title: Metallic gold slows disease progression, reduces cell death and induces astrogliosis while simultaneously increasing stem cell responses in an EAE rat model of multiple sclerosis.
abstract: Multiple sclerosis (MS) is the most common neurodegenerative disease in the Western world affecting younger, otherwise healthy individuals. Today no curative treatment exists. Patients suffer from recurring attacks caused by demyelination and underlying neuroinflammation, ultimately leading to loss of neurons. Recent research shows that bio-liberation of gold ions from metallic gold implants can ameliorate inflammation, reduce apoptosis and promote proliferation of neuronal stem cells (NSCs) in a mouse model of focal brain injury. Based on these findings, the present study investigates whether metallic gold implants affect the clinical signs of disease progression and the pathological findings in experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. Gold particles 20-45 μm suspended in hyaluronic acid were bilaterally injected into the lateral ventricles (LV) of young Lewis rats prior to EAE induction. Comparing gold-treated animals to untreated and vehicle-treated ones, a statistically significant slowing of disease progression in terms of reduced weight loss was seen. Despite massive inflammatory infiltration, terminal deoxynucleotidyl transferase dUTP nick end labeling staining revealed reduced apoptotic cell death in disease foci in the brain stem of gold-treated animals, alongside an up-regulation of glial fibrillary acidic protein-positive reactive astrocytes near the LV and in the brain stem. Cell counting of frizzled-9 and nestin-stained cells showed statistically significant up-regulation of NSCs migrating from the subventricular zone. Additionally, the neuroprotective proteins Metallothionein-1 and -2 were up-regulated in the corpus callosum. In conclusion, this study is the first to show that the presence of small gold implants affect disease progression in a rat model of MS, increasing the neurogenic response and reducing the loss of cells in disease foci. Gold implants might thus improve clinical outcome for MS patients and further research into the long-term effects of such localized gold treatment is warranted.
authors: Department of Biomedicine, Pharmacology, Aarhus University, Wilhelm Meyers Allé 4, Building 1240, 3rd Floor, 8000, Aarhus C, Denmark. dspe@farm.au.dk
authors: Dan Sonne
authors: DS
authors: Pedersen
authors: Pil Møntegaard
authors: PM
authors: Fredericia
authors: Mie Ostergaard
authors: MO
authors: Pedersen
authors: Meredin
authors: M
authors: Stoltenberg
authors: Milena
authors: M
authors: Penkowa
authors: Gorm
authors: G
authors: Danscher
authors: Jørgen
authors: J
authors: Rungby
authors: Agnete
authors: A
authors: Larsen
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D003337:Corpus Callosum / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D005911:Gliosis / Q000139:chemically induced* / Q000473:pathology; D006046:Gold / Q000627:therapeutic use*; D007381:Intermediate Filament Proteins / Q000032:analysis; D020547:Lateral Ventricles / Q000187:drug effects / Q000473:pathology; D008668:Metallothionein / Q000032:analysis; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000032:analysis; D064231:Nestin; D058953:Neural Stem Cells / Q000187:drug effects / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D017981:Receptors, Neurotransmitter / Q000032:analysis; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C498590:Fzd9 protein, rat; D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; C491055:Mt2A protein, rat; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; C577486:Nes protein, rat; D064231:Nestin; D017981:Receptors, Neurotransmitter; D006046:Gold; D008668:Metallothionein