Neuroprotective effect of the chemical chaperone, trehalose in a chronic MPTP-induced Parkinson's disease mouse model
Autor: | Larry C. Schmued, Dushyant Mann, James Raymick, Joseph P. Hanig, Merle G. Paule, John F. Bowyer, Thomas C. Schmitt, Richard D. Beger, Srinivasulu Chigurupati, Sumit Sarkar |
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Rok vydání: | 2014 |
Předmět: |
Male
medicine.medical_specialty Tyrosine 3-Monooxygenase Substantia nigra Nerve Tissue Proteins Biology Toxicology Neuroprotection chemistry.chemical_compound Mice Parkinsonian Disorders Dopamine Internal medicine Glial Fibrillary Acidic Protein medicine Animals Dopamine Plasma Membrane Transport Proteins Glucose Transporter Type 1 Tyrosine hydroxylase Pars compacta General Neuroscience MPTP Trehalose Corpus Striatum nervous system diseases Cell biology Mice Inbred C57BL Disease Models Animal Endocrinology Neuroprotective Agents nervous system chemistry Zonula Occludens-1 Protein Encephalitis Microglia Chemical chaperone medicine.drug Molecular Chaperones |
Zdroj: | Neurotoxicology. 44 |
ISSN: | 1872-9711 |
Popis: | Parkinson's disease (PD) is a progressive motor disease of unknown etiology in the majority of cases. The clinical features of PD emerge due to selective degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc), which project to the caudate putamen (CPu) where they release DA. In the current in vivo mouse model study, we tested trehalose for its ability to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced damage to DA neurons. Trehalose is a naturally occurring disaccharide present in plants and animals and appears capable of protecting cells against various environmental stresses. The effect of trehalose is likely due to its action as a pharmacological chaperone which promotes protein stability. In the present study, there were four treatment groups: saline only (control); probenecid only; MPTP + probenecid; and trehalose + MPTP + probenecid. MPTP-induced losses in tyrosine hydroxylase and DA transporter immunoreactivity in the ventral midbrain SNc and CPu were significantly reduced by trehalose. Decreases in CPu dopamine levels produced by MPTP were also blocked by trehalose. Microglial activation and astrocytic hypertrophy induced by MPTP were greatly reduced by trehalose, indicating protection against neuroinflammation. These effects are commensurate with the observed trehalose sparing of motor deficits produced by MPTP in this mouse model. Two tight junctional proteins, ZO-1 and occludin, are downregulated following MPTP treatment and trehalose blocks this effect. Likewise, the glucose transporter-1 that is expressed in brain endothelial cells is also protected by trehalose from MPTP-induced down-regulation. This study is the first to demonstrate using fluoro-turoquoise FT gel perfusion techniques, the protection afforded by trehalose from MPTP-induced damage to microvessels and endothelial and suggests that trehalose therapy may have the potential to slow or ameliorate PD pathology. |
Databáze: | OpenAIRE |
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