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A New Therapeutic Target for Spasticity and Neuropathic Pain

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A New Therapeutic Target for Spasticity and Neuropathic Pain UNIVERSITÉ D’AIX-MARSEILLE ÉCOLE DOCTORALE SCIENCES DE LA VIE ET DE LA SANTÉ FACULTÉ DE MÉDECINE UNIVERSITAT AUTÒNOMA DE BARCELONA INSTITUT DE NEUROCIÈNCIES UAB DEPARTAMENT DE BIOLOGIA CEL·LULAR, FISIOLOGIA I IMMUNOLOGIA Thesis Presented to obtain the degree of Doctor PhD program: Neuroscience Irene SANCHEZ-BRUALLA The potassium-chloride cotransporter KCC2: a new therapeutic target for spasticity and neuropathic pain Defended on November 26th 2018 before the jury: Dr. Frédérique SCAMPS (Chargé de recherche, Inserm, Montpellier) Reporter Dr. Julian TAYLOR (Directeur de recherche, Stoke Mandeville Spinal Research, Reporter Aylesbury) Dr. Sandrine BERTRAND (Directeur de recherche, CNRS, Bordeaux) Examiner Dr. Patrick DELMAS (Directeur de recherche, CNRS, Marseille) Examiner Dr. Hatice KUMRU (Praticien hospitalier, Institut Guttmann, Barcelona) Examiner Dr. Vicente MARTÍNEZ (Professeur titulaire, UAB, Barcelona) Examiner Dr. Frédéric BROCARD (Directeur de recherche, CNRS, Marseille) Thesis director Dr. Esther UDINA (Professeur titulaire, UAB, Barcelona) Thesis director This thesis was tutored by Dr. Xavier NAVARRO (Professeur titulaire, UAB, Barcelona) The potassium-chloride cotransporter KCC2 : a new therapeutic target for spasticity and neuropathic pain PhD Program in Integrative and Clinical Neuroscience Institut de Neurosciences de la Timone Aix-Marseille Université Programa de Doctorat en Neurociències Institut de Neurociències UAB Departament de Biologia Cel·lular, Fisiologia i Immunologia Universitat Autònoma de Barcelona Author Irene Sánchez Brualla Thesis director Thesis director Tutor Frédéric Brocard Esther Udina Bonet Xavier Navarro Acebes À mes directeurs, mes collègues et mes amis. A mis directores, mis compañeros de trabajo, mi familia y mis amigos. Acknowledgements Je veux remercier spécialement Laurent Vinay, sans lequel je n’aurai pas eu l’opportunité de faire cette thèse. Sa disparition prématurée a laissé un vide difficile à combler dans ce travail. Je veux remercier la Fondation A*MIDEX et le PhD Program in Integrative and Clinical Neuroscience, pour financer mon contrat doctoral. Je veux remercier aussi spécialement Frédéric Brocard, qui a été mon directeur pendant une grande partie de cette thèse, et qui m’a permis de faire une quatrième année, grâce au financement de la Fondation pour la Recherche Médicale. Vull agrair també a Esther Udina el haver estat la meva codirectora de tesi, i a Xavier Navarro el haver dedicat més temps i esforç a aquesta tesi del que es demana a un tutor. I want to thank Frédérique Scamps and Julian Taylor, for accepting to review this thesis as reporters. I want to thank also Sandrine Bertrand, Patrick Delmas, Hatice Kumru and Vicente Martínez for accepting to be part of the jury to evaluate my thesis. Merci à l’équipe Plasticité et Physio-Pathologie des réseaux Moteurs rythmiques (P3M) et à l’Institut de Neurosciences de la Timone pour votre support technique et pour les discussions qui ont contribué à l’avancement des travaux de cette thèse. Merci spécialement à Cécile Brocard et Julie Peyronnet-Roux, qui ont révisé ce manuscrit. Gràcies al Grup de Neuroplasticitat i Regeneració (GNPiR) i als membres de l’Institut de Neurociències de la UAB pel vostre support técnic i per haver contribuit a aquesta tesi amb els vostres coneixements. Gracias a mi familia y amigos cercanos. This thesis would not have been possible without the support from all of you. 4 Summary Spasticity and neuropathic pain are common symptoms affecting patients after spinal cord injury. Spasticity is defined as an increase of the muscle tone contributing to cramps, whereas neuropathic pain is characterized by painful responses caused by a damaged nervous system. Both symptoms decrease quality of life, and currently available drugs are not uniformly useful against them. Therefore, the need to expand the range of available treatments to control these diseases is a reality in clinics. Both symptoms arise from a reduced inhibition in the neural networks of the spinal cord. The inhibitory action depends on a low chloride ion concentration in postsynaptic neurons. This low chloride concentration is maintained by the potassium-chloride cotransporter type 2 (KCC2), which extrudes chloride ions from neurons. The expression of KCC2 is markedly decreased in motoneurons after spinal cord injury, which reduces inhibition and contributes to the development of spasticity. A similar reduction in the amount of KCC2 transporters happens in the dorsal horn of the spinal cord, causing neuropathic pain. KCC2 is an interesting therapeutic target to treat both spasticity and neuropathic pain. However, no marketed drug is able to increase KCC2 activity yet. The present thesis aims to identify drugs capable of activating KCC2 to recover inhibition and treat spasticity and neuropathic pain. Activation of serotoninergic 5-HT2A receptors with TCB-2 [(4-bromo-3,6- dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide] recovers KCC2 expression in motoneurons and reduces spasticity in rats with spinal cord injury. This led us to consider if TCB-2 would increase KCC2 in the dorsal horn and alleviate neuropathic pain. We found that TCB-2 increased KCC2 in the dorsal horn of rats with a spinal cord or peripheral nerve injury. TCB-2 reduces neuropathic pain too, but only on spinal cord injury; this analgesic effect is mediated by KCC2. In the next stage of the work, we performed a screening of drugs approved for human use from a library of compounds to identify a new KCC2 enhancer in a bioavailable and safe formulation. We identified prochlorperazine as an enhancer of KCC2 activity, recovering inhibition in motoneurons after spinal cord injury. Prochlorperazine alleviates spasticity with an efficacy that is similar to baclofen, the gold standard medication for the treatment of spasticity, and rescues the downregulation of KCC2 caused by the injury. Prochlorperazine also showed a modest reduction of mechanical hyperalgesia in animals with a spinal cord injury. 5 These preclinical data support prochlorperazine as a new therapy for the treatment of spasticity after spinal cord injury, having a moderate effect on neuropathic pain. Lastly, we studied the molecular mechanisms that cause the loss of KCC2 after a spinal cord injury. Our data prove that calpain is the upstream mechanism of KCC2 downregulation and motoneuron hyperexcitability after a spinal cord injury. This thesis validates KCC2 as a druggable target to treat spasticity and neuropathic pain after spinal cord injury. Keywords Spinal cord injury Spasticity Neuropathic pain KCC2 5-HT2A TCB-2 Prochlorperazine Calpain MDL28170 6 Résumé La spasticité et la douleur neuropathique sont deux symptômes qui apparaissent fréquemment après une lésion de la moelle épinière. La spasticité est définie comme une augmentation du tonus musculaire qui provoque des contractures, tandis que la douleur neuropathique se caractérise par des sensations douloureuses provoquées par une lésion du système nerveux. Les deux symptômes réduisent la qualité de vie, et les médicaments disponibles ne sont pas uniformément efficaces contre eux. Pour cette raison, le besoin d’augmenter la palette de traitements disponibles contre ces symptômes est une réalité clinique. Ces deux symptômes résultent en partie d’une désinhibition des réseaux neuronaux de la moelle épinière. Pour être efficace, l’inhibition nécessite une faible concentration de chlorure intracellulaire dans les neurones, maintenue grâce au cotransporteur potassium-chlorure type 2 (KCC2), qui extrait les ions chlorure des neurones. L’expression de KCC2 est réduite dans les motoneurones après une lésion de la moelle épinière, ce qui entraîne une perte de l’inhibition et contribue à l’apparition de la spasticité. De la même manière, une baisse de l’expression de KCC2 dans la corne dorsale de la moelle épinière, engendre le développement d’une douleur neuropathique. KCC2 semble donc être une cible thérapeutique intéressante pour traiter la spasticité et la douleur neuropathique. Malheureusement, il n’éxiste pas encore des médicaments commercialisés capables d’augmenter l’expression et l’activité des cotransporteurs KCC2. L’objectif de la présente thèse est d’identifier des médicaments capables d’activer KCC2 pour restaurer l’inhibition afin de traiter la spasticité et la douleur neuropathique. L’activation de récepteurs sérotoninergiques 5-HT2A avec le TCB-2 [(4-bromo-3,6- dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide] rétablit l’expression de KCC2 et réduit la spasticité des rats ayant subi une lésion de la moelle épinière. Ceci nous a amené à étudier l’effet du TCB-2 sur l’expression de KCC2 dans la corne dorsale et vérifier son action sur la douleur neuropathique. Nous avons découvert que TCB-2 augmente KCC2 dans la corne dorsale de rats après une lésion de la moelle épinière ou de nerf périphérique. TCB-2 réduit aussi la douleur neuropathique, mais seulement à la suite d’une lésion médullaire ; ainsi KCC2 semble intervenir dans l’effet antalgique. Dans l’étape suivante du travail, nous avons fait un screening d’une librairie de médicaments approuvés pour un usage chez l’homme, afin de déterminer un nouveau médicament capable d’augmenter l’expression et/ou la fonctionnalité de KCC2, en une 7 formulation biodisponible et sûre. Nous avons identifié la prochlorperazine comme une molécule susceptible d’augmenter l’activité de KCC2. Si la prochlorperazine réduit la spasticité avec une efficacité similaire au baclofène, médicament généralement prescrit
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