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.

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.

Bio-released gold ions modulate expression of neuroprotective and hematopoietic factors after brain injury.

The discovery of neural stem cells (NSCs) provides new therapeutic strategies for brain injury by means of endogenous cell renewal. In the injured mouse brain, bio-liberated gold ions from gold implants mediate anti-inflammatory and antiapoptotic effects and activation of NSCs. This paper investigates the neuroprotective effects of gold following brain injury in mice. We show for the first time that endogenous NSCs express macrophage colony-stimulating factor (M-CSF) as part of their post-injury activation and that gold implants increase this response. Also, gold increases expression of neurotrophin (NT)-4, transforming growth factor-beta 3 (TGF-beta 3), leukemia inhibitory factor (LIF) and metallothionein I+II (MT-I+II) post-injury. This paper shows that gold ions modulate neurotrophic factors after injury and that hematopoietic factor M-CSF is expressed in activated NSCs.

Metallic gold treatment reduces proliferation of inflammatory cells, increases expression of VEGF and FGF, and stimulates cell proliferation in the subventricular zone following experimental traumatic brain injury.

UNLABELLED: Traumatic brain injury represents a leading cause of morbidity in young individuals and there is an imperative need for neuroprotective treatments limiting the neurologic impairment following such injury. It has recently been demonstrated that bio-liberated gold ions liberated from small metallic gold implants reduce inflammation and neuronal apoptosis, while generating an increased neuronal stem cell response following focal brain damage. In this study mice were subjected to a unilateral traumatic cryo-lesion with concomitant injection of 25-45 microm gold particles near the lesion. Placebo-treated mice subjected to cryo-lesion served as controls. The effects of gold-treatment were investigated by examining gold-induced growth factor expression (VEGF and FGF) in the first two weeks after the insult, and the extent of the neurostimulatory effect of gold was explored by comparing cell proliferation in the subventricular zone as judged by immunohistochemical staining for CDC47. Vimentin staining revealed a decrease in activated microglia and a transient astrogliosis in response to the gold liberation. Moreover, gold ions significantly increase the expression of VEGF and FGF following trauma and a significant increase in cell proliferation in both the ipsilateral and the contralateral subventricular zone was found in response to gold-treatment. IN CONCLUSION: we confirmed the previously demonstrated anti-inflammatory effect of bio-liberated gold ions, and further show that metallic gold increases growth factor expression and adult neurogenesis.

Metallic gold reduces TNFalpha expression, oxidative DNA damage and pro-apoptotic signals after experimental brain injury.

Brain injury represents a major health problem and may result in chronic inflammation and neurodegeneration. Due to antiinflammatory effects of gold, we have investigated the cerebral effects of metallic gold particles following a focal brain injury (freeze-lesion) in mice. Gold particles 20-45 microm in size or the vehicle (placebo) were implanted in the cortical tissue followed by a cortical freeze-lesioning. At 1-2 weeks post-injury, brains were analyzed by using immunohistochemistry and markers of inflammation, oxidative stress and apoptosis. This study shows that gold treatment significantly reduces the cerebral levels of tumor necrosis factor alpha (TNFalpha), oxidative DNA damage (as judged by 8-oxoguanine levels), and pro-apoptotic markers (cleaved caspase-3, cytochrome c leakage), when compared to those of controls. The data presented here points toward gold particles as a tool to modulate the cerebral response to injury.

Gold ions bio-released from metallic gold particles reduce inflammation and apoptosis and increase the regenerative responses in focal brain injury.

Traumatic brain injury results in loss of neurons caused as much by the resulting neuroinflammation as by the injury. Gold salts are known to be immunosuppressive, but their use are limited by nephrotoxicity. However, as we have proven that implants of pure metallic gold release gold ions which do not spread in the body, but are taken up by cells near the implant, we hypothesize that metallic gold could reduce local neuroinflammation in a safe way. Bio-liberation, or dissolucytosis, of gold ions from metallic gold surfaces requires the presence of disolycytes i.e. macrophages and the process is limited by their number and activity. We injected 20-45 mum gold particles into the neocortex of mice before generating a cryo-injury. Comparing gold-treated and untreated cryolesions, the release of gold reduced microgliosis and neuronal apoptosis accompanied by a transient astrogliosis and an increased neural stem cell response. We conclude that bio-liberated gold ions possess pronounced anti-inflammatory and neuron-protective capacities in the brain and suggest that metallic gold has clinical potentials. Intra-cerebral application of metallic gold as a pharmaceutical source of gold ions represents a completely new medical concept that bypasses the blood-brain-barrier and allows direct drug delivery to inflamed brain tissue.

[Neisseria meningitidis. The pathophysiological role of lipopolysaccharides in association with meningococcal disease and septic shock]. / Neisseria meningitidis. Lipopolysakkariders patofysiologiske rolle ved meningokoksygdom og septisk shock.

A major pro-inflammatory and toxic component of N. meningitidis is lipopolysaccharide (LPS). LPS contributes to severe symptoms of meningococcal disease, septic shock and severe coagulopathy, in part by increasing pro-inflammatory mechanisms and reactive oxygen species. Recent technologies have increased the likelihood of developing an anti-meningococcal immunization strategy based upon the virulence of LPS which may lead to a vaccination against this important pathogen including serogroup B disease. This review summarizes recent findings that may provide a safe, effective prophylaxis and therapy.