RGD Reference Report - The loop diuretic bumetanide blocks posttraumatic p75NTR upregulation and rescues injured neurons. - Rat Genome Database

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The loop diuretic bumetanide blocks posttraumatic p75NTR upregulation and rescues injured neurons.

Authors: Shulga, A  Magalhaes, AC  Autio, H  Plantman, S  Di Lieto, A  Nykjaer, A  Carlstedt, T  Risling, M  Arumae, U  Castren, E  Rivera, C 
Citation: Shulga A, etal., J Neurosci. 2012 Feb 1;32(5):1757-70. doi: 10.1523/JNEUROSCI.3282-11.2012.
RGD ID: 10413905
Pubmed: PMID:22302815   (View Abstract at PubMed)
PMCID: PMC6703341   (View Article at PubMed Central)
DOI: DOI:10.1523/JNEUROSCI.3282-11.2012   (Journal Full-text)

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 show in vivo in rats and ex vivo in mouse organotypic slice cultures that posttraumatic GABA(A)-mediated depolarization is a cause for the well known phenomenon of pathological upregulation of pan-neurotrophin receptor p75(NTR). The increase in intracellular Ca(2+) triggered by GABA-mediated depolarization activates ROCK (Rho kinase), which in turn leads to the upregulation of p75(NTR). We further show that high levels of p75(NTR) and its interaction with sortilin and proNGF set the dependency on BDNF for survival. Thus, application of bumetanide prevents p75(NTR) upregulation and neuronal death in the injured areas with reduced levels of endogenous BDNF.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Peripheral Nerve Injuries  ISONgfr (Rattus norvegicus)10413905; 10413905 RGD 
Peripheral Nerve Injuries  IEP 10413905 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ngfr  (nerve growth factor receptor)

Genes (Mus musculus)
Ngfr  (nerve growth factor receptor (TNFR superfamily, member 16))

Genes (Homo sapiens)
NGFR  (nerve growth factor receptor)


Additional Information