salicylates and Neurodegenerative-Diseases

The EphA4 receptor has been proposed to be a key actor in neurodegenerative diseases. In the last years, several research groups focused their efforts on the discovery of small molecules capable of blocking EphA4 activity by binding its extracellular domain. However, none of the compounds so far identified possess adequate chemical and/or pharmacological profiles to assess the "druggability" of EphA4 in animal models. New efforts are required to deliver a new generation of suitable pharmacological tools.

Topics: Animals; Humans; Indole Alkaloids; Models, Molecular; Neurodegenerative Diseases; Oxindoles; Pyrroles; Receptor, EphA4; Salicylates; Signal Transduction

Cerebellar granule neurons undergo apoptosis when switched from a medium containing high potassium (HK) to one that has low potassium (LK). LK-induced cell death is blocked by GW5074 [5-Iodo-3-[(3,5-dibromo-4-hydroxyphenyl) methylene]-2-indolinone], a synthetic drug that inhibits c-Raf activity in vitro. GW5074 has no direct effect on the activities of several apoptosis-associated kinases when assayed in vitro. In contrast to its effect in vitro, treatment of neurons with GW5074 causes c-Raf activation (when measured in vitro in the absence of the drug) and stimulates the Raf-MEK-ERK pathway. Treatment of neurons with GW5074 also leads to an increase in the activity of B-Raf, which is not inhibited by GW5074 in vitro at concentrations at which the drug exerts its neuroprotective effect. PD98059 and U0126, two distinct inhibitors of MEK, block the activation of ERK by GW5074 but have no effect on its ability to prevent cell death. Overexpression of a dominant-negative form of Akt does not reduce the efficacy of GW5074, demonstrating an Akt-independent mechanism of action. Neuroprotection is inhibited by SN-50, a specific inhibitor of nuclear factor-kappa B (NF-kappaB) and by the Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS) implicating NF-kappaB and Ras in the neuroprotective signaling pathway activated by GW5074. In addition to preventing LK-induced apoptosis, treatment with GW5074 protects against the neurotoxic effects of MPP+ and methylmercury in cerebellar granule neurons, and glutathione depletion-induced oxidative stress in cortical neurons. Furthermore, GW5074 prevents neurodegeneration and improves behavioral outcome in an animal model of Huntington's disease. Given its neuroprotective effect on distinct types of cultured neurons, in response to different neurotoxic stimuli, and in an animal model of neurodegeneration, GW5074 could have therapeutic value against neurodegenerative pathologies in humans.

Topics: Animals; Cell Death; Cells, Cultured; Disease Models, Animal; Enzyme Inhibitors; Farnesol; Huntington Disease; Indoles; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Neurotoxins; Nitro Compounds; Phenols; Propionates; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-raf; Rats; Rats, Sprague-Dawley; Salicylates; Signal Transduction

We investigated the relative contribution of COX-1 and/or COX-2 to oxidative damage, prostaglandin E2 (PGE2) production and hippocampal CA1 neuronal loss in a model of 5 min transient global cerebral ischemia in gerbils. Our results revealed a biphasic and significant increase in PGE2 levels after 2 and 24-48 h of reperfusion. The late increase in PGE2 levels (24 h) was more potently reduced by the highly selective COX-2 inhibitor rofecoxib (20 mg/kg) relative to the COX-1 inhibitor valeryl salicylate (20 mg/kg). The delayed rise in COX catalytic activity preceded the onset of histopathological changes in the CA1 subfield of the hippocampus. Post-ischemia treatment with rofecoxib (starting 6 h after restoration of blood flow) significantly reduced measures of oxidative damage (glutathione depletion and lipid peroxidation) seen at 48 h after the initial ischemic episode, indicating that the late increase in COX-2 activity is involved in the delayed occurrence of oxidative damage in the hippocampus after global ischemia. Interestingly, either selective inhibition of COX-2 with rofecoxib or inhibition of COX-1 with valeryl salicylate significantly increased the number of healthy neurons in the hippocampal CA1 sector even when the treatment began 6 h after ischemia. These results provide the first evidence that both COX isoforms are involved in the progression of neuronal damage following global cerebral ischemia, and have important implications for the potential therapeutic use of COX inhibitors in cerebral ischemia.

Topics: Animals; Antioxidants; Biomarkers; Cell Count; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; Disease Progression; Gerbillinae; Glutathione; Hippocampus; Ischemic Attack, Transient; Isoenzymes; Lactones; Lipid Peroxidation; Male; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Oxidation-Reduction; Prostaglandin-Endoperoxide Synthases; Salicylates; Sulfones

The fluorinated salicylate triflusal has been shown to have a neuroprotective effect after an excitotoxic lesion to the postnatal brain. In this regard, the aim of this study was to elucidate whether neuroprotection was associated with changes in the expression of proinflammatory molecules such as interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), inducible nitric oxide synthase (iNOS), or cyclooxygenase-2 (COX-2), well-known mediators of oxidative stress and inflammation, mechanisms underlying secondary damage occurring after excitotoxic/ischemic brain injury.. Postnatal day 9 rats received an intracortical injection of N-methyl-D-aspartate followed by oral administration of triflusal (30 mg/kg) 8 hours later. Ten or 24 hours after lesion, animals were killed, and brain sections processed for the immunohistochemical demonstration of IL-1beta, TNF-alpha, iNOS, and COX-2.. Besides a reduction in the neurodegenerative area, triflusal strongly decreased iNOS immunolabeling at both survival times analyzed, attenuating iNOS immunoreactivity in astroglial cells and infiltrated neutrophils. Additionally, a moderate reduction in COX-2, IL-1beta, and TNF-alpha was observed. Triflusal decreased neuronal and microglial COX-2 expression at 10 and 24 hours after lesion and microglial and astroglial expression of IL-1beta and TNF-alpha at 24 hours after lesion. TNF-alpha expression in neuronal cells at 10 hours after lesion was, however, maintained.. This study suggests that triflusal neuroprotection is associated with a decrease of iNOS and other inflammatory mediators and therefore may constitute a good therapeutic agent in pathological situations in which regulation of inflammatory genes constitutes a relevant step in the outcome of the neurodegenerative event.

Topics: Administration, Oral; Animals; Astrocytes; Cyclooxygenase 2; Disease Models, Animal; Inflammation Mediators; Interleukin-1; Isoenzymes; Microglia; Microinjections; N-Methylaspartate; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Neurotoxins; Neutrophil Infiltration; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Long-Evans; Salicylates; Somatosensory Cortex; Tumor Necrosis Factor-alpha

Superoxide is produced as a result of normal energy metabolism within the mitochondria and is scavenged by the mitochondrial form of superoxide dismutase (sod2). Mice with inactivated SOD2 (sod2 nullizygous mice) die prematurely, exhibiting several metabolic and mitochondrial defects and severe tissue pathologies, including a lethal spongiform neurodegenerative disorder (Li et al., 1995; Melov et al., 1998, 1999). We show that treatment of sod2 nullizygous mice with synthetic superoxide dismutase (SOD)-catalase mimetics extends their lifespan by threefold, rescues the spongiform encephalopathy, and attenuates mitochondrial defects. This class of antioxidant compounds has been shown previously to extend lifespan in the nematode Caenorhabditis elegans (Melov et al., 2000). These new findings in mice suggest novel therapeutic approaches to neurodegenerative diseases associated with oxidative stress such as Friedreich ataxia, spongiform encephalopathies, and Alzheimer's and Parkinson's diseases, in which chronic oxidative damage to the brain has been implicated.

Topics: Animals; Antioxidants; Catalase; Catalysis; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Ethylenediamines; Free Radical Scavengers; Injections, Intraperitoneal; Lipids; Metalloporphyrins; Mice; Mice, Knockout; Mitochondria; Neurodegenerative Diseases; Organometallic Compounds; Oxidative Stress; Phenotype; Salicylates; Superoxide Dismutase; Survival Rate

Coenzyme Q10 is an essential cofactor of the electron transport chain and is an antioxidant. We examined the effects of oral feeding with coenzyme Q10 in young animals on brain concentrations. Feeding with coenzyme Q10 at a dose of 200 mg/kg for 1-2 months in young rats resulted in significant increases in liver concentrations, however, there was no significant increase in brain concentrations of either reduced- or total coenzyme Q10 levels. Nevertheless there was a reduction in malonate-induced increases in 2,5 dihydroxybenzoic acid to salicylate, consistent with an antioxidant effect. In other studies we found that oral administration of coenzyme Q10 significantly reduced increased concentrations of lactate in the occipital cortex of Huntington's disease patients. These findings suggest that coenzyme Q10 might be useful in treating neurodegenerative diseases.

Topics: Administration, Oral; Animals; Antioxidants; Brain; Coenzymes; Corpus Striatum; Electron Transport; Gentisates; Humans; Hydroxybenzoates; Injections; Liver; Male; Malonates; Neurodegenerative Diseases; Neuroprotective Agents; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Sprague-Dawley; Salicylates; Salicylic Acid; Ubiquinone