The influence of metallothionein treatment and treadmill running exercise on disease onset and survival in SOD1 amyotrophic lateral sclerosis mice.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterised by the degeneration of motor neurons innervating skeletal muscle. The mechanisms underlying neurodegeneration in ALS are not yet fully elucidated, and with current therapeutics only able to extend lifespan by a matter of months there is a clear need for novel therapies to increase lifespan and patient quality of life. Here, we evaluated whether moderate-intensity treadmill exercise and/or treatment with metallothionein-2 (MT2), a neuroprotective protein, could improve survival, behavioural or neuropathological outcomes in SOD1 familial ALS mice.

Combination treatment with leptin and pioglitazone in a mouse model of Alzheimer's disease.

Introduction: Combination therapy approaches may be necessary to address the many facets of pathologic change in the brain in Alzheimer's disease (AD). The drugs leptin and pioglitazone have previously been shown individually to have neuroprotective and anti-inflammatory actions, respectively, in animal models.

Methods: We studied the impact of combined leptin and pioglitazone treatment in 6-month-old APP/PS1 (APPswe/PSEN1dE9) transgenic AD mouse model.

Connectivity of Pathology: The Olfactory System as a Model for Network-Driven Mechanisms of Alzheimer's Disease Pathogenesis.

The pathogenesis of Alzheimer's disease (AD) has been postulated to preferentially impact specific neural networks in the brain. The olfactory system is a well-defined network that has been implicated in early stages of the disease, marked by impairment in olfaction and the presence of pathological hallmarks of the disease, even before clinical presentation. Discovering the cellular mechanisms involved in the connectivity of pathology will provide insight into potential targets for treatment.

Diffuse axonal injury in brain trauma: insights from alterations in neurofilaments.

Traumatic brain injury (TBI) from penetrating or closed forces to the cranium can result in a range of forms of neural damage, which culminate in mortality or impart mild to significant neurological disability. In this regard, diffuse axonal injury (DAI) is a major neuronal pathophenotype of TBI and is associated with a complex set of cytoskeletal changes. The neurofilament triplet proteins are key structural cytoskeletal elements, which may also be important contributors to the tensile strength of axons.

Olfactory ensheathing cells are the main phagocytic cells that remove axon debris during early development of the olfactory system.

During development of the primary olfactory system, axon targeting is inaccurate and axons inappropriately project within the target layer or overproject into the deeper layers of the olfactory bulb. As a consequence there is considerable apoptosis of primary olfactory neurons during embryonic and postnatal development and axons of the degraded neurons need to be removed. Olfactory ensheathing cells (OECs) are the glia of the primary olfactory nerve and are known to phagocytose axon debris in the adult and postnatal animal.

Microglia and motor neurons during disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis: changes in arginase1 and inducible nitric oxide synthase.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the motor system. Although the etiology of the disease is not fully understood, microglial activation and neuroinflammation are thought to play a role in disease progression.

Methods: We examined the immunohistochemical expression of two markers of microglial phenotype, the arginine-metabolizing enzymes inducible nitric oxide synthase (iNOS) and arginase1 (Arg1), in the spinal cord of a mouse model carrying an ALS-linked mutant human superoxide dismutase transgene (SOD1(G93A)) and in non-transgenic wild-type (WT) mice.

Denervation of the olfactory bulb leads to decreased Aβ plaque load in a transgenic mouse model of Alzheimer' s disease.

The aggregation of beta-amyloid (Aβ) into plaques in the extracellular compartment of the brain is a pathological hallmark of Alzheimer' s disease (AD). Although the pathways for misprocessing of Aβ leading to plaque formation are not well understood, they may be related to synapse turnover and neuron activity. In this study, we have utilised transgenic mice co-expressing mutations in the amyloid precursor protein and presenilin 1 genes (APP/PS1) to determine how long-term denervation of the olfactory bulb, a CNS area affected early by AD-like pathology, may affect Aβ plaque formation.

Distribution of exogenous metallothionein following intraperitoneal and intramuscular injection of metallothionein-deficient mice.

Metallothionein-I/II (MT-I/II) is a small metal-binding protein with antioxidant and neuroprotective properties, which has been used experimentally as a neurotherapeutic agent in multiple conditions. Therefore it is important to determine whether exogenous MT-I/II is retained in specific organs or expelled from the body following intramuscular and intraperitoneal injection. The distribution of exogenous MT-IIA (the major human MT-I/II isoform) was examined in MT-I/II-deficient mice, by immunohistochemistry of tissue samples and western blotting of urine samples.

Cytokines and olfactory bulb microglia in response to bacterial challenge in the compromised primary olfactory pathway.

Background: The primary olfactory pathway is a potential route through which microorganisms from the periphery could potentially access the central nervous system. Our previous studies demonstrated that if the olfactory epithelium was damaged, bacteria administered into the nasal cavity induced nitric oxide production in olfactory ensheathing cells. This study investigates the cytokine profile of olfactory tissues as a consequence of bacterial challenge and establishes whether or not the bacteria are able to reach the olfactory bulb in the central nervous system.

Metallothionein promotes regenerative axonal sprouting of dorsal root ganglion neurons after physical axotomy.

Prior studies have reported that metallothionein I/II (MT) promote regenerative axonal sprouting and neurite elongation of a variety of central nervous system neurons after injury. In this study, we evaluated whether MT is capable of modulating regenerative axon outgrowth of neurons from the peripheral nervous system. The effect of MT was firstly investigated in dorsal root ganglion (DRG) explants, where axons were scratch-injured in the presence or absence of exogenous MT.

Transcriptional insights on the regenerative mechanics of axotomized neurons in vitro.

Axotomized neurons have the innate ability to undergo regenerative sprouting but this is often impeded by the inhibitory central nervous system environment. To gain mechanistic insights into the key molecular determinates that specifically underlie neuronal regeneration at a transcriptomic level, we have undertaken a DNA microarray study on mature cortical neuronal clusters maintained in vitro at 8, 15, 24 and 48 hrs following complete axonal severance. A total of 305 genes, each with a minimum fold change of ± 1.

Olfactory ensheathing cells moderate nuclear factor kappaB translocation in astrocytes.

Nuclear factor kappaB (NFκB) is a key transcriptional regulator of inflammatory genes. We investigated the modulatory effects of olfactory ensheathing cells (OECs), microglia and meningeal fibroblasts on translocation of NFκB to astrocyte nuclei. The percentage of activated astrocytes in co-cultures with OECs was significantly less than for co-cultures with microglia (p<0.

Interaction of olfactory ensheathing cells with other cell types in vitro and after transplantation: glial scars and inflammation.

Olfactory ensheathing cells (OECs) have been investigated extensively as a therapy to promote repair in the injured CNS, with variable efficacy in numerous studies over the previous decade. In many studies that report anatomical and functional recovery, the beneficial effects have been attributed to the ability of OECs to cross the PNS-CNS boundary, their production of growth factors, cell adhesion molecules and extracellular matrix proteins that promote and guide axon growth, and their ability to remyelinate axons. In this brief review, we focus on the interaction between OECs and astrocytes in vivo and in vitro, in the context of how OECs may be overcoming the deleterious effects of the glial scar.

Glycoconjugates within the oviduct and their functional significance with special reference to marsupials.

In placental (eutherian) mammals, a number of important events take place within the oviduct including the pre-fertilisation maturation of gametes (including sperm storage), sperm-egg interactions, egg activation and early embryonic development. Many of these events involve interactions of glycoconjugates; both on the surface of the gametes and with the secretions of the oviductal epithelium and these have best been studied in eutherian mammals. In marsupials, however, while the oviduct is known to produce the extracellular egg coat, the mucoid layer, that comes to surround the zona pellucida, its role in the maturation of gametes is only now being elucidated, particularly in the oocyte.

Olfactory ensheathing cells: nitric oxide production and innate immunity.

Olfactory nerves extend from the nasal cavity to the central nervous system and provide therefore, a direct route for pathogenic infection of the brain. Since actual infection by this route remains relatively uncommon, powerful endogenous mechanisms for preventing microbial infection must exist, but these remain poorly understood. Our previous studies unexpectedly revealed that the unique glial cells that ensheath olfactory nerves, olfactory ensheathing cells (OECs), expressed components of the innate immune response.

Redefining the role of metallothionein within the injured brain: extracellular metallothioneins play an important role in the astrocyte-neuron response to injury.

A number of intracellular proteins that are protective after brain injury are classically thought to exert their effect within the expressing cell. The astrocytic metallothioneins (MT) are one example and are thought to act via intracellular free radical scavenging and heavy metal regulation, and in particular zinc. Indeed, we have previously established that astrocytic MTs are required for successful brain healing.

Bacteria and PAMPs activate nuclear factor kappaB and Gro production in a subset of olfactory ensheathing cells and astrocytes but not in Schwann cells.

The primary olfactory nerves provide uninterrupted conduits for neurotropic pathogens to access the brain from the nasal cavity, yet infection via this route is uncommon. It is conceivable that olfactory ensheathing cells (OECs), which envelope the olfactory nerves along their entire length, provide a degree of immunological protection against such infections. We hypothesized that cultured OECs would be able to mount a biologically significant response to bacteria and pathogen-associated molecular patterns (PAMPs).

Morphological and functional plasticity of olfactory ensheathing cells.

In the primary olfactory pathway, olfactory ensheathing cells (OECs) extend processes to envelop bundles of olfactory axons as they course towards their termination in the olfactory bulb. The expression of growth-promoting adhesion and extracellular matrix molecules by OECs, and their spatially close association with olfactory axons are consistent with OECs being involved in promoting and guiding olfactory axon growth. Because of this, OECs have been employed as a possible tool for inducing axonal regeneration in the injured adult CNS, resulting in significant functional recovery in some animal models and promising outcomes from early clinical applications.

Spinal cord tissue affects ensheathing cell proliferation and apoptosis.

This study investigates proliferation and apoptosis of olfactory ensheathing cells in cocultures with spinal cord tissue. Proliferation of ensheathing cells was significantly increased when cocultured with explants from uninjured spinal cord, and spinal cord that had been subjected to chronic contusion or chronic needle stab injury, but not to acute needle stab injury. Proliferation rate was highest in cocultures with chronically stabbed cord tissue.

Genetic expression profile of olfactory ensheathing cells is distinct from that of Schwann cells and astrocytes.

Olfactory ensheathing cells (OECs) accompany the axons of olfactory receptor neurons, which regenerate throughout life, from the olfactory mucosa into the olfactory bulb. OECs have shown widely varying efficacy in repairing the injured nervous system. Analysis of the transcriptome of OECs will help in understanding their biology and will provide tools for investigating the mechanisms of their efficacy and interactions with host tissues in lesion models.

alpha-Internexin immunoreactivity reflects variable neuronal vulnerability in Alzheimer's disease and supports the role of the beta-amyloid plaques in inducing neuronal injury.

This study investigated the role of alpha-internexin in the neuronal alterations associated with beta-amyloid plaque formation in Alzheimer's disease (AD). Cortical neurons could be defined by their variable content of neurofilament (NF) triplet and alpha-internexin proteins, with a distinct population of supragranular pyramidal cells containing alpha-internexin alone. Both NF triplet and alpha-internexin were localized to reactive axonal structures in physically damaged neurons in experimental trauma models.

Protective role of metallothioneins in the injured mammalian brain.

Metallothioneins (MTs) are small cysteine-rich proteins which are found widely throughout the mammalian body, including the CNS. There are extensive data on the structure and expression of MTs, and many basic properties pertinent to MT biology in the CNS appear to be well established. As discussed in this review, one isoform class (MT-I/II) is rapidly induced following many types of CNS insult, and is strongly neuroprotective, whilst another isoform class (MT-III) shows major differences in its expression profile and physiological properties.

Neuron-glia communication: metallothionein expression is specifically up-regulated by astrocytes in response to neuronal injury.

Recent data suggests that metallothioneins (MTs) are major neuroprotective proteins within the CNS. In this regard, we have recently demonstrated that MT-IIA (the major human MT-I/-II isoform) promotes neural recovery following focal cortical brain injury. To further investigate the role of MTs in cortical brain injury, MT-I/-II expression was examined in several different experimental models of cortical neuron injury.

Metallothionein-IIA promotes initial neurite elongation and postinjury reactive neurite growth and facilitates healing after focal cortical brain injury.

Metallothioneins (MTs) are small, cysteine-rich, metal binding proteins. Their function has often been considered as stress-related proteins capable of protecting cells from heavy metal toxicity and oxidative free radicals. However, recent interest has focused on the brain-specific MT-III isoform, which has neurite-inhibitory properties.

Morphological plasticity of olfactory ensheathing cells is regulated by cAMP and endothelin-1.

Olfactory ensheathing cells (ECs) are a promising tool for the repair of injury in the adult central nervous system. However, important aspects of the cell biology of ECs remain unclear, such as whether ECs exist as a single population or as two subpopulations with Schwann cell-like and astrocyte-like characteristics. The morphologies of these subpopulations are used as defining characteristics, yet ECs are known to be morphologically plastic.