[Animal models of balance pathologies: New tools to study peripheral vestibulopathies]. / Les vestibulopathies périphériques - De nouveaux modèles d'étude.

The different types of peripheral vestibulopathies (PVs) or peripheral vestibular disorders (PVDs) are essentially diagnosed on the basis of their clinical expression. The heterogeneity of vestibular symptoms makes it difficult to stratify patients for therapeutic management. Animal models of PVs are a good mean to search for clinical evaluation criteria allowing to objectively analyze the kinetics of expression of the vertigo syndrome and to evaluate the benefits of therapeutic strategies, whether they are pharmacological or rehabilitative. The question of the predictability of these animal models is therefore crucial for the identification of behavioral and biological biomarkers that could then be used in the human clinic. In this review, we propose an overview of the different animal models of PVs, and discuss their relevance for the understanding of the underlying pathophysiological mechanisms and the development of new and more targeted therapeutic approaches.

Title: Les vestibulopathies périphériques - De nouveaux modèles d'étude. Abstract: Les vestibulopathies périphériques (VP) ou désordres vestibulaires périphériques (DVP) sont diagnostiqués surtout selon leur expression clinique, mais l'hétérogénéité des symptômes vestibulaires rend difficile la stratification des patients pour leur prise en charge thérapeutique. Les modèles animaux constituent un moyen d'identifier des critères d'évaluation clinique afin d'analyser la cinétique d'expression du syndrome vertigineux et d'évaluer les bénéfices des stratégies thérapeutiques, qu'elles soient pharmacologiques ou rééducatives. La question de la prédictibilité de ces modèles est donc cruciale pour l'identification de biomarqueurs comportementaux et biologiques qui pourraient être exploités en clinique. Dans cette revue, nous proposons un état des lieux des différents modèles animaux de VP, et discutons de leur pertinence pour la compréhension des mécanismes physiopathologiques impliqués et le développement de nouvelles approches thérapeutiques plus ciblées.

How a Subclinical Unilateral Vestibular Signal Improves Binocular Vision.

The present study aimed to determine if an infra-liminal asymmetric vestibular signal could account for some of the visual complaints commonly encountered in chronic vestibular patients. We used infra-liminal galvanic vestibular stimulation (GVS) to investigate its potential effects on visuo-oculomotor behavior. A total of 78 healthy volunteers, 34 aged from 20 to 25 years old and 44 aged from 40 to 60 years old, were included in a crossover study to assess the impact of infra-liminal stimulation on convergence, divergence, proximal convergence point, and stereopsis. Under GVS stimulation, a repeated measures ANOVA showed a significant variation in near convergence (p < 0.001), far convergence (p < 0.001), and far divergence (p = 0.052). We also observed an unexpected effect of instantaneous blocking of the retest effect on the far divergence measurement. Further investigations are necessary to establish causal relationships, but GVS could be considered a behavioral modulator in non-pharmacological vestibular therapies.

Identification of Follow-Up Markers for Rehabilitation Management in Patients with Vestibular Schwannoma.

This study delves into the absence of prognostic or predictive markers to guide rehabilitation in patients afflicted with vestibular schwannomas. The objective is to analyze the reweighting of subjective and instrumental indicators following surgery, at 7 days and 1 month postoperatively. This retrospective cohort encompasses 32 patients who underwent unilateral vestibular schwannoma surgery at the Marseille University Hospital between 2014 and 2019. Variations in 54 indicators and their adherence to available norms are calculated. After 1 month, one-third of patients do not regain the norm for all indicators. However, the rates of variation unveil specific responses linked to a preoperative error signal, stemming from years of tumor adaptation. This adaptation is reflected in a postoperative visual or proprioceptive preference for certain patients. Further studies are needed to clarify error signals according to lesion types. The approach based on variations in normative indicators appears relevant for post-surgical monitoring and physiotherapy.

What Predictability for Animal Models of Peripheral Vestibular Disorders?

The different clinical entities grouped under the term peripheral vestibulopathies (PVs) or peripheral vestibular disorders (PVDs) are distinguished mainly based on their symptoms/clinical expression. Today, there are very few commonly accepted functional and biological biomarkers that can confirm or refute whether a vestibular disorder belongs to a precise classification. Consequently, there is currently a severe lack of reliable and commonly accepted clinical endpoints, either to precisely follow the course of the vertigo syndrome of vestibular origin or to assess the benefits of therapeutic approaches, whether they are pharmacological or re-educational. Animal models of PV are a good means to identify biomarkers that could subsequently be exploited in human clinical practice. The question of their predictability is therefore crucial. Ten years ago, we had already raised this question. We revisit this concept today in order to take into account the animal models of peripheral vestibular pathology that have emerged over the last decade, and the new technological approaches available for the behavioral assessment of vestibular syndrome in animals and its progression over time. The questions we address in this review are the following: are animal models of PV predictive of the different types and stages of vestibular pathologies, and if so, to what extent? Are the benefits of the pharmacological or reeducational therapeutic approaches achieved on these different models of PV (in particular the effects of attenuation of the acute vertigo, or acceleration of central compensation) predictive of those expected in the vertiginous patient, and if so, to what extent?

Sensorimotor Rehabilitation Promotes Vestibular Compensation in a Rodent Model of Acute Peripheral Vestibulopathy by Promoting Microgliogenesis in the Deafferented Vestibular Nuclei.

Acute peripheral vestibulopathy leads to a cascade of symptoms involving balance and gait disorders that are particularly disabling for vestibular patients. Vestibular rehabilitation protocols have proven to be effective in improving vestibular compensation in clinical practice. Yet, the underlying neurobiological correlates remain unknown. The aim of this study was to highlight the behavioural and cellular consequences of a vestibular rehabilitation protocol adapted to a rat model of unilateral vestibular neurectomy. We developed a progressive sensory-motor rehabilitation task, and the behavioural consequences were quantified using a weight-distribution device. This analysis method provides a precise and ecological analysis of posturolocomotor vestibular deficits. At the cellular level, we focused on the analysis of plasticity mechanisms expressed in the vestibular nuclei. The results obtained show that vestibular rehabilitation induces a faster recovery of posturolocomotor deficits during vestibular compensation associated with a decrease in neurogenesis and an increase in microgliogenesis in the deafferented medial vestibular nucleus. This study reveals for the first time a part of the underlying adaptative neuroplasticity mechanisms of vestibular rehabilitation. These original data incite further investigation of the impact of rehabilitation on animal models of vestibulopathy. This new line of research should improve the management of vestibular patients.

Phosphorus-stabilized titanium carbene complexes: synthesis, reactivity and DFT studies.

The synthesis of two novel titanium carbene complexes from the bis(thiophosphinoyl)methanediide geminal dianion 1 (SCS(2-) ) is described. Dianion 1 reacts cleanly with 0.5 equivalents of [TiCl4 (thf)2 ] to afford the bis-carbene complex [(SCS)2 Ti] (2) in 86 % yield. The mono-carbene complex [(SCS)TiCl2 (thf)] (3) can also be obtained by using an excess of [TiCl4 (thf)2 ]. The structures of 2 and 3 are confirmed by X-ray crystallography. A strong nucleophilic reactivity towards various electrophiles (ketones and aldehydes) is observed. The reaction of 3 with N,N'-dicyclohexylcarbodiimide (DCC) and phenyl isocyanate leads to the formation of two novel diphosphinoketenimines 8 a and 8 b. The bis-titanium guanidinate complex 9 is trapped as the by-product of the reaction with DCC. The X-ray crystal structures of 8 a and 9 are presented. The mechanism of the reaction between complex 3 and DCC is rationalized by DFT studies.

First stabilization of 14-electron rhodium(I) complexes by hemichelation.

Hemichelation is emerging as a new mode of coordination where non-covalent interactions crucially contribute to the cohesion of electron-unsaturated organometallic complexes. This study discloses an unprecedented demonstration of this concept to a Group 9 metal, that is, Rh(I). The syntheses of new 14-electron Rh(I) complexes were achieved by choosing the anti-[(η(6):η(6)-fluorenyl){Cr(CO)3}2] anion as the ambiphilic hemichelating ligand, which was treated with [{Rh(nbd)Cl}2] (nbd=norbornadiene) and [{Rh(CO)2Cl}2]. The new T-shaped Rh(I) hemichelates were characterized by analytical and structural methods. Investigations using the methods of the DFT and electron-density topology analysis (NCI region analysis, QTAIM theory) confirmed the closed-shell, non-covalent and attractive characters of the interaction between the Rh(I) center and the proximal Cr(CO)3 moiety. This study shows that, by appropriate tuning of the electronic properties of the ambiphilic ligand, truly coordination-unsaturated Rh(I) complexes can be synthesized in a manageable form.

Hemichelation, a way to stabilize electron-unsaturated complexes: the case of T-shaped Pd and Pt metallacycles.

A rational method of synthesis of stable neutral T-shaped 14 electron Pd and Pt complexes is proposed. It takes advantage of the ambiphilic character of the tricarbonyl(η(6)-indenyl)chromium anion, of which the main property is to behave as a hemichelating ligand, that is a nonconventional heteroditopic ligand capable of chelating a metal center by way of covalent and noncovalent bonding, thus preserving its unsaturated valence shell. The reaction of the in situ formed tricarbonyl(η(6)-2-methylindenyl)chromium anion with a series of Pd and Pt metallacycles afforded new air-stable and persistent synfacial heterobimetallic complexes in which the metallacycle binds the indenyl fragment via its metal in an η(1) fashion, leaving the fourth coordination site at the chelated metal virtually vacant. The structures of eight of these novel complexes are disclosed, and their bonding features are investigated by an array of theoretical methods based on the density functional theory (NBO, EDA, ETS-NOCV, AIM, NCI region analysis). Theory shows that the formation of these unusual structures of bimetallic synfacial η(1)-indenyl-Pd/Pt complexes is driven thermodynamically by attractive Coulombic occlusion of the fourth vacant coordination site at Pd/Pt centers by the Cr(CO)3 moiety.

Electron-deficient η1-Indenyl,η3-allylpalladium(II) complexes stabilized by fluxional non-covalent interactions.

Highly fluxional, solution-persistent, and formally electron-deficient (32e(-)) binuclear Pd(II)-C(0) complexes of 2-methyl-1H-indene were synthesized and structurally characterized by X-ray diffraction analysis. DFT investigations combined with a number of theoretical analyses of the bond framework suggest that the polar intermetallic interaction possesses no major covalent character. Instead of bearing a static metal-metal bond as suggested by structural X-ray diffraction analysis, the complexes display in solution significant fluxionality through haptotropy, i.e., a formal "oscillation" of the Pd(η(3)-allyl) moiety between two limiting η(1)-indenyl configurations.

Room temperature tandem hydroamination and hydrosilation/protodesilation catalysis by a tricarbonylchromium-bound iridacycle.

A chromiumtricarbonyl-bound iridacycle displays novel catalytic virtues for the conversion of terminal aromatic alkynes into racemic N-phenyl, 1-arylethylamines by tandem hydro-amination and hydrosilation/protodesilation reactions under mild "one pot" conditions.

Revisiting the molecular roots of a ubiquitously successful synthesis: nickel(0) nanoparticles by reduction of [Ni(acetylacetonate)2].

The widely used preparation of Ni(0) nanoparticles from [Ni(acac)(2)] (acac=acetylacetonate) and oleylamine, often considered to be a thermolysis or a radical reaction, was analyzed anew by using a combination of DFT modeling and designed mechanistic experiments. Firstly, the reaction was followed up by using TGA to evaluate the energy barrier of the limiting step. Secondly, all the byproducts were identified using NMR spectroscopy, mass spectrometry, FTIR, and X-ray crystallography. These methods allowed us to depict both main and side-reaction pathways. Lastly, DFT modeling was utilized to assess the validity of this new scheme by identifying the limiting steps and evaluating the corresponding energy barriers. The oleylamine was shown to reduce the [Ni(acac)(2)] complex not through a one-electron radical mechanism, as often stated, but as an hydride donor through a two-electron chemical reduction route. This finding has strong consequences not only for the design of further nanoparticles syntheses that use long-chain amine as a reactant, but also for advanced understanding of catalytic reactions for which these nanoparticles can be employed.

Room temperature reversible C-H activation mediated by a Pt(0) center, and stoichiometric biphenyl formation via solvent activation.

Room temperature reversible C-H activation mediated by a designed diphosphine platinum complex is presented. These findings are demonstrated through mechanistic studies involving kinetics, isotopic effects, and corroborated by DFT calculations. The coupling between two unactivated aromatic derivatives is also demonstrated.

Synthesis of planar chiral iridacycles by cationic metal π-coordination: facial selectivity, and conformational and stereochemical consequences.

Facial selectivity during the π-coordination of pseudo-tetrahedral iridacycles by neutral (Cr(CO)(3)), monocationic (Cp*Ru(+)), and biscationic (Cp*Ir(2+)) metal centers was directly influenced by the coulombic imbalance in the coordination sphere of the chelated Ir center. We also showed by using theoretical calculations that the feasibility of the related metallacycles that displayed metallocenic planar chirality was dependent to the presence of an electron-donating group, such as NMe(2), which contributed to the overall stability of the complexes. When the π-bonded moiety was the strongly electron-withdrawing Cp*Ir(2+) group, the electron donation from NMe(2) resulted in major conformational changes, with a barrier to rotation of about 17 kcal mol(-1) for this group that became spectroscopically diastereotopic (high-field (1)H NMR spectroscopy). This peculiar property is proposed as a means to introduce a new type of constitutional chirality at the nitrogen center: planar chirality at tertiary aromatic amines.

Transmetalation of a nucleophilic carbene fragment: from early to late transition metals.

Early transition metal nucleophilic carbene complexes have been used as stoichiometric carbene transfer agents in a transmetalation process.

Room-temperature palladium-catalyzed Negishi-type coupling: a combined experimental and theoretical study.

An air-stable, bulky electron-accepting phosphine ligand (phosphabarrelene) allows the easy reduction of a Pd(II) precursor to a Pd(0) complex, highly active in room-temperature Negishi-type cross-coupling. DFT calculations show that the use of the electron-accepting ligand favors both transmetalation (TM) and reductive-elimination (RE) processes (see scheme; OA = oxidative addition).

Synthesis and structure of divalent thulium borohydrides, and their application in ε-caprolactone polymerisation.

The new divalent thulium compound [Tm(BH(4))(2)(DME)(2)] could be prepared by reduction of [Tm(BH(4))(3)(THF)(3)] or from TmI(2) and KBH(4). It was used as a precursor to the divalent [(Tp(tBu,Me))Tm(BH(4))(THF)] by reaction with potassium tris(2-tBu-4-Me)pyrazolylborate (KTp(tBu,Me)). Both Tm(II) compounds were found active as ε-caprolactone polymerisation catalysts.

Straightforward four-component access to spiroindolines.

Spiroindolines could be synthesized via a very convenient one-pot procedure combining a Ugi coupling and a new copper-catalyzed oxidative process at a peptidyl position. Due to the nature of the first step, this method offers a straightforward access to complex alkaloids with four points of molecular diversity.

Charge-induced facial-selectivity in the formation of new cationic planar chiral iridacycles derived from aniline.

The reaction of chiral chlorido-iridacyclic 2-(4-N,N-dimethylaminophenyl)pyridines with solvato-type [Cp*M(S)(3)](q+) (M = Ru, S = MeCN, q = 1; M = Ir, S = MeC(O)Me, q = 2) complexes produces new cationic racemic planar chiral iridacycles in an efficient and diastereospecific way.

Synthesis of samarium(II) borohydrides and their behaviour as initiators in styrene and epsilon-caprolactone polymerisation.

The bisborohydrido samarium compound Sm(BH(4))(2)(THF)(2) (1) was prepared in high yield by comproportionation between Sm and 2 equivalents of Sm(BH(4))(3)(THF)(3). Reaction of 1 with KCp* (Cp* = C(5)Me(5)) afforded the half-sandwich Cp*Sm(BH(4))(THF)(2) (2). The (1)H NMR borohydride resonances of both complexes, observed at very high field, are typical of divalent Sm compounds. X-Ray single crystal analysis revealed polymeric and dimeric molecular arrangements for 1 and 2, respectively. Complex 1 was found moderately active towards styrene polymerisation when activated with Al((i)Bu)(3), or with a borate/Al combination, whereas 2 showed no activity. Ring-opening polymerisation of epsilon-caprolactone could be performed rapidly at room temperature with both initiators. Complex 2 leads to narrow polydispersities and higher activity. Two different mechanisms, by monoelectronic transfer or by insertion into the Sm-(BH(4)) bond can be proposed.