Bruno Buisson

• PhD
• President & CSO at NEUROSERVICES-ALLIANCE

Introduction: Failures in drug development often result from the emergence of unexpected adverse drug reactions. It is clear that adverse drug reactions, including seizure liability, should be assessed earlier. The goal of the present work was to develop a new platform of in vitro assays, NS-PC set (for Neuroservice proconvulsive set), to determin...

Mirogabalin, which is a novel ligand for the α₂δ subunit of voltage-gated calcium channels, is being developed for treating neuropathic pain including diabetic peripheral neuropathy and postherpetic neuralgia. Mirogabalin possesses unique α₂δ subunit binding characteristics and has potent and long-lasting analgesic effects in neuropathic pain model...

Histaminergic H3 inverse agonists, by stimulating central histamine release, represent attractive drug candidates to treat cognitive disorders. The present studies aimed to describe the mechanistic profile of S 38093 a novel H3 receptors inverse agonist. S 38093 displays a moderate affinity for rat, mouse and human H3 receptors (Ki=8.8, 1.44 and 1....

Huntington’s disease (HD) symptoms are driven to a large extent by dysfunction of the basal ganglia circuitry. HD patients exhibit reduced striatal phoshodiesterase 10 (PDE10) levels. Using HD mouse models that exhibit reduced PDE10, we demonstrate the benefit of pharmacologic PDE10 inhibition to acutely correct basal ganglia circuitry deficits. PD...

GluN2A is the most abundant of the GluN2 NMDA receptor subunits in the mammalian CNS. Physiological and genetic evidence implicate GluN2A-containing receptors in susceptibility to autism, schizophrenia, childhood epilepsy and neurodevelopmental disorders such as Rett Syndrome. However, GluN2A-selective pharmacological probes to explore the therapeu...

A simple and versatile fabrication process is used to define conducting polymer microelectrode arrays (MEAs), patterning at the same time the recording electrodes as well as the insulating layer. Thanks to the low impedance of poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS) electrodes, these MEAs allow in vitro recording of acti...

Myotonic dystrophy type 1 is a complex multisystemic inherited disorder, which displays multiple debilitating neurological manifestations. Despite recent progress in the understanding of the molecular pathogenesis of myotonic dystrophy type 1 in skeletal muscle and heart, the pathways affected in the central nervous system are largely unknown. To a...

Huntington's disease (HD) is an autosomal neurodegenerative disorder, characterized by severe behavioral, cognitive, and motor deficits. Since the discovery of the huntingtin gene (HTT) mutation that causes the disease, several mouse lines have been developed using different gene constructs of Htt. Recently, a new model, the zQ175 knock-in (KI) mou...

MRI volmetry power analysis in zQ175 and WT mice. Summary of the sample size needed to detect a 50% effect in the MRI volumetry for whole brain, striatum and cortex, and in the concentrations of selected MRS striatal metabolites with an alpha of 0.05 and a power of 0.8 for the heterozygote (HET) and homozygote (HOMO) mice at 12 months of age. N/A,...

3,5-Seco-4-nor-cholestan-5-one oxime-3-ol (TRO40303) is a new cardioprotective compound coming from a chemical series identified initially for neuroprotective properties. TRO40303 binds specifically to the mitochondrial translocator protein 18 kDa (TSPO) at the cholesterol site. After intravenous administration, TRO40303 tissue distribution was com...

Diabetes and cancer chemotherapies are often associated with painful neuropathy. The mechanisms underlying neuropathic pain remain poorly understood, and the current therapies have limited efficacy and are associated with dose-limiting side effects. We recently described the pharmacological characterization of cholest-4-en-3-one, oxime (TRO19622),...

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive death of cortical and spinal motor neurons, for which there is no effective treatment. Using a cell-based assay for compounds capable of preventing motor neuron cell death in vitro, a collection of approximately 40,000 low-molecular-weight compoun...

The multi-electrode arrays (MEA) technology for the recording of brain slices is available for more than 10 years. However, despite its relative simplicity, this recording technique is not widely used in academic or pharmaceutical research laboratories. We illustrate here that MEA provide multiple possibilities to investigate some network physiolog...

Ligand-gated ion channels (LGICs) are cell surface proteins that play an important role in fast synaptic transmission and in the modulation of cellular activity. Due to their intrinsic properties, LGICs respond to neurotransmitters and other effectors (e.g. pH) and transduce the binding of a ligand into an electrical current on a microsecond timesc...

Nicotine addiction is initiated by its binding to high-affinity nicotinic receptors in brain composed primarily of alpha4 and beta2 subunits. For nicotinic receptors expressed in vivo or heterologously, nicotine exposure over hours to days increases or "upregulates" high-affinity nicotine binding to receptors through a posttranslational mechanism t...

We examined the potential expression and function of alpha7 nicotinic acetylcholine receptors (nAChRs) in leukocytes. RT-PCR with alpha7 specific primers revealed the presence of the receptor mRNA in leukocytes. Immunoblotting and immunofluorescence experiments demonstrated the expression of a protein that is recognized by alpha7 specific antibodie...

Upregulation of binding to nicotinic acetylcholine receptors (nAChRs) is observed in the brains of both smokers and animals chronically exposed to nicotine, although whether this in vivo change is accompanied by an increase in receptor function is unknown. In vitro recordings indicate that alpha4beta2- and alpha7-subtypes of nAChRs, which are the m...

The modulation of neurotransmitter receptors by various substances can reflect important physiological mechanisms involved in the regulation of neural function. Furthermore, such substances, in particular specific allosteric modulators, can reveal promising therapeutic targets for diseases of the nervous system. From this perspective, we investigat...

Nicotinic acetylcholine receptors (nAChR) composed of chick alpha7 subunits mutated to threonine at amino acid valine-251 in the putative channel-lining M2 domain were expressed heterologously in several neuron-like and non-neuronal mammalian cell lines. Expression of mutant alpha7-nAChR is toxic to neuron-like cells of the human neuroblastoma cell...

Widely expressed in the brain, the alpha4beta2 nicotinic acetylcholine receptor (nAChR) is proposed to play a major role in the mechanisms that lead to and maintain nicotine addiction. Using the patch-clamp technique and pharmacological protocols, we examined the consequences of long-term exposure to 0.1-10 micrometer nicotine in K-177 cells expres...

The identification of an equatorial frog toxin, epibatidine, as a potent non-morphinic analgesic, selective for neuronal nicotinic acetylcholine receptors, provoked a marked renewal in our understanding of pain and its mechanisms. In this work we have examined the effects of epibatidine at the major brain rat α4β2 nicotinic acetylcholine receptor e...

The identification of an equatorial frog toxin, epibatidine, as a potent non-morphinic analgesic, selective for neuronal nicotinic acetylcholine receptors, provoked a marked renewal in our understanding of pain and its mechanisms. In this work we have examined the effects of epibatidine at the major brain rat alpha4beta2 nicotinic acetylcholine rec...

The fabrication, characterization and application of polyimide-based flexible microelectrodes for recording from and stimulation of biological tissue are described. The planar electrodes consist of a polyimide-platinum-polyimide sandwich structure with a total thickness of 10 to 40 μm fabricated on Pyrex or silicon wafers. Several designs with mono...

Receptors that mediate neurotransmission can be divided into two groups: the ionotropic and the metabotropic receptors. The ionotropic receptors, which mediate the fast transmission, present both ligand-binding domains and an ion channel and they are usually designed as “ligand-gated channels.” Following the binding of the neurotransmitter molecule...

We report that preapplication of ivermectin, in the micromolar range, strongly enhances the subsequent acetylcholine-evoked current of the neuronal chick or human #7 nicotinic acetylcholine receptors reconstituted in Xenopus laevis oocytes and K-28 cells. This potentiation does not result from nonspecific Cl # currents. The concomitant increase in...

Steroid hormones can be divided into five classes: progestins, estrogens, androgens, glucocorticosteroids, and mineralocorticosteroids. The principal site of synthesis are the corpus luteum and the placenta for the progestatifs, the ovary or testes for the estrogens or androgens, and the adrenal glands for the glucocorticosteroids and mineralocorti...

The structure-function relationship of the neuronal nicotinic acetylcholine receptor is examined in the light of the allosteric concepts. Effects of site-directed mutagenesis as well as those caused by allosteric effector of the physiological and pharmacological receptor properties are discussed.

A simple and efficient technique for the fabrication of buried microfluidic channels is presented. Microchannels made using a contribution of thick liquid and laminated photopolymers are used for the realization of smart microchips for culture, stimulation and recording of neural cell arrays.

To extend our knowledge of the pharmacological profile of human alpha4beta2 neuronal nicotinic receptors, we investigated the action of hexamethonium on the major brain human nicotinic acetylcholine receptor (nAChR) stably expressed in human embryonic kidney 293 cells. This compound displays all of the characteristics of an open-channel blocker at...

We report that preapplication of ivermectin, in the micromolar range, strongly enhances the subsequent acetylcholine-evoked current of the neuronal chick or human alpha7 nicotinic acetylcholine receptors reconstituted in Xenopus laevis oocytes and K-28 cells. This potentiation does not result from nonspecific Cl- currents. The concomitant increase...

Mutation of the conserved leucine residue, in the second transmembrane domain of the neuronal alpha7 acetylcholine receptor to a threonine (L247T) causes pleiotropic alterations of receptor properties. In this study we examined the effects of competitive inhibitors on the alpha7-L247T physiological responses. While the alpha7 competitive inhibitor...

The unidentified cell-surface antigen recognized by monoclonal antibody M7412 is distributed along motoneuron axonal outgrowth pathways in chicken embryos. To better characterize its role in motoneuron development, the M7412 antigen was purified from chicken embryos by immunoaffinity chromatography. Its N-terminal amino acid sequence corresponded t...

Ligand-gated channels (LGCs) play a fundamental role in the fast transmission of electrical activity from neuron to neuron and/or to effector cells. Studies of LGCs in isolation have become possible since the identification of genes coding for these membrane proteins together with the establishment of reconstitution techniques in host systems. Meth...

The cloning and expression of genes encoding for the human neuronal nicotinic acetylcholine receptors (nAChRs) has opened new possibilities for investigating their physiological and pharmacological properties. Cells (HEK 293) stably transfected with two of the major brain subunits, alpha4 and beta2, were characterized electrophysiologically using t...

The alpha 7 neuronal nicotinic acetylcholine receptor subtype forms a Ca(2+)-permeable homooligomeric ion channel sensitive to alpha-bungarotoxin in Xenopus oocytes. In this study, we have stably and functionally expressed the human alpha 7 cDNA in a mammalian cell line, HEK-293 and examined its pharmacologic properties. [125I] alpha-Bungarotoxin b...

We compared the survival requirements of early- and late-born motoneurons from E5 chicken spinal cord. Density gradient centrifugation followed by immunopanning using SC1 antibody allowed us to purify two size classes of motoneuron. Large motoneurons retained by 6.8% metrizamide were shown by BrdU labeling in ovo to be born on average 1.5 d earlier...

In non-differentiated NG108-15 cells, both angiotensin II (Ang II) (100 nM) and CGP 42112 (100 nM) decreased the T-type calcium current amplitude by 24 +/- 2% and 21 +/- 3%, respectively. cGMP is not a mediator of the Ang II effect, since loading of cells with 50 microM cGMP did not prevent the inhibitory effects of Ang II. The effects of Ang II in...

The structure function relationship of ligand-gated channels was investigated at the molecular level using the α7 homomeric nicotinic acetylcholine receptor as a model of the superfamily of allosteric proteins. Chimera between the neuronal nicotinic acetylcholine receptor (nAChR) and the serotoninergic (5HT3) receptor revealed functional protein do...

Neuronal nicotinic acetylcholine receptors (nAChR) are made from different combinations of subunits encoded by a diverse family of genes. However, the recently cloned alpha 7 gene codes for subunits that can form homooligomeric nAChR complexes when expressed in Xenopus oocytes. Electrophysiological studies reveal that these alpha 7-nAChR function a...

We report here that angiotensin II (AII) and the AT2 receptor-selective ligand, CGP 42112, modulate the T-type calcium current in non-differentiated NG108-15 cells, which express only AT2 receptors. Both peptides decrease the T-type calcium current at membrane potentials above -40 mV and shift the current-voltage curve at lower potentials with maxi...

The release of arachidonic acid (ArA) metabolites from mouse neurons and astrocytes in primary culture has been studied in response to ionomycin or glutamate stimulation. Cells were preincubated with [3H] ArA for 24 h and the radioactivity released was examined by HPLC. In striatal, cortical and hippocampal neurons, glutamate and ionomycin strongly...

The Multi-Electrode Array (MEA) technology for the recording of brain slices is available for more than 10 years. However, despite its relative simplicity, this recording technique is not widely used in academic or pharmaceutical research laboratories. We illustrate here that MEA provide multiple possibilities to investigate some network physiologi...