Home About us Contact
|
Home About us Contact | ||
|
|
||
Motor Neuron Loss (motor + neuron_loss)
Selected AbstractsNAALADase (GCP II) inhibitors protect in models of amyotrophic lateral sclerosis (ALS)JOURNAL OF NEUROCHEMISTRY, Issue 2002A. G. Thomas Chronic glutamate toxicity is implicated in the pathogenesis of ALS. The neuropeptide N-acetyl-aspartyl glutamate (NAAG) appears to function both as a storage form for glutamate and as a neuromodulator at glutamatergic synapses. Catabolism of NAAG by N-acetylated-,-linked acidic dipeptidase (NAALADase; also termed glutamate carboxypeptidase II), yields N-acetyl aspartate (NAA) and glutamate. Since prior studies demonstrate an up-regulation of NAALADase in motor cortex and increased levels of NAA and glutamate in the CSF of ALS patients, we hypothesized that inhibition of NAALADase could protect against neuronal degeneration in ALS. Neuroprotective effects of two NAALADase inhibitors were assessed. 2-(Phosphonomethyl)pentanedioic acid (2-PMPA) decreased motor neuron loss and prevented loss of choline acetyltransferase (ChAT) activity in an in vitro model of ALS wherein chronic glutamate toxicity was induced by blocking glutamate transport. Gross morphology was preserved in 2-PMPA-treated cultures. In a SOD-1 transgenic mouse model of ALS, oral administration of a structurally different NAALADase inhibitor (GPI 5693) increased survival by 29 days and delayed onset of clinical symptoms by 17 days. Preliminary analysis of spinal cord pathology revealed severe neuronal depletion and astrocytosis with white matter changes in control mice. In mice treated with GPI 5693, normal neuronal populations with modest vacuolar changes were observed. These data suggest that NAALADase inhibition may provide an exciting therapeutic approach to the devastating disease, ALS. [source] Therapeutic benefits of intrathecal protein therapy in a mouse model of amyotrophic lateral sclerosisJOURNAL OF NEUROSCIENCE RESEARCH, Issue 13 2008Yasuyuki Ohta Abstract When fused with the protein transduction domain (PTD) derived from the human immunodeficiency virus TAT protein, proteins can cross the blood,brain barrier and cell membrane and transfer into several tissues, including the brain, making protein therapy feasible for various neurological disorders. We have constructed a powerful antiapoptotic modified Bcl-XL protein (originally constructed from Bcl-XL) fused with PTD derived from TAT (TAT-modified Bcl-XL), and, to examine its clinical effectiveness in a mouse model of familial amyotrophic lateral sclerosis (ALS), transgenic mice expressing human Cu/Zn superoxide dismutase (SOD1) bearing a G93A mutation were treated by intrathecal infusion of TAT-modified Bcl-XL. We demonstrate that intrathecally infused TAT-fused protein was effectively transferred into spinal cord neurons, including motor neurons, and that intrathecal infusion of TAT-modified Bcl-XL delayed disease onset, prolonged survival, and improved motor performance. Histological studies show an attenuation of motor neuron loss and a decrease in the number of cleaved caspase 9-, cleaved caspase 3-, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells in the lumbar cords of TAT-modified Bcl-XL -treated G93A mice. Our results indicate that intrathecal protein therapy using a TAT-fused protein is an effective clinical tool for the treatment of ALS. © 2008 Wiley-Liss, Inc. [source] Prevention of spinal motor neuron death by insulin-like growth factor-1 associating with the signal transduction systems in SODG93A transgenic miceJOURNAL OF NEUROSCIENCE RESEARCH, Issue 4 2005Hisashi Narai Abstract The role of insulin-like growth factor-1 (IGF-1) in amyotrophic lateral sclerosis (ALS) and its mechanism of action are important from both pathogenic and therapeutic points of view. The present study investigated the changes of IGF-1R, and the key intracellular downstream protein insulin receptor substrate-1 (IRS-1) by using SOD1G93A transgenic mice with continuous intrathecal IGF-1 treatment. The number of lumbar spinal motor neurons was preserved with IGF-1 treatment in a dose-dependent manner. The numbers of immunopositive motor neurons for IGF-1R, and IRS-1 were not significantly different between wild-type and Tg mice with vehicle treatment, whereas treatment of Tg mice with IGF-1 decreased the numbers of immunopositive motor neurons in a dose-dependent manner. On the other hand, the ratio of immunopositive motor neurons per total living motor neurons in vehicle-treated mice was greatly increased in Tg mice with vehicle treatment compared with wild-type mice. With IGF-1 treatment, the ratio was dramatically decreased in a dose-dependent manner. These results suggest that IGF-1 treatment prevents motor neuron loss by affecting the signal transduction system through IGF-1R and the main downstream signal, IRS-1. © 2005 Wiley-Liss, Inc. [source] Oxidative stress and antioxidant enzyme upregulation in SOD1-G93A mouse skeletal muscleMUSCLE AND NERVE, Issue 6 2006Douglas J. Mahoney PhD Abstract Amyotrophic lateral sclerosis (ALS) is caused by motor neuron loss in the spinal cord, but the mechanisms responsible are not known. Ubiquitous transgenic overexpression of copper/zinc superoxide dismutase (SOD1) mutations causing familial ALS (SOD1mut) leads to an ALS phenotype in mice; however, restricted expression of SOD1mut in neurons alone is not sufficient to cause this phenotype, suggesting that non-neuronal SOD1mut expression is also required for disease manifestation. Recently, several investigators have suggested that SOD1mut -mediated oxidative stress in skeletal muscle may contribute to ALS pathogenesis. The purpose of this study was to examine oxidative stress and antioxidant enzyme adaptation in 95-day-old SOD1-G93A skeletal muscle. We observed significant elevations in both malondialdehyde (22% and 31% in red and white gastrocnemius, respectively) and protein carbonyls (53% in red gastrocnemius) in SOD1-G93A mice. Copper/zinc SOD activity was higher in red and white SOD1-G93A gastrocnemius (7- and 10-fold, respectively), as was manganese SOD (4- and 5-fold, respectively) and catalase (2- and 2.5-fold, respectively). Taken together, our data demonstrate oxidative stress and compensatory antioxidant enzyme upregulation in SOD1-G93A skeletal muscle. Muscle Nerve, 2006 [source] Lower motor neuron loss in multiple sclerosis and experimental autoimmune encephalomyelitis,ANNALS OF NEUROLOGY, Issue 3 2009Johannes Vogt MD Objective Multiple sclerosis (MS) is considered a chronic inflammatory and demyelinating disease of the central nervous system. Evidence that axonal and neuronal pathology contributes to the disease is accumulating, however, the distribution of neuronal injury as well as the underlying mechanisms have not yet been fully clarified. Here, we investigated the role of neuronal cell loss in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Methods We performed electrophysiological investigations in MS patients, including assessment of compound muscle action potentials and motor unit numbers and quantified neuronal cell loss in human MS samples and different EAE models by high-precision stereology. Results Both electrophysiological and morphological analyses indicated a massive loss of lower motor neurons in MS patients. We regularly found dying spinal motor neurons surrounded by CD3+ (CD4+ as well as CD8+) T cells expressing tumor necrosis factor,related apoptosis-inducing ligand (TRAIL). We observed a similar degree of damage and immune attack in different variants of EAE; the lower motor neurons were preserved in adoptive transfer EAE induced with TRAIL-deficient T lymphocytes. Interpretation Our study indicates that damage to lower motor neurons and TRAIL-mediated inflammatory neurodegeneration in the spinal cord contribute to MS pathology. Ann Neurol 2009;66:310,332 [source] PGE2 receptors rescue motor neurons in a model of amyotrophic lateral sclerosisANNALS OF NEUROLOGY, Issue 2 2004Masako Bilak PhD Recent studies suggest that the inducible isoform of cyclooxygenase, COX-2, promotes motor neuron loss in rodent models of ALS. We investigated the effects of PGE2, a principal downstream prostaglandin product of COX-2 activity, on motor neuron survival in an organotypic culture model of ALS. We find that PGE2 paradoxically protects motor neurons at physiological concentrations in this model. PGE2 exerts its downstream effects by signaling through a class of four distinct G-protein,coupled E-prostanoid receptors (EP1,EP4) that have divergent effects on cAMP. EP2 and EP3 are dominantly expressed in ventral spinal cord in neurons and astrocytes, and activation of these receptor subtypes individually or in combination also rescued motor neurons. The EP2 receptor is positively coupled to cAMP, and its neuroprotection was mimicked by application of forskolin and blocked by inhibition of PKA, suggesting that its protective effect is mediated by downstream effects of cAMP. Conversely, the EP3 receptor is negatively coupled to cAMP, and its neuroprotective effect was blocked by pertussis toxin, suggesting that its protective effect is dependent on Gi-coupled heterotrimeric signaling. Taken together, these data demonstrate an unexpected neuroprotective effect mediated by PGE2, in which activation of its EP2 and EP3 receptors protected motor neurons from chronic glutamate toxicity. Ann Neurol 2004;56:240,248 [source] Low-affinity neurotrophin receptor with targeted mutation of exon 3 is capable of mediating the death of axotomized neuronsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2003Simon S Murray Summary 1.,In vivo studies have shown that the low-affinity 75 kDa neurotrophin receptor (p75NTR) is involved in axotomy-induced cell death of sensory and motor neurons. To further examine the importance of p75NTR in mediating neuronal death in vivo, we examined the effect of axotomy in the p75NTR-knockout mouse, which has a disrupted ligand-binding domain. 2.,The extent of sensory and motor neuron loss in the p75NTR-knockout mouse following axotomy was not significantly different to that in wild-type mice. This suggests that disruption of the ligand-binding domain is insufficient to block the cell death process in axotomized neurons. 3.,Immunohistochemical studies showed that axotomized neurons continue to express this mutant receptor with its intracellular death-signalling moiety intact. 4.,Treatment with antisense oligonucleotides targeted against p75NTR resulted in significant reduction in the loss of axotomized neurons in the knockout mouse. 5.,These data suggest that the intracellular domain of p75NTR is essential for death-signalling and that p75NTR can signal apoptosis, despite a disrupted ligand-binding domain. [source] | |||||||||||||