Intermittent theta burst stimulation attenuates oxidative stress and reactive astrogliosis in the streptozotocin-induced model of Alzheimer's disease-like pathology.

Introduction: Intracerebroventricularly (icv) injected streptozotocin (STZ) is a widely used model for sporadic Alzheimer's disease (sAD)-like pathology, marked by oxidative stress-mediated pathological progression. Intermittent theta burst stimulation (iTBS) is a noninvasive technique for brain activity stimulation with the ability to induce long-term potentiation-like plasticity and represents a promising treatment for several neurological diseases, including AD. The present study aims to investigate the effect of the iTBS protocol on the animal model of STZ-induced sAD-like pathology in the context of antioxidant, anti-inflammatory, and anti-amyloidogenic effects in the cortex, striatum, hippocampus, and cerebellum. Methods: Male Wistar rats were divided into four experimental groups: control (icv normal saline solution), STZ (icv STZ-3 mg/kg), STZ + iTBS (STZ rats subjected to iTBS protocol), and STZ + Placebo (STZ animals subjected to placebo iTBS noise artifact). Biochemical assays and immunofluorescence microscopy were used to evaluate functional and structural changes. Results: The icv STZ administration induces oxidative stress and attenuates antioxidative capacity in all examined brain regions. iTBS treatment significantly reduced oxidative and nitrosative stress parameters. Also, iTBS decreased Aß-1-42 and APP levels. The iTBS enhances antioxidative capacity reported as elevated activity of its enzymatic and non-enzymatic components. In addition, iTBS elevated BDNF expression and attenuated STZ-induced astrogliosis confirmed by decreased GFAP+/VIM+/C3+ cell reactivity in the hippocampus. Discussion: Our results provide experimental evidence for the beneficial effects of the applied iTBS protocol in attenuating oxidative stress, increasing antioxidant capacity and decreasing reactive astrogliosis in STZ-administrated rats.

Pharmacogenetics may Influence Tacrolimus Daily Dose, but not Urinary Tubular Damage Markers in the Long-Term Period after Renal Transplantation.

BACKGROUND: The primary goal of this study was to evaluate the influence of cytochrome P450 (CYP) 3A5 (6986A>G) and ABCB1 (3435C>T) polymorphisms on tacrolimus (TAC) dosage regimen and exposure. Second, we evaluated the influence of TAC dosage regimen and the tested polymorphisms on renal oxidative injury, as well as the urinary activities of tubular ectoenzymes in a long-term period after transplantation. Also, we aimed to determine the association between renal oxidative stress and tubular damage markers in the renal transplant patients. METHODS: The study included 72 patients who were on TAC based immunosuppression. Allele-specific PCR was used for polymorphism determination. We measured the urinary thiobarbituric acid reactive substances (TBARS) and reactive carbonyl derivates (RCD) in order to evaluate oxidative injury, as well as the urinary activities of ectoenzymes (N-acetyl-ß-D-glucosaminidase, aminopeptidase N and dipeptidyl peptidase IV) to evaluate tubular damage. RESULTS: The carriers of CYP 3A5*1 allele required statistically higher daily doses of TAC than CYP *3/*3 carriers, as well as the carriers of C allele of ABCB1 gene compared to those with TT genotype. Also, there were no differences in TBARS, RCD and the activities of ectoenzymes between the patients' genotypes. Our results showed significant correlations between urinary TBARS and RCD and the ectoenzymes' activities. CONCLUSIONS: Our findings suggest that CYP 3A5 and ABCB1 3435 polymorphism may affect TAC daily doses, but not the drug's tubular toxicity. Furthermore, tubular damage may be associated with increased renal oxidative stress.

The role of glutamate and its receptors in multiple sclerosis.

Glutamate is an excitatory neurotransmitter of the central nervous system, which has a central role in a complex communication network established between neurons, astrocytes, oligodendrocytes, and microglia. Multiple abnormal triggers such as energy deficiency, oxidative stress, mitochondrial dysfunction, and calcium overload can lead to abnormalities in glutamate signaling. Thus, the disturbance of glutamate homeostasis could affect practically all physiological functions and interactions of brain cells, leading to excitotoxicity. Excitotoxicity is the pathological process by which nerve cells are damaged or killed by excessive stimulation by glutamate. Although neuron degeneration and death are the ultimate consequences of multiple sclerosis (MS), it is now widely accepted that alterations in the function of surrounding glial cells are key features in the progression of the disease. The present knowledge raise the possibility that the modulation of glutamate release and transport, as well as receptors blockade or glutamate metabolism modulation, might be relevant targets for the development of future therapeutic interventions in MS.

Gender differences in oxidative and nitrosative stress parameters in kidney transplant patients on tacrolimus-based immunosuppression.

BACKGROUND: Cardiovascular (CV) morbidity and mortality rates are still higher after kidney transplantation than in general population. It is known that oxidative and nitrosative stress may contribute to the progress of CV disease in a post-transplant period, but still gender aspect has not been elucidated completely. The aim of this study was to analyze the gender differences in the oxidative and nitrosative stress parameters, as well as asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels among kidney transplant patients on tacrolimus-based immunosuppression. METHODS: Our research included 35 patients (20 men and 15 women) with renal transplant and 25 healthy volunteers. Patients were on chronic immunosuppressive regimen, which included tacrolimus, mycophenolate mofetil and prednisone. In order to estimate oxidative and nitrosative stress, we determined plasma levels of thiobarbituric acid-reactive substances (TBARS), activity of catalase (CAT), levels of total (protein and non-protein) sulfhydryl (SH) groups, advanced oxidation protein products (AOPP), ADMA and SDMA, as well as nitrite/nitrate (NOx) ratio. RESULTS: TBARS, CAT and SH in plasma were significantly higher in male patients than in female patients (p < 0.05, p < 0.01 and p < 0.05, respectively). There were no gender-dependent differences in AOPP, ADMA, SDMA and NOx in kidney transplant patients. Correlation analysis, Pearson and Spearman, showed significant correlations between tested oxidative and nitrosative stress parameters in male kidney transplant patients. Alternatively, in female patients, there were no significant correlations between tested parameters. CONCLUSION: Our findings show that men might be more prone to oxidative damage than women. ADMA, the proven marker of CV morbidity and mortality, may be more significant in male kidney transplant patients concerning oxidative stress control of its level and function.

Endothelial dysfunction, inflammation and malnutrition markers as predictors of mortality in dialysis patients: multimarker approach.

BACKGROUNDS: Cardiovascular disease is reported to be major cause of mortality in dialysis patients. Multimarker approach is new approach in risk stratification. Creating a common predictive value, many different pathophysiological components are covered. The aim of this study was to examine the combined predictive value of markers of endothelial dysfunction (ADMA), inflammation (CRP, SAA) and malnutrition (albumin) in dialysis patients. METHODS: In this prospective 3-year follow-up study, 153 prevalent patients (105 males and 48 females) on hemodialysis were included. ADMA were measured by HPLC; CRP and SAA were measured using immunonephelometric assays. Albumins were measured by the use of standard methods on the automated analyzer. The patients were stratified into five groups based on the presence of 1, 2, and 3 or more risk markers, respectively, namely high ADMA (≥0.49 µmol/L), high CRP (≥6.0 mg/L), high SAA (≥7.6 mg/L) and low albumin (<30.3 g/L). RESULTS: The patients with 1, 2, 3 or more risk markers had an adjusted hazard ratio (HR) of 2.419 (0.728-8.034), 6.720 (2.100-21.503), 10.455 (3.193-24.227), respectively, for mortality, compared to those without risk markers. The patients with 1, 2, 3 or more risk markers had an adjusted HR of 1.838 (0.307-11.006), 9.924 (2.052-28.003), 14.823 (0.2.962-34.189), respectively, for cardiovascular mortality than those without risk markers. CONCLUSIONS: The results of this study demonstrate that the common predictive value of several markers is higher than individual predictive value of examined risk factors. Patients with multiple risk factors had higher mortality. Multimarker approach provides an opportunity for better risk stratification in dialysis patients.

How the duration period of erythropoietin treatment influences the oxidative status of hemodialysis patients.

BACKGROUND: End-stage renal disease is a state of enhanced oxidative stress (OS) and hemodialysis (HD) and renal anemia further augment this disbalance. Anemia correction with erythropoietin (EPO) may improve oxidative status. However, there is no evidence of time dependent effects of EPO therapy on redox status of HD patients. OBJECTIVE: The aim of this study was to evaluate whether the duration of EPO treatment may affect OS parameters in uremic patients. PATIENTS AND METHODS: 104 HD patients and 29 healthy volunteers were included. Patients were divided into 3 groups according to the duration of EPO treatment. Forth group consisted of HD patients without EPO treatment. Plasma and erythrocyte malondialdehyde (MDA, MDA(rbc)), reactive carbonyl groups (RCG), plasma sulfhydryl (-SH) groups and total antioxidative capacity (TAC) levels were evaluated. RESULTS: HD patients both with and without EPO treatment, showed a significant increase in all oxidative parameters without significance between EPO treated and -untreated group. The decrease in MDA and MDA(rbc) levels coincided with the duration of EPO treatment. A negative correlation was observed between the duration of EPO treatment and serum MDA (r=-0.309, p=0.003). Increasing periods of EPO treatment were associated with decrease in RCG, without significance between EPO groups. Increase in TAC accompanied increasing durations of EPO treatment, with EPO treatment for more than 24 months causing the most striking changes (p<0.05). There were no significant differences in -SH levels between EPO subgroups. CONCLUSION: Our results suggest that long term administration of EPO attenuated the lipid peroxidation process and restored the levels of antioxidants.