Publications by authors named "Mehmet Alkanat"

9 Publications

  • Page 1 of 1

Apelin-13 activates the hippocampal BDNF/TrkB signaling pathway and suppresses neuroinflammation in male rats with cisplatin-induced cognitive dysfunction.

Behav Brain Res 2021 Jun 15;408:113290. Epub 2021 Apr 15.

Recep Tayyip Erdogan University, Faculty of Medicine, Department of Biochemistry, Rize, Turkey. Electronic address:

It has been established that cisplatin causes neuronal damage and cognitive impairment. However, the mechanism is not sufficiently clear. Apelin-13 is an endogenous peptide with strong neuroprotective effects through the synthesis of neurotrophic factors and suppression of inflammation. The aim of this study was to investigate the role of brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) signaling pathway and the potential inhibitory effects of apelin-13 in the mechanism of cisplatin-induced hippocampal damage and cognitive impairment. Apelin-13 was administered to adult sprague dawley male rats at a dose of 20 nmol/kg every day for 4 weeks, cisplatin was administered at a dose of 5 mg/kg once a week for 4 weeks. The spatial and recognition memory tests of the rats were performed on the 5th week. BDNF and the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels were measured by ELISA in hippocampal homogenates. Pyramidal neuron and glial cell damage in the hippocampal CA1, CA3 and dentate gyrus (DG) were analyzed histologically. TrkB activity in the hippocampus was determined by immunohistochemical methods. Cisplatin impaired spatial and recognition memory in rats, while apelin-13 improved spatial memory but did not affect recognition memory. Cisplatin suppressed BDNF in the hippocampus while increased IL-1β and TNF-α. In contrast, apelin-13 administration increased BDNF but significantly suppressed TNF-α and IL-1B. Cisplatin caused pyramidal neuron and glial cell damage in CA1, CA3 and DG. In the cisplatin + apelin-13 group, however, pyramidal neuron and glial cell damage was less than those without apelin-13. Cisplatin increased TrkB activity in the hippocampus, which was counteracted by apelin-13. In conclusion, apelin-13 reduced the cisplatin-induced cognitive deficiency, by suppressing inflammation and stimulating the synthesis and activation of neurotrophic factors in hippocampal tissue.
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http://dx.doi.org/10.1016/j.bbr.2021.113290DOI Listing
June 2021

GSPE is superior to NAC in the prevention of contrast-induced nephropathy: might this superiority be related to caspase 1 and calpain 1?

Life Sci 2014 May 12;103(2):101-10. Epub 2014 Apr 12.

Department of Biochemistry, Karadeniz Technical University, School of Medicine, Trabzon, Turkey.

Aims: Our study was intended to evaluate the role of inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), caspases 1 and 3 and calpain 1 in the pathogenesis of contrast-induced nephropathy (CIN) and to compare the protective effects of N acetyl cysteine (NAC) and grape seed proanthocyanidin extract (GSPE) against the development of CIN.

Main Methods: 32 rats were divided into four groups; control, contrast media (CM), CM+NAC and CM+GSPE. CIN was induced by administration of 7 ml/kg diatrizoate. The experiment was discontinued on the ninth day. Blood was collected for blood urea nitrogen (BUN) and creatinine measurement. Rat kidney tissues were removed for histopathological evaluation and the investigation of caspases 1 and 3, iNOS, eNOS, TUNEL and calpain 1.

Key Findings: A significant increase in BUN, creatinine, renal histopathological injury, TUNEL, caspases 1, 3, calpain 1, iNOS and eNOS was observed in the CM group compared to the control group. There was amelioration in all these parameters in the CM+GSPE group, while there was no significant amelioration in BUN, creatinine and renal histopathological injury in the CM+NAC group. In addition, calpain 1 staining and creatinine were significantly lower in the CM+GSPE group compared to the CM+NAC group.

Significance: Our study showed, for the first time in the literature, that GSPE has a greater renoprotective effect compared with NAC and that this effective protection may be related to decrease in calpain 1 levels.
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http://dx.doi.org/10.1016/j.lfs.2014.03.030DOI Listing
May 2014

How does colistin-induced nephropathy develop and can it be treated?

Antimicrob Agents Chemother 2013 Aug 29;57(8):3463-9. Epub 2013 Apr 29.

Department of Nephrology, Karadeniz Technical University, School of Medicine, Trabzon, Turkey.

Colistin is an old antibiotic used in the treatment of Gram-negative infections. It was once suspended because of its nephrotoxic effect but has since been reintroduced due to multidrug-resistant bacterial infections. The pathogenesis of colistin-associated nephropathy has not been clarified, and there is currently no effective therapeutic or prophylactic agent available. The aim of this study was to investigate the roles of caspase-associated apoptosis and caspase 1, calpain 1, inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) expression in the pathogenesis of colistin-associated nephrotoxicity and the effect of grape seed proanthocyanidin extract (GSPE) in preventing it. Twenty-four rats were divided into three groups: control, colistin, and colistin plus GSPE (colistin+GSPE). Colistin-associated nephropathy was induced by the administration of 300,000 IU/kg of body weight/day colistin intraperitoneally for 7 days. The experiment was discontinued on the seventh day. Blood was collected for measurements of blood urea nitrogen (BUN) and creatinine levels. Histopathological examination of kidney tissue and caspase 1 and 3, iNOS, eNOS, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL), and calpain 1 staining was also performed. Significant increases in BUN levels; creatinine levels; renal histopathological scores; and TUNEL, caspase 1 and 3, calpain 1, iNOS, and eNOS staining were observed for the colistin group compared to the control group. Significant decreases in BUN levels; creatinine levels; renal histopathological scores; and TUNEL, caspase 1 and 3, calpain 1, iNOS, and eNOS staining were observed in the colistin+GSPE group compared to the colistin group. Our study shows, for the first time in the literature, that caspase-mediated apoptosis, iNOS, caspase 1, and calpain 1 are involved in the pathogenesis of colistin-associated nephropathy. GSPE had a renoprotective effect, as shown by the lowered levels of these mediators.
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http://dx.doi.org/10.1128/AAC.00343-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3719728PMC
August 2013

Protective effect of the grape seed proanthocyanidin extract in a rat model of contrast-induced nephropathy.

Kidney Blood Press Res 2012 6;35(6):445-53. Epub 2012 Jun 6.

Department of Nephrology, Karadeniz Technical University, School of Medicine, Trabzon, Turkey. gulsumozkan78 @ hotmail.com

Aim: Contrast-induced nephropathy (CIN) is a common cause of hospital-acquired acute renal failure. Although it is so common, there has been no approved therapy yet. We aimed to investigate the effect of grape seed proanthocyanidin extract (GSPE) on preventing CIN.

Materials And Methods: 24 rats were divided into four groups as control group, GSPE group, contrast medium (CM) group, and CM+GSPE group. The experiment was discontinued on the ninth day. Blood samples were obtained for the measurement of renal function parameters. Renal tissues of the rats were removed for the analysis of oxidative system parameters. In addition to renal histopathology, transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) was performed to determine apoptosis.

Results: There was a significant increase in BUN, creatinine, malondialdehyde (MDA) levels, apoptotic index (AI) and histopathological alteration in the CM group as compared to the control group. Furthermore, BUN, creatinine, MDA, total oxidant system and oxidative stress index levels, AI as well as renal histopathological alteration were significantly decreased in the CM+GSPE group.

Conclusion: For the first time in the literature, we showed that GSPE provided biochemical and histopathological improvement in CIN. Our findings revealed that this improvement was associated with the decrease in oxidative damage and apoptosis.
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http://dx.doi.org/10.1159/000337926DOI Listing
October 2013

Antiapoptotic and antioxidant effects of GSPE in preventing cyclosporine A-induced cardiotoxicity.

Ren Fail 2012 2;34(4):460-6. Epub 2012 Feb 2.

Department of Nephrology, School of Medicine, Karadeniz Technical University, Trabzon, Turkey.

Objectives: Cyclosporine A (CsA) is an immunosuppressive drug, but cardiotoxicity is one of its side effects. Free oxygen radical damage and apoptosis are considered to be responsible for CsA-induced cardiotoxicity. Grape seed proanthocyanidin extract (GSPE) displays antioxidant and antiapoptotic activities. Therefore, we aimed to evaluate the effect of GSPE on CsA-induced cardiotoxicity.

Materials And Methods: Twenty-four rats were divided into four groups, with six rats in each group. CsA-induced nephropathy was induced by administration of 25 mg/kg CsA. The experiment was discontinued on day 21, and total oxidant system (TOS), total antioxidant system (TAS), oxidative stress index (OSI), and malondialdehyde (MDA) were measured in order to evaluate oxidative damage to the heart tissue. In addition to cardiac histopathology, transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) was performed to determine apoptosis.

Results: The CsA group showed a significant increase in TOS, OSI, MDA, cardiac histopathological score, and apoptotic index (AI); in the CsA + GSPE group, OSI, MDA, cardiac histopathological score, and AI decreased significantly, and TAS levels showed a significant increase.

Conclusion: In this study, we demonstrated for the first time in the literature that GSPE prevents CsA cardiotoxicity and that this effect can be achieved by antiapoptotic and antioxidant activities.
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http://dx.doi.org/10.3109/0886022X.2012.656563DOI Listing
August 2012

The effect of grape seed proanthocyanidin extract in preventing amikacin-induced nephropathy.

Ren Fail 2012 23;34(2):227-34. Epub 2012 Jan 23.

Department of Nephrology, School of Medicine, Karadeniz Technical University, Trabzon, Turkey.

Background/aims: Nephrotoxicity induced by aminoglycosides (AGs) limits their clinical use. As yet, no molecules have been approved to prevent AG nephropathy. We aim to investigate the effectiveness of grape seed proanthocyanidin extract (GSPE) in the prevention of amikacin (AK)-induced nephrotoxicity.

Methods: A total of 24 rats were allocated into control, GSPE, AK, and AK + GSPE groups. While 1 mL saline was administered for 6 days in control and AK groups, 100 mg/kg GSPE was administered in GSPE and AK + GSPE groups. On day 7, intraperitoneal (i.p.) saline was administered in control and GSPE groups, while 1.2 g/kg i.p. AK was administered in AK and AK + GSPE groups. The experiment was terminated on day 9. Blood samples were taken for the measurement of renal functions. Renal tissues of the rats were removed for the analysis of malondialdehyde (MDA), total oxidant system (TOS), total antioxidant system, oxidative stress index (OSI), and for histopathological examination.

Results: MDA level was found to be lower in GSPE group compared with other study groups. There was significantly more renal histopathological damage and higher blood urea nitrogen, creatinine, TOS, OSI, and MDA levels in the AK group compared with the control and AK + GSPE groups. The same parameters showed significant improvement in AK + GSPE group compared with AK group.

Conclusion: Our findings demonstrate for the first time that GSPE reduces oxidative damage in AK nephropathy and provides biochemical and renal histopathological improvements.
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http://dx.doi.org/10.3109/0886022X.2011.643391DOI Listing
May 2012

Anti-apoptotic and anti-oxidant effects of grape seed proanthocyanidin extract in preventing cyclosporine A-induced nephropathy.

Nephrology (Carlton) 2012 May;17(4):372-9

Departments of Nephrology, School of Medicine, Karadeniz Technical University, Trabzon, Turkey.

Aim: Although the pathogenesis of cyclosporine (CsA) nephropathy is not completely understood, it is attributed to oxidative damage and apoptosis. Grape seed proanthocyanidin extract (GSPE) is a molecule with anti-oxidant and anti-apoptotic properties. Our aim was to demonstrate the effects of GSPE in preventing CsA nephropathy.

Methods: Twenty-four Sprague-Dawley rats were divided into four groups. The control, GSPE, CsA and CsA+GSPE groups were given 1 mL olive oil, 100 mg/kg GSPE, 25 mg/kg CsA and 100 mg/kg GSPE+25 mg/kg CsA, respectively. On day 21, blood samples were taken for blood urea nitrogen (BUN), creatinine and CsA levels, and renal tissue was used for total oxidant system (TOS), total anti-oxidant system (TAS), oxidative stress index (OSI) and malondialdehyde (MDA) measurements. In addition to renal histopathology, apoptosis staining was performed on renal tissue.

Results: The BUN, creatinine, TOS, OSI, MDA, histopathological score, and apoptotic index exhibited increases in the CsA group. In the CsA+GSPE group, however, BUN, creatinine, OSI, MDA, renal histopathological score and apoptotic index (AI) decreased and TAS levels increased. In addition, there was no difference between the CsA and CsA+GSPE groups with regard to CsA levels.

Conclusion: We demonstrated that GSPE prevents CsA nephropathy and that this effect is achieved by anti-apoptotic and anti-oxidant activity. We also achieved a significant recovery in kidney functions without affecting CsA plasma levels.
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http://dx.doi.org/10.1111/j.1440-1797.2012.01565.xDOI Listing
May 2012

Simvastatin impairs spatial memory in rats at a specific dose level.

Tohoku J Exp Med 2008 Apr;214(4):341-9

Department of Physiology, Medical School, Karadeniz Technical University, Trabzon, Turkey.

Statins, inhibitors of cholesterol synthesis, are used to prevent cardiovascular complications. Moreover, statins have been shown to influence some cognitive functions. The modulating effects of simvastatin, one member of the statin family, on memory-related neurotransmitters and neuronal structures have also been reported. We aimed to investigate the behavioral effects of long-term simvastatin application on daily activity, psychomotor performance and spatial memory using Sprague-Dawley rats. Simvastatin (10 or 30 mg/kg/day) was administered orally to rats, in parallel with a vehicle-treated group. Daily activity test results of both simvastatin groups were found similar to the vehicle group after five weeks of simvastatin or vehicle application. Psychomotor performance was measured with the rotarod test. After 6 weeks of simvastatin or vehicle application, the vehicle-treated group stayed on the rotarod device for a shorter time compared with both simvastatin-treated groups. Spatial memory was evaluated by the Barnes maze test. Four weeks of 10 mg/kg/day simvastatin application led to poorer scores on spatial memory compared to the vehicle group, but surprisingly, this effect was not seen in the 30 mg/kg/day group. Our results revealed that simvastatin administration had no significant effect on daily activity. Psychomotor performance test results suggested that simvastatin alters psychomotor behavior at higher nervous system levels. Spatial memory test results indicate that long-term simvastatin usage impairs spatial memory only at 10 mg/kg/day dose.
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http://dx.doi.org/10.1620/tjem.214.341DOI Listing
April 2008

Fluvastatin alters psychomotor performance and daily activity but not the spatial memory in rats.

Tohoku J Exp Med 2006 Aug;209(4):311-20

Department of Physiology, Karadeniz Technical University, Medical School, Trabzon, Turkey.

Statins, inhibitors of cholesterol synthesis for treating dyslipidemia and preventing cardiovascular complications, have been shown to alter central nervous system functions. Our aim was to investigate the effects of the fluvastatin, a member of statin family, on psychomotor performance, daily activity and spatial memory. Sprague-Dawley rats were treated with fluvastatin (n = 8) or placebo as a control (n = 11) regardless of sex. Fluvastatin (7.5 mg/kg) was administered orally once a day for four weeks, while the control group was administered only placebo. Psychomotor performance was measured by rotarod tests. No significant difference was observed in the fluvastatin group over the course of weeks, but the control group preferred to stay on the device shorter times (p < 0.05). For the first three weeks of the drug administration there was a statistical difference between the groups, however no difference was found after the 4th week. There was no difference in the Barnes maze spatial memory test between the groups and also within the groups over the course of time. Daily activity tests revealed that stereotypical and vertical movements of the fluvastatin group were significantly less than the control group in all four weeks. Ambulatory movements and the distances taken by the fluvastatin group were decreased significantly over the course of time (p < 0.005 and p < 0.001, respectively), but the control group did not reveal any significant change. Our results suggest that fluvastatin altered psychomotor performance and daily activity in rats, but it did not affect the spatial memory. These behavioral changes might be associated with alterations in the composition of the brain lipids caused by fluvastatin.
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http://dx.doi.org/10.1620/tjem.209.311DOI Listing
August 2006