ABSTRACT
Alzheimer's disease (AD) is associated with beta-amyloid accumulation, oxidative stress and mitochondrial dysfunction. However, the effects of genetic mutation of AD on oxidative status and mitochondrial manganese superoxide dismutase (MnSOD) production during neuronal development are unclear. To investigate the consequences of genetic mutation of AD on oxidative damages and production of MnSOD during neuronal development, we used primary neurons from new born wild-type (WT/WT) and amyloid precursor protein (APP) (NLh/NLh) and presenilin 1 (PS1) (P264L) knock-in mice (APP/PS1) which incorporated humanized mutations in the genome. Increasing levels of oxidative damages, including protein carbonyl, 4-hydroxynonenal (4-HNE) and 3-nitrotyrosine (3-NT), were accompanied by a reduction in mitochondrial membrane potential in both developing and mature APP/PS1 neurons compared with WT/WT neurons suggesting mitochondrial dysfunction under oxidative stress. Interestingly, developing APP/PS1 neurons were significantly more resistant to beta-amyloid 1-42 treatment, whereas mature APP/PS1 neurons were more vulnerable than WT/WT neurons of the same age. Consistent with the protective function of MnSOD, developing APP/PS1 neurons have increased MnSOD protein and activity, indicating an adaptive response to oxidative stress in developing neurons. In contrast, mature APP/PS1 neurons exhibited lower MnSOD levels compared with mature WT/WT neurons indicating that mature APP/PS1 neurons lost the adaptive response. Moreover, mature APP/PS1 neurons had more co-localization of MnSOD with nitrotyrosine indicating a greater inhibition of MnSOD by nitrotyrosine. Overexpression of MnSOD or addition of MnTE-2-PyP(5+) (SOD mimetic) protected against beta-amyloid-induced neuronal death and improved mitochondrial respiratory function. Together, the results demonstrate that compensatory induction of MnSOD in response to an early increase in oxidative stress protects developing neurons against beta-amyloid toxicity. However, continuing development of neurons under oxidative damage conditions may suppress the expression of MnSOD and enhance cell death in mature neurons.
Subject(s)
Alzheimer Disease/metabolism , Brain/metabolism , Mitochondria/metabolism , Mitochondrial Diseases/metabolism , Neurons/metabolism , Oxidative Stress/genetics , Aldehydes/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/physiopathology , Amyloid beta-Protein Precursor/genetics , Animals , Animals, Newborn , Brain/physiopathology , Cell Respiration/drug effects , Cell Respiration/physiology , Cells, Cultured , Disease Models, Animal , Humans , Membrane Potential, Mitochondrial/genetics , Metalloporphyrins/pharmacology , Mice , Mice, Transgenic , Mitochondria/drug effects , Mitochondrial Diseases/physiopathology , Mutation/genetics , Neurons/drug effects , Oxidative Stress/drug effects , Presenilin-1/genetics , Protein Carbonylation/physiology , Superoxide Dismutase/metabolism , Superoxide Dismutase-1 , Tyrosine/analogs & derivatives , Tyrosine/metabolismABSTRACT
The most widely used discriminant functions and red cell indices for differential diagnosis of thalassemia traits from iron deficiency anemia were evaluated for their abilities to identify HbE-containing blood samples. The functions were as follows: F1 = 0.01 x MCH x (MCV)2; F2 = RDW x MCH x (MCV)2/Hb x 100; F3 = MCV/RBC; and F4 = MCH/RBC. Other red cell parameters including RDW, hemoglobin content, mean cell volume, mean cell hemoglobin as well as red cell counts, were also evaluated to distinguish HbE from the normal population. Hemoglobin electrophoresis was used as a confirmatory test. The results showed that F1, F2 and F3 as well as other red cell parameters of HbE-containing samples were different from those of HbA2A-containing red cells although there was no statistical significance. However, F4 and MCHC showed no difference between the two groups. It can be concluded from the present study that identification of hemoglobin E especially the heterozygous form by using parameters from an electronic cell counter is not easy. Discriminant functions and red cell indicies might be used as an initial diagnosis. But confirmation is needed in all cases. Applying the MCV of 80 fl will miss 5 per cent of hemoglobin E carrier but will not miss the homozygous form.
Subject(s)
Anemia, Iron-Deficiency/diagnosis , Hemoglobin E/analysis , Thalassemia/diagnosis , Anemia, Iron-Deficiency/blood , Diagnosis, Differential , Erythrocyte Indices , Hemoglobinometry/methods , Humans , Sensitivity and Specificity , Thalassemia/bloodABSTRACT
Tumor necrosis factor-alpha (TNF-alpha) is an endogenous mediator of shock and inflammation including malaria. Many lines of evidence suggest that cytoadherence, the life-threatening pathology associated with complicated and cerebral malaria, results from the overproduction of TNF in response to malarial parasite. Quinine has been shown to inhibit TNF synthesis and cytoadherence in vitro suggesting an additional beneficial effect of quinine on its anti-TNF action. On the other hand, artesunate inhibits cytoadherence better than quinine does not suppress TNF production in vitro. The present study compares the effect of artesunate and quinine on TNF levels of malaria-infected patients. Surprisingly, plasma TNF levels increased dramatically after quinine administration but did not increase after artesunate administration. This difference may be explained by previous observations showing that artesunate kills parasites in vitro and clears parasitemias in vivo for more rapidly than quinine. The rapid clearance of plasma TNF in quinine treated patients might be due to the drug's TNF-suppressive activity.
Subject(s)
Antimalarials/therapeutic use , Artemisinins , Malaria, Falciparum/blood , Malaria, Falciparum/drug therapy , Quinine/therapeutic use , Sesquiterpenes/therapeutic use , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/drug effects , Adult , Antimalarials/pharmacology , Artesunate , Cell Adhesion/drug effects , Drug Monitoring/methods , Female , Humans , Infusions, Intravenous , Malaria, Falciparum/immunology , Malaria, Falciparum/parasitology , Male , Middle Aged , Quinine/pharmacology , Sesquiterpenes/pharmacology , Time Factors , Treatment OutcomeABSTRACT
Thalassemia is common in Southeast Asia, where artemisinin derivatives are frequently used in the treatment of malaria. It has been previously reported that artemisinin derivatives can be concentrated by uninfected thalassemic erythrocytes in vitro but not by normal erythrocytes. As a follow-up to this report, we studied the antimalarial kinetics of intravascular artesunate (2.4 mg/kg of body weight) in 10 persons with normal hemoglobins and in 10 patients with thalassemia (2 with alpha-thalassemia type 1-hemoglobin Constant Spring and 8 with alpha-thalassemia type 1-alpha-thalassemia type 2). Concentrations of artesunate and its active metabolites in plasma were measured by bioassay and expressed relative to those of dihydroartemisinin, the major biologically active metabolite. Concentrations of intravascular artesunate in plasma peaked in both the normal individuals and the thalassemic individuals 15 min after injection (the first time point). Plasma drug concentrations at all time intervals, except that at 1 h, were significantly higher in thalassemic subjects than in normal subjects (P < 0.05). The area under the concentration-time curve was 9-fold higher (P < 0.001) and the volume of distribution at steady state was 15-fold lower (P < 0.001) in thalassemic than in normal subjects. In light of the potential neurotoxicity of artemisinin derivatives, these results suggest that thalassemic subjects may need a drug administration regimen different from that of normal patients.
