The Loop Diuretic Bumetanide Blocks Posttraumatic p75NTRUpregulation and Rescues Injured Neurons
| Autor: | Eero Castrén, Thomas Carlstedt, Antonio Di Lieto, Stefan Plantman, Claudio Rivera, Urmas Arumäe, Anastasia Shulga, Anders Nykjaer, Henri Autio, Ana Cathia Magalhães, Mårten Risling |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Receptors Nerve Growth Factor Biology Mice 03 medical and health sciences chemistry.chemical_compound Organ Culture Techniques 0302 clinical medicine Sodium Potassium Chloride Symporter Inhibitors Downregulation and upregulation Neurotrophic factors medicine Animals Low-affinity nerve growth factor receptor Rats Wistar Neurotransmitter Rho-associated protein kinase Bumetanide Cells Cultured 030304 developmental biology Mice Knockout Neurons 0303 health sciences General Neuroscience Depolarization Articles Rats Up-Regulation Nerve growth factor nervous system chemistry Female sense organs Spinal Nerve Roots Neuroscience 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Shulga, A, Magalhães, A C, Autio, H, Plantman, S, di Lieto, A, Nykjær, A, Carlstedt, T, Risling, M, Arumäe, U, Castrén, E & Rivera, C 2012, ' The loop diuretic bumetanide blocks posttraumatic p75NTR upregulation and rescues injured neurons ', Journal of Neuroscience, vol. 32, no. 5, pp. 1757-70 . https://doi.org/10.1523/JNEUROSCI.3282-11.2012 |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | Injured neurons become dependent on trophic factors for survival. However, application of trophic factors to the site of injury is technically extremely challenging. Novel approaches are needed to circumvent this problem. Here, we unravel the mechanism of the emergence of dependency of injured neurons on brain-derived neurotrophic factor (BDNF) for survival. Based on this mechanism, we propose the use of the diuretic bumetanide to prevent the requirement for BDNF and consequent neuronal death in the injured areas. Responses to the neurotransmitter GABA change from hyperpolarizing in intact neurons to depolarizing in injured neurons. We showin vivoin rats andex vivoin mouse organotypic slice cultures that posttraumatic GABAA-mediated depolarization is a cause for the well known phenomenon of pathological upregulation of pan-neurotrophin receptor p75NTR. The increase in intracellular Ca2+triggered by GABA-mediated depolarization activates ROCK (Rho kinase), which in turn leads to the upregulation of p75NTR. We further show that high levels of p75NTRand its interaction with sortilin and proNGF set the dependency on BDNF for survival. Thus, application of bumetanide prevents p75NTRupregulation and neuronal death in the injured areas with reduced levels of endogenous BDNF. |
| Databáze: | OpenAIRE |
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