PET imaging studies show enhanced expression of mGluR5 and inflammatory response during progressive degeneration in ALS mouse model expressing SOD1-G93A geneReport as inadecuate




PET imaging studies show enhanced expression of mGluR5 and inflammatory response during progressive degeneration in ALS mouse model expressing SOD1-G93A gene - Download this document for free, or read online. Document in PDF available to download.

Journal of Neuroinflammation

, 12:217

First Online: 24 November 2015Received: 05 June 2015Accepted: 18 November 2015

Abstract

BackgroundAmyotrophic lateral sclerosis ALS is a progressive neurodegenerative motor neuron disorder. Genetic studies have linked mutation of the gene SOD1 to ALS pathology as well as several other pathological processes including modulation of glutamatergic function and inflammatory processes. Since therapeutic approaches for ALS are focused on glutamatergic function, we investigated modulation of glutamate transport based on its receptor function as well as excitotoxicity-induced inflammatory response.

MethodsIn vivo positron emission tomography PET imaging studies of metabotropic glutamate receptor subtype 5 mGluR5 using FFPEB F3-fluoro-5-2-pyridylethynylbenzonitrile and inflammatory response using CPBR28 peripheral benzodiazepine receptor ligand 28 were done in an early and a late phase of neurodegeneration in four ALS mice expressing SOD1-G93A gene and four control base mice C57-BL6. Accumulation of FFPEB and CPBR28 were quantitated in several brain areas and spinal cord to determine degeneration-induced modulation. The studies were completed with immunohistochemical analyses of mGluR5 and inflammatory response.

ResultsThese studies showed enhanced binding potential of FFPEB in several brain areas including striatum, hippocampus, and frontal cortex. In the whole brain, the binding potential increased 49 ± 9 % from base mice to ALS-type mice and further enhanced 23 ± 4 % during disease progression. Also, in the spinal cord 6–22 %, enhanced accumulation of FFPEB was observed during progression of the disease. The accumulation of CPBR28 increased by 110 ± 33 % in the whole brain during progression of the disease indicating significant inflammatory process. CPBR28 accumulation enhanced 89–264 % in the spinal cord and 204 % in the lungs. The end point immunohistochemical analyses verified the enhanced mGluR5 expression and inflammation.

ConclusionsThese results confirm the role of glutamate and inflammation in ALS-type pathology. These data also support the hypothesis that excessive glutamate may contribute to inflammation in the chronic neurodegenerative processes in ALS.

KeywordsALS Glutamate mGluR5 Inflammation FFPEB CPBR28 AbbreviationsCPBR28peripheral benzodiazepine receptor ligand 28

FFPEBF3-fluoro-5-2-pyridylethynylbenzonitrile

3D-MLEMthree-dimensional-minimum likelihood estimation method

ALSamyotrophic lateral sclerosis

BPNDbinding potential using reference tissue model

CTcomputerized tomography

DAB3,3′-diaminobenzidine

IBA1marker for inflammation calcium binding adaptor molecule

IHSimmunohistological studies

mCimilli Curie

mGluR5metabotropic glutamate receptor subtype 5

PETpositron emission tomography

PFAparaformaldehyde

SOD1-G93Asuperoxide dismutase 1-glycine 93S mutation glycine 93 changed to alanine

TSPOtranslocator protein 18 kDA kilo Dalton

μmolmicromole

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Author: Anna-Liisa Brownell - Darshini Kuruppu - Kun-Eek Kil - Kimmo Jokivarsi - Pekka Poutiainen - Aijun Zhu - Michelle Maxwell

Source: https://link.springer.com/



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