ABSTRACT
We investigated whether the angiotensin converting enzyme inhibitor, ramipril, could attenuate white matter lesions caused by chronic hypoperfusion in the rat, and whether suppression of oxidative stress is involved in the resulting neuroprotection. The ramipril treatment group showed significant protection from development of white matter lesions in the optic tract, the anterior commissure, the corpus callosum, the internal capsule and the caudoputamen. The level of malondialdehyde (MDA) and the oxidized glutathione (GSSG)/total glutathione (GSH t) ratio was also significantly decreased in the ramipril group compared to the vehicle-treated group. These results suggest that ramipril can protect against white matter lesions that result from chronic ischemia due to its effects on free radical scavenging. Further efficacy should be studied in the treatment of cerebrovascular insufficiency states and vascular dementia.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Brain Injuries/pathology , Brain Injuries/prevention & control , Free Radicals/metabolism , Neuroglia/drug effects , Ramipril/therapeutic use , Animals , Brain Injuries/etiology , Brain Ischemia/complications , Chronic Disease , Disease Models, Animal , Glutathione/metabolism , Glutathione Disulfide/metabolism , Malondialdehyde/metabolism , Neuroglia/pathology , Rats , Rats, Sprague-DawleyABSTRACT
The lysosomal destabilization that precedes mitochondrial apoptotic changes is an important step in cell death, particularly in oxidative cell death. This study describes the novel pharmacological effects of zaprinast, a cGMP-elevating phosphodiesterase inhibitor, on the inhibition of oxidative cell death in astrocyte cultures. H2O2-induced oxidative cytotoxicity was measured grossly by monitoring lactate dehydrogenase (LDH) release, and was found to be associated with lysosomal acridine orange relocation, lysosomal cathepsin D release into cytosol, and reduced mitochondrial potentials. Moreover, zaprinast (100 microM) inhibited all of these cytotoxic phenomena. In addition, H2O2-induced LDH release was not inhibited by 8-pCPT-cGMP, and the inhibition of this release by zaprinast was unaffected by Rp-8-pCPT-cGMP, a protein kinase G inhibitor. Zaprinast was found to inhibit sphingosine-induced lysosomal acridine orange relocation and the induced decrease in mitochondrial potential, but zaprinast had no effect on rotenone-induced mitochondrial collapse, which was not associated with lysosomal destabilization. However, zaprinast did not inhibit the cellular increase of reactive oxygen species induced by H2O2, which suggests that its protective mechanism differs from that of desferrioxamine, which does inhibit such cellular increase of oxygen free radicals. We suggest that the novel protective effect of zaprinast on H2O2-induced oxidative cell death is primarily associated with its inhibition of lysosomal destabilization.
Subject(s)
Astrocytes/drug effects , Cerebral Cortex/drug effects , Hydrogen Peroxide/toxicity , Lysosomes/drug effects , Oxidative Stress/drug effects , Phosphodiesterase Inhibitors/pharmacology , Protective Agents/pharmacology , Purinones/pharmacology , Animals , Animals, Newborn , Astrocytes/enzymology , Astrocytes/metabolism , Astrocytes/pathology , Cathepsin D/metabolism , Cell Death/drug effects , Cells, Cultured , Cerebral Cortex/enzymology , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Cyclic GMP/analogs & derivatives , Cyclic GMP/metabolism , Cyclic GMP/pharmacology , Cyclic GMP-Dependent Protein Kinases/metabolism , Cytoprotection , Cytosol/enzymology , Cytosol/metabolism , Deferoxamine/pharmacology , Dose-Response Relationship, Drug , Intracellular Membranes/drug effects , L-Lactate Dehydrogenase/metabolism , Lysosomes/enzymology , Lysosomes/metabolism , Lysosomes/pathology , Membrane Potential, Mitochondrial/drug effects , Mitochondria/drug effects , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Rotenone/toxicity , Sphingosine/toxicity , Thionucleotides/pharmacology , Uncoupling Agents/toxicityABSTRACT
BACKGROUND: Recent studies have demonstrated the molecular basis of the immunomodulatory and anti-inflammatory activities of 1,25-dihydroxyvitamin D(3)(1,25-(OH)(2)D(3)). This hormone improves behavioral deficits and normalizes the nigral dopamine levels in animal models of Parkinson's disease (PD). METHODS: We studied whether the administration of 1,25-(OH)(2)D(3) would protect against 6-hydroxydopa (6-OHDA)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neuronal injury, and its potential regulatory effect on microglia activation. RESULTS: We found that 1,25-(OH)(2)D(3) pretreatment significantly decreased 6-OHDA- and MPTP-induced dopaminergic neuronal loss in the substantia nigra pars compacta by preventing the activation of microglia. This observed neuroprotective effect in MPTP-treated mice that were given 1,25-(OH)(2)D(3) may be attributable to inhibition of proinflammatory cytokine expression. CONCLUSION: These results suggest that 1,25-(OH)(2)D(3) is a potentially valuable neuroprotective agent; it may therefore be considered for the treatment of pathologic conditions of the central nervous system, such as PD, where inflammation-induced neurodegeneration occurs.
