WT mice but in a genetic model of frontotemporal lobar degeneration (FUS[1-359]-tg mice) the drug reduced despair. There was also a tendency for celecoxib to reduce IFN-α induced despair in male S-D rats ( Fischer et al, 2015 ).…”

Section: Resultsmentioning

confidence: 99%

Antidepressant Effects of NSAIDs in Rodent Models of Depression—A Systematic Review

Bay-Richter

Wegener

2022

Front. Pharmacol.

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In recent years much focus has been on neuroimmune mechanisms of depression. As a consequence, many preclinical and clinical trials have been performed examining potential antidepressant effects of several anti-inflammatory drugs. The results of such trials have been varied. With the current manuscript we wished to elucidate the effects of non-steroidal anti-inflammatory drugs (NSAIDs) on depressive-like behaviour in rodent models of depression by performing a systematic review of the available literature. We performed a systematic literature search in PubMed for rodent models of depression where NSAIDs were administered and a validated measure of depressive-like behaviour was applied. 858 studies were initially identified and screened using Covidence systematic review software. Of these 36 met the inclusion criteria and were included. The extracted articles contained data from both rat and mouse studies but primarily male animals were used. Several depression models were applied and 17 different NSAIDs were tested for antidepressant effects. Our results suggest that stress models are the best choice when examining antidepressant effects of NSAIDs. Furthermore, we found that rat models provide a more homogenous response than mouse models. Intriguingly, the use of female animals was only reported in three studies and these failed to find antidepressant effects of NSAIDs. This should be explored further. When comparing the different classes of NSAIDs, selective COX-2 inhibitors were shown to provide the most stable antidepressant effect compared to non-selective COX-inhibitors. Suggested mechanisms behind the antidepressant effects were attenuation of neuroinflammation, HPA-axis dysregulation and altered monoamine expression.

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Section: Resultsmentioning

confidence: 99%

Antidepressant Effects of NSAIDs in Rodent Models of Depression—A Systematic Review

Bay-Richter

Wegener

2022

Front. Pharmacol.

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“…We have found that chronic treatment with DF402, a bioisostere of Dimebon, an over‐the‐counter drug that demonstrated a mild ability to suppress pathological changes in several models of neurodegenerative diseases, slowed down the development and progression of the disease in S‐FUS[1–359] mice with a statistically significant prolongation effect observed on all three main parameters, namely time to the disease onset (+11%), disease duration (+24%), and animal lifespan (+13%). Although it is difficult to directly compare results of studies that used different experimental setups and endpoints, the efficacy of chronic administration of a low dose of DF402 via drinking water is comparable and possibly higher than the efficacy of a similar protocol of chronic Riluzole administration to S‐FUS[1–359] mice 59–61 . It should be also noted that chronic administration of Dimebon showed a delayed onset of clinical signs and an increase in lifespan of SOD1(G93A) mouse model of ALS, 28 whereas the efficacy of Riluzole in this model was negligible 62 .…”

Section: Discussionmentioning

confidence: 99%

A bioisostere of Dimebon/Latrepirdine delays the onset and slows the progression of pathology in FUS transgenic mice

et al. 2021

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Aims To assess effects of DF402, a bioisostere of Dimebon/Latrepirdine, on the disease progression in the transgenic model of amyotrophic lateral sclerosis (ALS) caused by expression of pathogenic truncated form of human FUS protein. Methods Mice received DF402 from the age of 42 days and the onset of clinical signs, the disease duration and animal lifespan were monitored for experimental and control animals, and multiple parameters of their gait were assessed throughout the pre‐symptomatic stage using CatWalk system followed by a bioinformatic analysis. RNA‐seq was used to compare the spinal cord transcriptomes of wild‐type, untreated, and DF402‐treated FUS transgenic mice. Results DF402 delays the onset and slows the progression of pathology. We developed a CatWalk analysis protocol that allows detection of gait changes in FUS transgenic mice and the effect of DF402 on their gait already at early pre‐symptomatic stage. At this stage, a limited number of genes significantly change expression in transgenic mice and for 60% of these genes, DF402 treatment causes the reversion of the expression pattern. Conclusion DF402 slows down the disease progression in the mouse model of ALS, which is consistent with previously reported neuroprotective properties of Dimebon and its other bioisosteres. These results suggest that these structures can be considered as lead compounds for further optimization to obtain novel medicines that might be used as components of complex ALS therapy.

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“…A relative optical density of immunoreactive protein bands was examined using ImageJ software (NIH, Bethesda, MD, USA). Results were normalized to the relative intensity of the βtubulin band that was selected as a reference protein as described elsewhere (8,66). Blots were stripped by incubation with Restore Western Blot stripping buffer (Thermo Scientific, Rockford, IL, USA) at room temperature for 15 min.…”

Section: Western Blot Assaymentioning

confidence: 99%

Increased Oxidative Stress in the Prefrontal Cortex as a Shared Feature of Depressive- and PTSD-Like Syndromes: Effects of a Standardized Herbal Antioxidant

et al. 2021

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Major depression (MD) and posttraumatic stress disorder (PTSD) share common brain mechanisms and treatment strategies. Nowadays, the dramatically developing COVID-19 situation unavoidably results in stress, psychological trauma, and high incidence of MD and PTSD. Hence, the importance of the development of new treatments for these disorders cannot be overstated. Herbal medicine appears to be an effective and safe treatment with fewer side effects than classic pharmaca and that is affordable in low-income countries. Currently, oxidative stress and neuroinflammation attract increasing attention as important mechanisms of MD and PTSD. We investigated the effects of a standardized herbal cocktail (SHC), an extract of clove, bell pepper, basil, pomegranate, nettle, and other plants, that was designed as an antioxidant treatment in mouse models of MD and PTSD. In the MD model of “emotional” ultrasound stress (US), mice were subjected to ultrasound frequencies of 16–20 kHz, mimicking rodent sounds of anxiety/despair and “neutral” frequencies of 25–45 kHz, for three weeks and concomitantly treated with SHC. US-exposed mice showed elevated concentrations of oxidative stress markers malondialdehyde and protein carbonyl, increased gene and protein expression of pro-inflammatory cytokines interleukin (IL)-1β and IL-6 and other molecular changes in the prefrontal cortex as well as weight loss, helplessness, anxiety-like behavior, and neophobia that were ameliorated by the SHC treatment. In the PTSD model of the modified forced swim test (modFST), in which a 2-day swim is followed by an additional swim on day 5, mice were pretreated with SHC for 16 days. Increases in the floating behavior and oxidative stress markers malondialdehyde and protein carbonyl in the prefrontal cortex of modFST-mice were prevented by the administration of SHC. Chromatography mass spectrometry revealed bioactive constituents of SHC, including D-ribofuranose, beta-D-lactose, malic, glyceric, and citric acids that can modulate oxidative stress, immunity, and gut and microbiome functions and, thus, are likely to be active antistress elements underlying the beneficial effects of SHC. Significant correlations of malondialdehyde concentration in the prefrontal cortex with altered measures of behavioral despair and anxiety-like behavior suggest that the accumulation of oxidative stress markers are a common biological feature of MD and PTSD that can be equally effectively targeted therapeutically with antioxidant therapy, such as the SHC investigated here.

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Molecular and behavioural abnormalities in the FUS‐tg mice mimic frontotemporal lobar degeneration: Effects of old and new anti‐inflammatory therapies

Cited by 12 publications

References 17 publications

Antidepressant Effects of NSAIDs in Rodent Models of Depression—A Systematic Review

Antidepressant Effects of NSAIDs in Rodent Models of Depression—A Systematic Review

A bioisostere of Dimebon/Latrepirdine delays the onset and slows the progression of pathology in FUS transgenic mice

Increased Oxidative Stress in the Prefrontal Cortex as a Shared Feature of Depressive- and PTSD-Like Syndromes: Effects of a Standardized Herbal Antioxidant

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