etifoxine and Disease-Models--Animal

Topics: Analgesics; Animals; Anti-Anxiety Agents; Benzodiazepines; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Neuralgia; Neuroprotective Agents; Oxazines; Pain Measurement

The aim of this study is to examine the effect of etifoxine on β-amyloid-induced toxicity models.. Etifoxine is an anxiolytic compound with a dual mechanism of action; it is a positive allosteric modulator of GABAergic receptors as well as a ligand for the 18 kDa mitochondrial Translocator Protein (TSPO). TSPO has recently raised interest in Alzheimer's Disease (AD), and experimental studies have shown that some TSPO ligands could induce neuroprotective effects in animal models.. In this study, we examined the potential protective effect of etifoxine in an in vitro and an in vivo model of amyloid beta (Aβ)-induced toxicity in its oligomeric form, which is a crucial factor in AD pathologic mechanisms.. Neuronal cultures were intoxicated with Aβ1-42, and the effects of etifoxine on oxidative stress, Tau-hyperphosphorylation and synaptic loss were quantified. In a mice model, behavioral deficits induced by intracerebroventricular administration of Aβ25-35 were measured in a spatial memory test, the spontaneous alternation and in a contextual memory test, the passive avoidance test.. In neuronal cultures intoxicated with Aβ1-42, etifoxine dose-dependently decreased oxidative stress (methionine sulfoxide positive neurons), tau-hyperphosphorylation and synaptic loss (ratio PSD95/synaptophysin). In a mice model, memory impairments were fully alleviated by etifoxine administered at anxiolytic doses (12.5-50mg/kg). In addition, markers of oxidative stress and apoptosis were decreased in the hippocampus of these animals.. Our results have shown that in these two models, etifoxine could fully prevent neurotoxicity and pathological changes induced by Aβ. These results confirm that TSPO ligands could offer an interesting therapeutic approach to Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Anxiety Agents; Apoptosis; Disease Models, Animal; Hippocampus; Male; Mice; Neurons; Neuroprotective Agents; Oxazines; Oxidative Stress

Obesity is intimately associated with diet and dysbiosis of gut microorganisms but anxiolytics, widely used in treatment of psychiatric conditions, frequently result in weight gain and associated metabolic disorders. We are interested in effects of the anxiolytic etifoxine, which has not been studied with respect to weight gain or effects on gut microorganisms. Here we induced obesity in mice by feeding a high-fat diet but found that intraperitoneal administration of etifoxine resulted in weight loss and decreased serum cholesterol and triglycerides. Obese mice had increased hepatic transcripts associated with lipid metabolism (cyp7a1, cyp27a1, abcg1 and LXRα) and inflammatory factors (TNFα and IL18) but these effects were reversed after etifoxine treatment other than cyp7a1. Taxonomic profiles of the organisms from the caecum were generated by 16S rRNA gene sequencing and Obese and etifoxine mice show differences by diversity metrics, Differential Abundance and functional metagenomics. Organisms in genus Oscillospira and genera from Lachnospiraceae family and Clostridiales order are higher in Control than Obese and at intermediate levels with etifoxine treatment. With respect to community metabolic potential, etifoxine mice have characteristics similar to Control and particularly with respect to metabolism of butanoate, sphingolipid, lipid biosynthesis and xenobiotic metabolism. We suggest mechanisms where-by etifoxine influences processes of host, such as on bile acid synthesis, and microbiota, such as signalling from production of butanoate and sphingosine, resulting in decreased cholesterol, lipids and inflammatory factors. We speculate that the indirect effect of etifoxine on microbial composition is mediated by microbial β-glucuronidases that metabolise excreted etifoxine glucuronides.

Topics: Animals; Anti-Anxiety Agents; Colon; Diet, High-Fat; Disease Models, Animal; Gastrointestinal Microbiome; Male; Mice; Mice, Inbred C57BL; Obesity; Oxazines; Weight Gain; Weight Loss

Inflammatory processes are critical promoting factors of chronic pain states, mostly by inducing peripheral and central sensitization of the nociceptive system. These processes are associated with a massive increase in glutamatergic transmission, sometimes facilitated by spinal disinhibition. In this study, we used etifoxine, a non-benzodiazepine anxiolytic known to amplify inhibition mediated by gamma-aminobutyric acid type A (GABA

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Carrageenan; Disease Models, Animal; Edema; Formaldehyde; Hyperalgesia; Male; Mice; Oxazines; Pain; Rats, Sprague-Dawley; Tetradecanoylphorbol Acetate

Cerebral ischemia is a leading cause of death and disability with limited treatment options. Although inflammatory and immune responses participate in ischemic brain injury, the molecular regulators of neuroinflammation after ischemia remain to be defined. Translocator protein 18 kDa (TSPO) mainly localized to the mitochondrial outer membrane is predominantly expressed in glia within the central nervous system during inflammatory conditions. This study investigated the effect of a TSPO agonist, etifoxine, on neuroinflammation and brain injury after ischemia/reperfusion.. We used a mouse model of middle cerebral artery occlusion (MCAO) to examine the therapeutic potential and mechanisms of neuroprotection by etifoxine.. TSPO was upregulated in Iba1. These findings indicate that the TSPO agonist, etifoxine, reduces neuroinflammation and brain injury after ischemia/reperfusion. The therapeutic potential of targeting TSPO requires further investigations in ischemic stroke.

Topics: Animals; Brain Edema; Brain Infarction; Cytokines; Disease Models, Animal; Drug Administration Schedule; Flow Cytometry; Gene Expression Regulation; Infarction, Middle Cerebral Artery; Mice; Microglia; Neurologic Examination; Neuroprotective Agents; Oxazines; Receptors, GABA; Reperfusion Injury; RNA, Messenger; Time Factors; Tumor Necrosis Factor-alpha

Neurosteroids such as progesterone and allopregnanolone have been shown to exert neuroprotective effects under a variety of pathological or insult conditions, and there is evidence that the neurosteroid system is perturbed in Multiple Sclerosis (MS) patients. Neurosteroids are synthesized in the central nervous system (CNS) through a series of metabolic transformations, beginning with a rate-limiting step of cholesterol transport through the outer mitochondrial membrane via the transporter translocator protein (TSPO). We examined the effects of etifoxine and XBD-173, two different brain penetrant TSPO agonists, for their ability to ameliorate clinical signs in two different experimental autoimmune encephalitis (EAE) models. Etifoxine, as previously reported, was efficacious in EAE, while XBD-173 was not. Surprisingly, XBD-173, but not etifoxine elevated relevant neurosteroids in brain of female rats and differed in its ability to exert anti-inflammatory and direct neuroprotective effects in vitro as compared to etifoxine. We conclude that the neurosteroid elevations produced in brain by XBD-173 are not sufficient to ameliorate EAE and suggest that etifoxine may have additional mechanisms of action that provide therapeutic benefit in this model system.

Topics: Animals; Cell Line, Tumor; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalomyelitis, Autoimmune, Experimental; Female; Ligands; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Oxazines; Purines; Rats; Receptors, GABA; Treatment Outcome

Traumatic brain injury (TBI) results in important neurological impairments which occur through a cascade of deleterious physiological events over time. There are currently no effective treatments to prevent these consequences. TBI is followed not only by an inflammatory response but also by a profound reorganization of the GABAergic system and a dysregulation of translocator protein 18 kDa (TSPO). Etifoxine is an anxiolytic compound that belongs to the benzoxazine family. It potentiates GABAergic neurotransmission, either through a positive allosteric effect or indirectly, involving the activation of TSPO that leads to an increase in neurosteroids synthesis. In several models of peripheral nerve injury, etifoxine has been demonstrated to display potent regenerative and anti-inflammatory properties and to promote functional recovery. Prior study also showed etifoxine efficacy in reducing brain edema in rats. In light of these positive results, we used a rat model of TBI to explore etifoxine treatment effects in a central nervous system injury, from functional outcomes to the underlying mechanisms.. Male Sprague-Dawley rats received contusion (n = 18) or sham (n = 19) injuries centered laterally to bregma over the left sensorimotor cortex. They were treated with etifoxine (50 mg/kg, i.p.) or its vehicle 30 min following injury and every day during 7 days. Rats underwent behavioral testing to assess sensorimotor function. In another experiment, injured rats (n = 10) or sham rats (n = 10) received etifoxine (EFX) (50 mg/kg, i.p.) or its vehicle 30 min post-surgery. Brains were then dissected for analysis of neuroinflammation markers, glial activation, and neuronal degeneration.. Brain-injured rats exhibited significant sensorimotor function deficits compared to sham-injured rats in the bilateral tactile adhesive removal test, the beam walking test, and the limb-use asymmetry test. After 2 days of etifoxine treatment, behavioral impairments were significantly reduced. Etifoxine treatment reduced pro-inflammatory cytokines levels without affecting anti-inflammatory cytokines levels in injured rats, reduced macrophages and glial activation, and reduced neuronal degeneration.. Our results showed that post-injury treatment with etifoxine improved functional recovery and reduced neuroinflammation in a rat model of TBI. These findings suggest that etifoxine may have a therapeutic potential in the treatment of TBI.

Topics: Animals; Anti-Inflammatory Agents; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Brain Injuries, Traumatic; Cytokines; Disease Models, Animal; Encephalitis; Functional Laterality; Gait Ataxia; Glial Fibrillary Acidic Protein; Locomotion; Macrophages; Male; Nerve Degeneration; Neuroglia; Oxazines; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Recovery of Function

Pathological pain states are often associated with neuronal hyperexcitability in the spinal cord. Reducing this excitability could theoretically be achieved by amplifying the existing spinal inhibitory control mediated by GABAA receptors (GABAARs). In this study, we used the non-benzodiazepine anxiolytic etifoxine (EFX) to characterize its interest as pain killer and spinal mechanisms of action. EFX potentiates GABAAR function but can also increase its function by stimulating the local synthesis of 3α-reduced neurosteroids (3αNS), the most potent endogenous modulators of this receptor.. The efficacy of EFX analgesia and the contribution of 3αNS were evaluated in a rat model of mononeuropathy. Spinal contribution of EFX was characterized through changes in pain symptoms after intrathecal injections, spinal content of EFX and 3αNS, and expression of FosB-related genes, a marker of long-term plasticity.. We found that a 2-week treatment with EFX (>5 mg/kg, i.p.) fully suppressed neuropathic pain symptoms. This effect was fully mediated by 3αNS and probably by allopregnanolone, which was found at a high concentration in the spinal cord. In good agreement, the level of EFX analgesia after intrathecal injections confirmed that the spinal cord is a privileged target as well as the limited expression of FosB/ΔFosB gene products that are highly expressed in persistent pain states.. This preclinical study shows that stimulating the production of endogenous analgesics such as 3αNS represents an interesting strategy to reduce neuropathic pain symptoms. Since EFX is already prescribed as an anxiolytic in several countries, a translation to the human clinic needs to be rapidly evaluated.

Topics: Analgesia; Analgesics; Animals; Disease Models, Animal; Male; Mononeuropathies; Neuralgia; Oxazines; Pain Management; Pain Threshold; Pregnanolone; Rats; Rats, Sprague-Dawley; Spinal Cord

Acellular nerve grafts are good candidates for nerve repair, but the clinical outcome of grafting is not always satisfactory. We investigated whether etifoxine could enhance nerve regeneration.. Seventy-two Sprague-Dawley rats were divided into 3 groups: (1) autograft; (2) acellular nerve graft; and (3) acellular nerve graft plus etifoxine. Histological and electrophysiological examinations were performed to evaluate the efficacy of nerve regeneration. Walking-track analysis was used to examine functional recovery. Quantitative polymerase chain reaction was used to evaluate changes in mRNA level.. Etifoxine: (i) increased expression of neurofilaments in regenerated axons; (ii) improved sciatic nerve regeneration measured by histological examination; (iii) increased nerve conduction velocity; (iv) improved walking behavior as measured by footprint analysis; and (v) boosted expression of neurotrophins.. These results show that etifoxine can enhance peripheral nerve regeneration across large nerve gaps repaired by acellular nerve grafts by increasing expression of neurotrophins.

Topics: Animals; Disease Models, Animal; Electric Stimulation; Evoked Potentials; Gene Expression; Glial Cell Line-Derived Neurotrophic Factor; Locomotion; Male; Nerve Growth Factor; Nerve Regeneration; Neural Conduction; Neurofilament Proteins; Oxazines; Rats; Rats, Sprague-Dawley; Recovery of Function; Sciatic Neuropathy; Skin; Transplantation, Autologous; Vascular Endothelial Growth Factor A

Local production of neurosteroids such as progesterone and allopregnanolone confers neuroprotection in central nervous system (CNS) inflammatory diseases. The mitochondrial translocator protein (TSPO) performs a rate-limiting step in the conversion of cholesterol to pregnenolone and its steroid derivatives. Previous studies have shown that TSPO is upregulated in microglia and astroglia during neural inflammation, and radiolabelled TSPO ligands such as PK11195 have been used to image and localize injury in the CNS. Recent studies have shown that modulating TSPO activity with pharmacological ligands such as etifoxine can initiate the production of neurosteroids locally in the injured CNS. In this study, we examined the effects of etifoxine, a clinically available anxiolytic drug, in the development and progression of mouse experimental autoimmune encephalomyelitis (EAE), an experimental model for multiple sclerosis (MS). Our results showed that etifoxine attenuated EAE severity when administered before the development of clinical signs and also improved symptomatic recovery when administered at the peak of the disease. In both cases, recovery was correlated with diminished inflammatory pathology in the lumbar spinal cord. Modulation of TSPO activity by etifoxine led to less peripheral immune cell infiltration of the spinal cord, and increased oligodendroglial regeneration after inflammatory demyelination in EAE. Our results suggest that a TSPO ligand, e.g. etifoxine, could be a potential new therapeutic option for MS with benefits that could be comparable to the administration of systemic steroids but potentially avoiding the detrimental side effects of long-term direct use of steroids.

Topics: Animals; Anti-Anxiety Agents; Cells, Cultured; Cytokines; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Ligands; Mice; Mice, Inbred C57BL; Microglia; Oxazines; Receptors, GABA; Spinal Cord

Etifoxine is an anxiolytic compound structurally unrelated to benzodiazepine and neurosteroids but potentiating GABA(A) receptor function by a dual mode of action including a direct positive allosteric modulation through a site distinct from that of benzodiazepines. Etifoxine has been shown to possess some anxiolytic-like effects in rodents.. Using the four-plate test (FPT) model of anxiety in mice the potential anxiolytic-like effect of etifoxine was first to re-evaluate. In a second part, in order to better understand the mechanism of action of etifoxine, interaction studies with 5-HT(2) ligands were performed in the FPT as mixed serotonergic and GABAergic mechanisms are highly implicated in the anxiolytic-like effect observed in the FPT.. A dose response effect was observed for etifoxine from the dose of 40-100 mg/kg. Doses above to 60 mg/kg induced a sedative effect as was determined in the actimeter test. The 5-HT(2A) receptor antagonist SR 46349B blocked the anti-punishment activity of etifoxine (40 and 50 mg/kg), while the 5-HT(2B/2C) receptor antagonist, SB 206553 and the 5-HT(2C) receptor antagonist, RS 10-2221 did not alter its effects. In a same way, only the 5-HT(2A) agonist DOI induced anti-punishment effect when co-administered with subthreshold doses of etifoxine.. The present results demonstrated that etifoxine effect was modulated by 5-HT(2A) ligands co-administration. The large literature concerning GABA and 5-HT suggests that they could be co-released and could act as co-transmitters in some regions of the CNS and cross-communication between the two neurotransmitters might be an important modulator process of neuronal activity.

Topics: Amphetamines; Analysis of Variance; Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Electroshock; Locomotion; Male; Mice; Oxazines; Protein Subunits; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists

1. The aim of the present study was to test the hypothesis that increasing GABAergic neurotransmission is involved in the prevention or treatment of brain oedema. The study was conducted in the well-established rat triethyltin (TET) model of brain oedema and examined the effects of etifoxine, a compound that increases GABAergic neurotransmission through multiple mechanisms, including neurosteroid synthesis. 2. Daily oral administration of 3 mg/kg per day TET for 5 consecutive days strongly perturbed rat behaviour and induced reproducible cerebral oedema. Coadministration of etifoxine (2 x 25 or 2 x 50 mg/kg per day, p.o.) over the 5 days of TET treatment blocked the development of brain oedema and the increase in brain sodium content induced by TET, as well as reducing the increase in brain chloride content. Moreover, etifoxine inhibited the decrease in bodyweight, the neurological deficit and the altered locomotor activity induced by TET. At a lower dose (2 <--> 10 mg/kg per day, p.o.), etifoxine did not have any preventive effects. 3. To examine the curative effects of etifoxine, it was administered from the 4th day of TET treatment for 5 consecutive days, when brain oedema was already established. In these experiments, etifoxine (2 <--> 50 mg/kg per day, p.o.) significantly reduced cerebral oedema and the outcomes induced by TET treatment. Moreover, etifoxine reduced the mortality in response to TET treatment. 4. In conclusion, because etifoxine has a good safety profile as an anxiolytic, the results of the present study suggest that it is worth further clinical investigation as a neuroprotectant.

Topics: Animals; Brain Edema; Disease Models, Animal; Male; Oxazines; Rats; Rats, Wistar

The central processing of peripheral nociceptive messages is highly controlled by the activity of local inhibitory networks in the spinal cord and supraspinal centers. Recently, it has been shown that endogenous 3alpha-reduced neurosteroids (3alphaNS) exert a significant spinal antinociception by potentiating GABA(A) receptor function. Because endogenous 3alphaNS can be produced in many relay structures of the nociceptive system, we tested the potential analgesic efficacy of promoting the production of neurosteroids by using etifoxine (ETX, 50mg/kg i.p.). This prescribed non-benzodiazepine anxiolytic was shown previously to stimulate neurosteroidogenesis in its early step after binding to the mitochondrial translocator protein complex (TSPO). Using an animal model of generalized neuropathic pain resulting from a 2-week treatment with the antitumoral agent vincristine sulfate (VCR, 0.1mg/kg i.p.), we show that injections of ETX (50mg/kg i.p.) given every day reduced the VCR-induced mechanical and thermal pain symptoms but also prevented their appearance, if used in prophylaxia 1 week before VCR. Both the curative and preventive effects of ETX on pain symptoms were mediated by the production of 3alphaNS as demonstrated in animals treated with the enzymatic inhibitor provera (6-medroxyprogesterone acetate; 20mg/kg s.c.). Altogether, this study shows for the first time that promoting 3alphaNS could be a possible therapeutic strategy to treat neuropathic pain symptoms. Since ETX is already available as an anxiolytic, its use in humans, provided that its analgesic properties are confirmed, could be rapidly considered.

Topics: Analysis of Variance; Animals; Anti-Anxiety Agents; Chi-Square Distribution; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hyperalgesia; Medroxyprogesterone Acetate; Neurotransmitter Agents; Oxazines; Pain Measurement; Pain Threshold; Physical Stimulation; Rats; Rats, Sprague-Dawley; Reaction Time; Time Factors; Vincristine

Etifoxine (6-chloro-2-ethylamino-4-methyl-4-phenyl-4H-3,1-benzoxazine hydrochloride), a nonbenzodiazepine anxiolytic drug, potentiates GABA(A) receptor function perhaps through stimulation of neurosteroid biosynthesis. However, the exact mechanism of etifoxine action is not fully understood. In this study, we have assessed the possible role of GABAergic neurosteroid like allopregnanolone (ALLO) in the anxiolytic-like effect of etifoxine in rats using elevated plus maze test. Selective GABA(A) receptor agonist, muscimol, ALLO or neurosteroidogenic agents like progesterone, metyrapone or mitochondrial diazepam binding inhibitor receptor (MDR) agonist, FGIN 1-27 significantly heightened the etifoxine-induced anxiolysis. On the other hand, GABA(A) receptor antagonist, bicuculline or neurosteroid biosynthesis inhibitors like finasteride, indomethacin, trilostane or PBR antagonist, PK11195 significantly blocked the effect of etifoxine. Bilateral adrenalectomy did not influence anti-anxiety effect of etifoxine thereby ruling out contribution of adrenal steroids. Thus, our results provide behavioral evidence for the role of neurosteroids like ALLO in the anti-anxiety effect of etifoxine.

Topics: Adrenalectomy; Analysis of Variance; Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Bicuculline; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Interactions; Enzyme Inhibitors; GABA Agonists; GABA Antagonists; Male; Maze Learning; Muscimol; Oxazines; Pregnanolone; Rats; Rats, Sprague-Dawley; Reaction Time

Anxiety disorders are often associated with autonomic symptoms, including heart palpitations, sweating, elevation of body temperature and alterations of gastrointestinal motility. Some of the alterations observed in animals exposed to stress are analogous to changes in a number of physiological and endocrine parameters observed in anxious patients. With the purpose to guide further clinical studies in subtypes of anxious patients, etifoxine, a nonbenzodiazepine anxiolytic compound, was evaluated in two rat models of anxiety with measures of physiological manifestations: stress-induced hyperthermia (SIH) and conditioned-fear-stress-induced freezing behavior and activation of colonic motility. The sequential handling of animals induced a rise in body temperature attenuated by etifoxine (50 mg/kg IP). The emotional stress induced by fear to receive electric foot shocks is accompanied by freezing behavior and an increase of the frequency of ceco-colonic spike bursts: both parameters were reduced by etifoxine (25-50 mg/kg IP), independently of changes in pain perception and memory-related processes. In response to a stressful event, the stimulation of the corticotropin-releasing hormone (CRH) system is probably involved in the observed modifications of body temperature and colonic motility. It is hypothesized that stress-induced CRH activation is attenuated by the enhancement of the inhibitory GABAergic system activity associated with etifoxine. These findings will guide future evaluation of etifoxine in the treatment of selected anxious patients with altered autonomic symptomatology.

Topics: Analysis of Variance; Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Body Temperature; Bromazepam; Colon; Conditioning, Classical; Corticotropin-Releasing Hormone; Disease Models, Animal; Dose-Response Relationship, Drug; Electromyography; Fear; Fever; Gastrointestinal Motility; Immobilization; Male; Oxazines; Rats; Rats, Wistar; Reaction Time; Stress, Physiological