ABSTRACT
OBJECTIVE: Mitoxantrone (MTX)- induced cardiotoxicity is a clinical concern that is limiting its use. The aim of this paper, therefore, was to investigate the subchronic administration of MTX plus nonspecific/specific inhibitors of CYP450/2E1, to assess the extent of oxidative-induced injury by measuring levels of oxidative cardiac and injury biomarkers in mice and to evaluate the effects of CYP2E1 on caspase 3 activity and nuclear factor erythroid 2-related factor-2 (NRF-2). MATERIALS AND METHODS: Mice (n = 32) were divided into four treatment groups of eight: control, MTX, MTX + 4-methlypyrazole (4MP) and MTX + disulfiram (Disf). After 6 weeks of treatments, blood and heart samples were collected. RESULTS: Liquid chromatography-mass spectrometry (LCMS) analysis of MTX-treated plasma samples revealed several metabolites with different retention times. Cardiac antioxidant enzymes and creatine kinase (CK) levels were not significantly different among the groups. However, cardiac troponin and caspase 3 activity were significantly raised, with increased CYP2E1 expressions and reduced NRF-2 expression. Tissue damage was observed in all the treatment groups, including MTX, leading to the conclusion that MTX-induced cardiotoxicity was mediated by CYP2E1 activity, which initiated caspase 3 production, and decreased NRF-2 expression. CONCLUSIONS: Therefore, agents that inhibit CPY2E1 expression might attenuate MTX-induced cardiotoxicity by increasing NRF-2 expression.
Subject(s)
Antineoplastic Agents/toxicity , Cardiotoxicity/drug therapy , Cytochrome P-450 CYP2E1 Inhibitors/therapeutic use , Disulfiram/therapeutic use , Fomepizole/therapeutic use , Mitoxantrone/toxicity , Animals , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacokinetics , Cardiotoxicity/blood , Cardiotoxicity/metabolism , Cardiotoxicity/pathology , Caspase 3/metabolism , Cytochrome P-450 CYP2E1/metabolism , Cytochrome P-450 CYP2E1 Inhibitors/pharmacology , Disulfiram/pharmacology , Female , Fomepizole/pharmacology , Male , Mice, Inbred BALB C , Mitoxantrone/blood , Mitoxantrone/pharmacokinetics , Myocardium/metabolism , Myocardium/pathology , NF-E2-Related Factor 2/metabolism , Troponin I/metabolismABSTRACT
Basal synaptic transmission and activity-dependent synaptic plasticity were evaluated in superior cervical sympathetic ganglia (SCG) of amyloid-ß rat model of Alzheimer's disease (Aß rat) using electrophysiological and molecular techniques. Rats were administered Aß peptides (a mixture of 1:1 Aß1-40 and Aß1-42) by chronic intracerebroventricular infusion via 14-day mini-osmotic pumps (300 pmol/day). Control rats received Aß40-1 (inactive reverse peptide: 300 pmol/day). Ganglionic compound action potentials were recorded before (basal) and after repetitive stimulation. In isolated SCG, ganglionic long-term potentiation (gLTP) was generated by a brief train of stimuli (20Hz for 20s) and ganglionic long-term depression (gLTD) was produced with trains of paired pulses. The input/output (I/O) curves of ganglia from Aß rats showed a marked downward shift along all stimulus intensities, compared to those of ganglia from control animals, indicating impaired basal synaptic transmission. In addition, repetitive stimulation induced robust gLTP and gLTD in ganglia isolated from control animals, but, the same protocols failed to induce gLTP or gLTD in ganglia from Aß rats indicating impairment of activity-dependent synaptic plasticity in these animals. Western blotting of SCG homogenate from Aß rats revealed reduction in the ratio of phosphorylated-/total-CaMKII and in calcineurin protein levels. Although other mechanisms could be involved, these changes in signaling molecules could represent an important molecular mechanism linked to the failure to express synaptic plasticity in Aß rat ganglia. Results of the current study could explain some of the peripheral nervous system manifestations of Alzheimer's disease.
Subject(s)
Alzheimer Disease/chemically induced , Alzheimer Disease/pathology , Amyloid beta-Peptides/toxicity , Neuronal Plasticity/physiology , Superior Cervical Ganglion/pathology , Synaptic Transmission/physiology , Animals , Biophysics , Calcineurin/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Disease Models, Animal , Electric Stimulation/methods , Evoked Potentials/drug effects , Evoked Potentials/physiology , Gene Expression Regulation/drug effects , Long-Term Potentiation/drug effects , Long-Term Synaptic Depression/drug effects , Male , Neuronal Plasticity/drug effects , Rats , Rats, Wistar , Signal Transduction/drug effects , Superior Cervical Ganglion/physiopathology , Synaptic Transmission/drug effectsABSTRACT
Rapid eye movement (REM) sleep deprivation (SD) is implicated in impairment of spatial learning and memory and hippocampal long-term potentiation (LTP). An increase in nicotine consumption among habitual smokers and initiation of tobacco use by nonsmokers was observed during SD. Although nicotine treatment was reported to attenuate the impairment of learning and memory and LTP associated with several mental disorders, the effect of nicotine on SD-induced learning and memory impairment has not been studied. Modified multiple platform paradigm was used to induce SD for 24 or 48 h during which rats were injected with saline or nicotine (1 mg kg(-1) s.c.) twice a day. In the radial arm water maze (RAWM) task, 24- or 48-h SD significantly impaired learning and short-term memory. In addition, extracellular recordings from CA1 and dentate gyrus (DG) regions of the hippocampus in urethane anesthetized rats showed a significant impairment of LTP after 24- and 48-h SD. Treatment of normal rats with nicotine for 24 or 48 h did not enhance spatial learning and memory or affect magnitude of LTP in the CA1 and DG regions. However, concurrent, acute treatment of rats with nicotine significantly attenuated SD-induced impairment of learning and STM and prevented SD-induced impairment of LTP in the CA1 and DG regions. These results show that acute nicotine treatment prevented the deleterious effect of sleep loss on cognitive abilities and synaptic plasticity.
