Electrocardiographic, biochemical, and scintigraphic evidence for the cardioprotective effect of paricalcitol and vitamin D3 on doxorubicin-induced acute cardiotoxicity in rats.

AIM: We aimed to investigate the possible cardioprotective effects of paricalcitol (PR), its vitamin D receptor agonist, and vitamin D3 (VIT-D3) on an experimental model of doxorubicin (DX) cardiotoxicity by 99mTc-PYP scintigraphy, electrocardiographic (ECG) and biochemical methods. METHOD: Forty-two male Wistar/Albino rats (250‒300 g; aged 10‒12 weeks) were randomly separated into six groups, namely into control (CN), doxorubicin (DX), paricalcitol (PR), vitamin D3 (VIT-D3), paricalcitol + doxorubicin (PR+DX), and vitamin D3 + doxorubicin (VIT-D3+DX) groups. Cardiotoxicity was induced by three doses of DX (18 mg/kg, i.p.) at 24-hour intervals on days 18, 19 and 20. PR (0.5 ug/ kg, i.p) and VIT-D3 (5,000 IU/kg, i.p) were injected for 20 days before and after the application of DX (18 mg/kg, i.p.). On day 21 of the experiment, biochemical parameters [tumor necrosis factor TNF-alpha (TNF-α); interleukin-6 (IL-6), nitric oxide (NO), and cardiac troponin T (cTnT)], as well as ECG and scintigraphic (99mTc-PYP) features were assessed. RESULTS: Compared to CN, DX significantly raised TNF-α, IL-6, and NO in heart tissue, cTnT in serum, 99mTc-PYP uptake in the myocardium, and ECG parameters, specifically QRS complex duration, QT interval duration, and ST-segment amplitude, while also reducing heart rate (p<0.001). Pretreatment with PR and VIT-D3 mitigated these abnormalities produced by DX in the heart (p<0.001). CONCLUSION: Results show that vitamin D receptor agonist paricalcitol and vitamin D protect against DX-induced cardiotoxicity through anti-inflammatory and antioxidant effects (Fig. 4, Ref. 59). Text in PDF www.elis.sk Keywords: paricalcitol, doxorubicin, vitamin D, ECG, 99mTc-PYP scintigraphy, cardiotoxicity, inflammation.

The effect of quercetin on absence epilepsy in WAG/Rij rats.

AIM: In the present study, the effect of quercetin, a powerful antioxidant flavonoid, on genetic absence epilepsy was studied in WAG/Rij rats. MATERIAL AND METHOD: Tripolar electrodes were implanted into WAG/Rij rats. Basal electrocorticography (ECoG) was recorded following a recovery period. After basal ECoG recording, different doses of quercetin (QRC) (25, 50 and 100 mg/kg) were injected intraperitoneally (i.p.) for 30 days. ECoG recording was continued for 31 days, three hours a day. After recording, the rats were anesthetized and euthanized through cervical dislocation and their brains were excised. Biochemically, TNF-alpha, IL-6 and NO were studied in whole rat brains. RESULTS: In WAG/Rij rats, low-dose quercetin (25 mg/kg) reduced the number and duration of spike-wave discharges (SWDs) compared to the control group. However, 50 and 100 mg/kg quercetin doses increased SWDs. Duration of SWDs was prolonged only with 100 mg/kg dose. None of the quercetin doses had any effect on average amplitude of SWDs. In addition, it was observed in biochemical analyses that 25 mg/kg quercetin reduced TNF-alpha, IL-6 and NO levels compared to the control group. While TNF-alpha and IL-6 levels in rat brains were not affected by 50 or 100 mg/kg doses, both doses were found to increase NO levels in rat brains. CONCLUSION: Based on the results of the present study, 25 mg/kg low-dose quercetin may have reduced absence seizures by reducing proinflammatory cytokines and NO, but high-dose quercetin may have increased absence seizures through increasing the NO level. This contrasting effect of quercetin on absence seizures needs to be investigated by advanced mechanisms.

Electrophysiological, histopathological, and biochemical evaluation of the protective effect of probiotic supplementation against pentylenetetrazole-induced seizures in rats.

BACKGROUND AND PURPOSE: Research on the relationship between the gut microbiome and epilepsy is accumulating. The present study was conducted to evaluate the effect of probiotic supplementation on pentylenetetrazole (PTZ)-induced seizures in rats. METHODS: Twenty-one adult male Wistar albino rats were included. The animals were divided into three groups of seven rats. Group 1 was a control group, whereas Group 2 rats received PTZ treatment and Group 3 rats had PTZ+PB (probiotic) treatment. For 6 weeks, Groups 1 and 2 were given saline (1 ml), whereas Group 3 had probiotic supplement. In the 5th week, tripolar electrodes were attached to the rats. Electrophysiological, behavioral, biochemical, and immunohistochemical evaluations were performed in the 6 weeks after the treatment. RESULTS: PB treatment significantly reduced seizures. In the PTZ group, expression levels of brain-derived neurotrophic factor, nerve growth factor (NGF), and Sox2 (SRY sex-determining region Y-box 2) in rat brains decreased significantly compared to the control group, whereas the expression levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), total oxidant status (TOS), and nitric oxide (NO) levels increased. In the PTZ+PB group, NGF expression increased significantly compared to the PTZ group, whereas TNF-α, IL-6, TOS, and NO levels decreased. In histopathological examination, an abundance of necrotic neurons was notable in the PTZ group, which was less in the PTZ+PB group. In addition, body weight of the group supplemented with probiotics decreased after the treatment. CONCLUSIONS: Our results suggest that probiotic supplementation may alleviate seizure severity and exert neuroprotective effects by reducing neuroinflammation and oxidative stress and altering the expression of neurotrophins in epileptogenic brains.

Probiotic supplementation alleviates absence seizures and anxiety- and depression-like behavior in WAG/Rij rat by increasing neurotrophic factors and decreasing proinflammatory cytokines.

AIM: Epilepsy is one of the most common chronic brain disorders that affect millions of people worldwide. In the present study, we investigated the effects of probiotic supplementation on absence epilepsy and anxiety-and depression-like behavior in WAG/Rij rats. MATERIAL AND METHOD: Fourteen male WAG/Rij rats (absence-epileptic) and seven male Wistar rats (nonepileptic) were used. The effects of probiotic VSL#3 (12.86 bn living bacteria/kg/day for 30 day/gavage) on absence seizures, and related psychiatric comorbidities were evaluated in WAG/Rij rats. Anxiety-like behavior was evaluated by the open-field test and depression-like behavior by the forced swimming test. In addition, the brain tissues of rats were evaluated histopathologically for nerve growth factor [NGF], brain-derived neurotrophic factor [BDNF], SRY sex-determining region Y-box 2 [SOX2] and biochemically for nitric oxide [NO], tumor necrosis factor-alpha [TNF-α] ,and Interleukin-6 [IL-6]. RESULTS: Compared to Wistar rats, WAG/Rij rats exhibited anxiety- and depression-like behavior, and had lower BDNF, NGF and SOX2 immunoreactivity, and higher TNF-α, IL-6 levels in brain tissue. VSL#3 supplementation reduced the duration and number of spike-wave discharges (SWDs) and exhibited anxiolytic or anti-depressive effect. VSL#3 supplement also increased the NGF immunoreactivity while decreasing IL-6, TNF-α and NO levels in WAG/Rij rat brain. CONCLUSION: The findings of the present study showed that neurotrophins, SOX2 deficiency, and pro-inflammatory cytokines may play a role in the pathogenesis of absence epilepsy. Our data support the hypothesis that the probiotics have anti-inflammatory effect. The present study is the first to show the positive effects of probiotic bacteria on absence seizures and anxiety- and depression-like behavior.

The Beneficial Effect of Probiotics Supplementation on Penicillin-Induced Focal Seizure in Rats.

The focal epilepsy is a chronic neurological brain disorder which affects millions of people in the world. There is emerging evidence that changes in the gut microbiota may have effects on epileptic seizures. In the present study, we examined the effect of probiotics on penicillin-induced focal seizure model in rats. Male Wistar Albino rats (n: 21) were randomly divided into three groups: control (no medication), penicillin and penicillin + probiotic. Probiotic VSL#3 (12.86 bn living bacteria/kg/day) was given by gavage for 30 days. The seizures were induced by intracortical injection of penicillin G (500 IU) into the cortex. An ECoG recordings were made for 180 min after penicillin G application. The spike frequency and the amplitude were used to assess the severity of seizures. Tumor necrosis factor (TNF-α), nitric oxide (NO) and interleukin (IL-6) levels in the brain were studied biochemically. Our results indicated that probiotic supplementation improved focal seizures through increasing the latency (p < 0.001) and decreasing the spike frequency (p < 0.01) compared to the penicillin group. Penicillin-induced seizure in rats significantly enhanced TNF-α (p < 0.01), NO (p < 0.01) and IL-6 (p < 0.05) compared to the control. Probiotic supplementation significantly decreased IL-6 (p < 0.05), TNF-α (p < 0.01) and NO (p < 0.001) compared to the penicillin group. When the body weights were compared before and after the experiment, there was no difference between the control and penicillin groups, but it was observed that the body weight decreased after probiotic supplementation in the penicillin + probiotic group. Probiotic supplementation may have anti-seizure effect by reducing proinflammatory cytokine and NO levels in epileptic rat brain.

Evaluation of the protective effect of paricalcitol and vitamin D3 at doxorubicin nephrotoxicity in rats with 99mTechnetium-dimercaptosuccinic acid renal scintigraphy and biochemical methods.

AIM: The present study aimed to examine the effect of paricalcitol (PRC) and vitamin D3 (vit D3) on doxorubicin (DOX)-induced nephrotoxicity in rats. MATERIALS AND METHODS: Forty-two Wistar rats were randomly categorized into six groups: control; 2) PRC(0.5 µg/kg) and 3) vit D3(5.000 IU/kg) administered for 14 days; 4) DOX, 18 mg/kg administered on the 12th, 13th and 14th days of the study; 5) PRC (0.5 µg/kg, +DOX(18 mg/kg); vit D3(5.000 IU)+DOX(18 mg/kg). On the 15th day of the experiment, 99mTc-DMSA uptake level and biochemical parameter in serum and tissue were assay. RESULTS: Activities of 99mTechnetium-Dimercaptosuccinic Acid (99mTc-DMSA) were lower in groups receiving DOX and/or PRC+DOX, vit D3+DOX than in control groups. The 99mTc-DMSA level in the group PRC+DOX and vit D3+DOX were importantly higher than DOX group. DOX caused an important increase in blood urea nitrogen (BUN), creatinine, Tumor Necrosis Factor-α(TNF- α), interleukin-6(IL-6) and nitric oxide(NO) levels compared to control groups. However, PRC and vit D3 pretreatments lowered them. Uptake of 99mTc-DMSA level was higher in groups PRC+DOX than in vit D3+DOX group. Administration of PRC and vit D3 alone did not change alterations all of parameters. CONCLUSION: The results indicated that PRC administration protects kidney in DOX-induced nephrotoxic rats. In addition, PRC has a stronger nephroprotective effect than vit D3.

Evaluation of the protective effect of edaravone on doxorubicin nephrotoxicity by [99mTc]DMSA renal scintigraphy and biochemical methods.

To evaluate the nephroprotective effect of edaravone on doxorubicin-induced nephrotoxicity. In this experimental study, twenty-eight Wistar male rats were used. The rats were separated into 4 groups (n = 7); group І (control), rats were treated with saline (4 ml/kg) and group ІІ (doxorubicin), nephrotoxicity was induced by three doses of 18 mg/kg/i.p. doxorubicin, at a 24-h interval on the 12th, 13th, and 14th days. Group ІІІ (edaravone), rats were treated with edaravone (30 mg/kg/for 14 days), and group ІV (edaravone + doxorubicin), rats were treated with edaravone (30 mg/kg/for 14 days) and doxorubicin were injected (18 mg/kg/for 3 days; at a 24-h interval on the 12th, 13th, and 14th days). On the 15th day of the experiment, technetium-99m-labeled dimercaptosuccinic acid ([99mTc]DMSA) uptake was obtained in both kidneys and biochemical parameters from serum and kidney tissue were measured. Doxorubicin led to nephrotoxicity through elevation of serum blood urea nitrogen (BUN), creatinine and tumor necrosis factor-α (TNF-α), nitric oxide (NO), and interleukin-6 (IL-6) in kidney tissue and decreased [99mTc]DMSA uptake level in the kidney when compared with control group (p < 0.01). Pretreatment edaravone significantly decreased BUN and creatinine, also kidney tissue TNF-α, IL-6, NO, and increased [99mTc]DMSA uptake level compared with the doxorubicin. Edaravone has a significant nephroprotective effect through the attenuation of oxidative stress and inflammatory markers during doxorubicin-induced nephrotoxicity in rats.

Protective effect of melatonin on adriamycin-induced cardiotoxicity in rats.

OBJECTIVES: Adriamycin is one of the most widely used anticancer drugs. The major limiting factor of using this drug is the development of cardiotoxicity. However, melatonin (N-acetyl-5-methoxytryptamine) is a ubiquitous molecule as a good antioxidant that may protect the heart. We investigated whether or not pretreatment with melatonin can attenuate adriamycin-induced cardiotoxicity. STUDY DESIGN: All procedures and experiments were approved by the Animal Ethics Committee of Gazi Osman Pasa University (2012-HADYEK-022). Adult male Wistar-Albino rats were randomly divided into four groups, namely control (CON, n=7), melatonin (MEL, n=7), adriamycin (ADR, n=7), and adriamycin+melatonin (ADR+MEL, n=7) groups. Cardiotoxicity in rats was induced by adriamycin injection (cumulative dose: 18 mg/kg, intraperitoneal [i.p.]) at an interval of 24 hours (h) on the 5th, 6th and 7th days. Rats receiving melatonin treatment in the adriamycin group received melatonin (10 mg/kg/day, i.p.) for 7 days and were injected with adriamycin (18 mg/kg, i.p.) on 5th, 6th and 7th days. On the 8th day, gravimetric, electrocardiography (ECG) and biochemical parameters were assessed. RESULTS: Adriamycin induction caused changes in the ECG pattern, including ST-segment elevation and decreased R-amplitude, increase in the serum levels of cardiac injury markers (creatine kinase [CK], CK-MB, aspartate transaminase, and lactate dehydrogenase), decrease in the antioxidant enzymes activity (superoxide dismutase, glutathione peroxidase), elevated lipid peroxidation (malondialdehyde), and altered lipid profile in the serum. Melatonin treatment prevented all the parameters of adriamycin-induced cardiotoxicity in rats. CONCLUSION: Melatonin has a protective effect on the heart against adriamycin-induced cardiotoxicity in rats.

Our clinical experience about prenatal diagnosis and neonatal outcomes of fetal central nervous system anomalies.

OBJECTIVE: To present a retrospective analysis of the prenatal diagnosis and the outcome of fetuses diagnosed with central nervous system (CNS) anomalies. MATERIALS AND METHODS: We reviewed the medical records and ultrasound data of 69 cases diagnosed with CNS anomalies from 2007 to 2008. We described the prenatal diagnosis, associated findings, and outcome of these patients. RESULTS: Sixty-nine patients were diagnosed with CNS anomalies. Of these, 31 had ventriculomegaly + hydrocephaly, 14 had spina bifida + meningomyelosel, 5 had choroid plexus cyst, 5 had Dandy Walker malformation, 3 had sacrocoxigeal teratoma, 2 had encephalosel, 1 had microcephaly, and 1 had Arnold Chiari malformation. Eight amniocentesis, three cord blood sampling, and two fetal reduction procedure were performed. Nine pregnancy termination and 36 delivery were performed. Neurosurgical correction was performed for neonates with spina bifida, hydrocephaly and sacrocoxigeal teratoma. Twenty-one neonates were discharged with cure, 4 neonates with follow-up, 7 neonates with paraplegia, and 13 neonates died. CONCLUSION: The outcome of fetuses with CNS anomalies was shown to depend mainly on the degree of neural tube defect and the associated anomalies were the most important factors in surviving.