Antiviral and Anti-Inflammatory Activities of Fluoxetine in a SARS-CoV-2 Infection Mouse Model

The coronavirus disease 2019 (COVID-19) pandemic continues to cause significant morbidity and mortality worldwide. Since a large portion of the world’s population is currently unvaccinated or incompletely vaccinated and has limited access to approved treatments against COVID-19, there is an urgent need to continue research on treatment options, especially those at low cost and which are immediately available to patients, particularly in low- and middle-income countries. Prior in vitro and observational studies have shown that fluoxetine, possibly through its inhibitory effect on the acid sphingomyelinase/ceramide system, could be a promising antiviral and anti-inflammatory treatment against COVID-19. In this report, we evaluated the potential antiviral and anti-inflammatory activities of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and against variants of concern in vitro, i.e., SARS-CoV-2 ancestral strain, Alpha B.1.1.7, Gamma P1, Delta B1.617 and Omicron BA.5. Fluoxetine, administrated after SARS-CoV-2 infection, significantly reduced lung tissue viral titres and expression of several inflammatory markers (i.e., IL-6, TNFα, CCL2 and CXCL10). It also inhibited the replication of all variants of concern in vitro. A modulation of the ceramide system in the lung tissues, as reflected by the increase in the ratio HexCer 16:0/Cer 16:0 in fluoxetine-treated mice, may contribute to explain these effects. Our findings demonstrate the antiviral and anti-inflammatory properties of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and its in vitro antiviral activity against variants of concern, establishing fluoxetine as a very promising candidate for the prevention and treatment of SARS-CoV-2 infection and disease pathogenesis

SK Channels Modulation Accelerates Equilibrium Recovery in Unilateral Vestibular Neurectomized Rats

International audienceWe have previously reported in a feline model of acute peripheral vestibulopathy (APV) that the sudden, unilateral, and irreversible loss of vestibular inputs induces selective overexpression of small conductance calcium-activated potassium (SK) channels in the brain stem vestibular nuclei. Pharmacological blockade of these ion channels by the selective antagonist apamin significantly alleviated the evoked vestibular syndrome and accelerated vestibular compensation. In this follow-up study, we aimed at testing, using a behavioral approach, whether the antivertigo (AV) effect resulting from the antagonization of SK channels was species-dependent or whether it could be reproduced in a rodent APV model, whether other SK channel antagonists reproduced similar functional effects on the vestibular syndrome expression, and whether administration of SK agonist could also alter the vestibular syndrome. We also compared the AV effects of apamin and acetyl-DL-leucine, a reference AV compound used in human clinic. We demonstrate that the AV effect of apamin is also found in a rodent model of APV. Other SK antagonists also produce a trend of AV effect when administrated during the acute phase of the vertigo syndrome. Conversely, the vertigo syndrome is worsened upon administration of SK channel agonist. It is noteworthy that the AV effect of apamin is superior to that of acetyl-DL-leucine. Taken together, these data reinforce SK channels as a pharmacological target for modulating the manifestation of the vertigo syndrome during APV

Oxytocin Disturbs Vestibular Compensation and Modifies Behavioral Strategies in a Rodent Model of Acute Vestibulopathy

Unilateral inner ear injury is followed by behavioral recovery due to central vestibular compensation. The therapeutic effect of oxytocin (OT) on vestibular compensation was investigated by behavioral testing in a rat model of unilateral vestibular neurectomy (UVN). Animals in the oxytocin group (UVN-OT) exhibited delayed vestibular compensation on the qualitative scale of vestibular deficits and aggravated static postural deficits (bearing surface) compared to animals in the NaCl group (UVN-NaCl). Surprisingly, oxytocin-treated animals adopt a different postural strategy than untreated animals. Instead of shifting their weight to the ipsilesional paws (left front and hind paws), they shift their weight to the front paws (right and left) without modification along the lateral axis. Furthermore, some locomotor strategies of the animals to compensate for the vestibular loss are also altered by oxytocin treatment. UVN-OT animals do not induce an increase in the distance traveled, their mean velocity is lower than that in the control group, and the ipsilesional body rotations do not increase from 7 to 30 days after UVN. This study reveals that oxytocin treatment hinders the restoration of some postural and locomotor deficits while improving others following vestibular lesions. The mechanisms of the action of oxytocin that support these behavioral changes remain to be elucidated

Quantitative Evaluation of a New Posturo-Locomotor Phenotype in a Rodent Model of Acute Unilateral Vestibulopathy

International audienceVestibular pathologies are difficult to diagnose. Existing devices make it possible to quantify and follow the evolution of posturo-locomotor symptoms following vestibular loss in static conditions. However, today, there are no diagnostic tools allowing the quantitative and spontaneous analysis of these symptoms in dynamic situations. With this in mind, we used an open-field video tracking test aiming at identifying specific posturo-locomotor markers in a rodent model of vestibular pathology. Using Ethovision XT 14 software (Noldus), we identified and quantified several behavioral parameters typical of unilateral vestibular lesions in a rat model of vestibular pathology. The unilateral vestibular neurectomy (UVN) rat model reproduces the symptoms of acute unilateral peripheral vestibulopathy in humans. Our data show deficits in locomotion velocity, distance traveled and animal mobility in the first day after the injury. We also highlighted alterations in several parameters, such as head and body acceleration, locomotor pattern, and position of the body, as well as “circling” behavior after vestibular loss. Here, we provide an enriched posturo-locomotor phenotype specific to full and irreversible unilateral vestibular loss. This test helps to strengthen the quantitative evaluation of vestibular disorders in unilateral vestibular lesion rat model. It may also be useful for testing pharmacological compounds promoting the restoration of balance. Transfer of these novel evaluation parameters to human pathology may improve the diagnosis of acute unilateral vestibulopathies and could better follow the evolution of the symptoms upon pharmacological and physical rehabilitation

Unilateral vestibular neurectomy induces a remodeling of somatosensory cortical maps

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Identification of New Biomarkers of Posturo-Locomotor Instability in a Rodent Model of Vestibular Pathology

International audienceThe vestibular system plays a crucial role in maintaining postural balance. Unilateral vestibular lesions result in a typical syndrome characterized by postural imbalance, altered locomotor patterns and gaze stabilization, as well as cognitive and neurovegetative disorders. One of the main difficulties encountered in the development of new anti-vertigo drugs is the lack of sensitivity in the evaluation of this syndrome. Qualitative assessments of the vestibular syndrome have been developed, but methods of conducting quantitative evaluations are critically lacking. Recently, assessments with a dynamic weight-bearing device (DWB®, Bioseb) revealed postural alterations in rats subjected to unilateral vestibular neurectomy (UVN). Our team is evaluating a new version of this device capable of quantifying additional parameters of postural and locomotor equilibrium. The objective of this study was to use this device to assess these new posturo-locomotor parameters in a rat model of a vestibular pathology. The biomarkers measured by this device are as follows: the barycenter, the support surface and the weight distribution of the rats when they were moving or stationary. Before UVN, the rats showed a symmetric distribution of their weight along the lateral axis. In the acute phase after UVN on the left side, the rats distributed more weight on the right side than on the left side and then distributed more weight on the left side. These results corroborate those presented in our previous study. The support surface of the rats increased between 1 day and 30 days after UVN, and the barycenter distribution reflected the weight distribution. In addition, our results show smaller changes in the weight distributions when the animals are moving compared with when they are stationary in the acute phase after UVN. This study provides new information on the static and dynamic postural balance patterns observed after unilateral vestibular loss in rats. These data are relevant because they objectively quantify the posturo-locomotor component of vestibular syndrome as well as the compensatory strategies used after vestibular loss. These results may guide the development of rehabilitation protocols for vestibular patients and the validation of pharmacological compounds favoring the restoration of equilibrium

Long-lasting spatial memory deficits and impaired hippocampal plasticity following unilateral vestibular loss

International audienceUnilateral vestibular loss (UVL) induces a characteristic vestibular syndrome composed of various posturo-locomotor, oculomotor, vegetative and perceptivo-cognitive symptoms. Functional deficits are progressively recovered over time during vestibular compensation, that is supported by the expression of multiscale plasticity mechanisms. While the dynamic of post-UVL posturo-locomotor and oculomotor deficits is well characterized, the expression over time of the cognitive deficits, and in particular spatial memory deficits, is still debated. In this study we aimed at investigating spatial memory deficits and their recovery in a rat model of unilateral vestibular neurectomy (UVN), using a wide spectrum of behavioral tasks. In parallel, we analyzed markers of hippocampal plasticity involved in learning and memory. Our results indicate the UVN affects all domains of spatial memory, from working memory to reference memory and object-in-place recognition. These deficits are associated with long-lasting impaired plasticity in the ipsilesional hippocampus. These results highlight the crucial role of symmetrical vestibular information in spatial memory and contribute to a better understanding of the cognitive disorders observed in vestibular patients