Bulbul, Ozlem; Mammadov, Renad; Suleyman, Bahadır; Kulaber, Ali; Karaca, Yunus; Yaman, Huseyin; Yenilmez, Engin; Sahin, Aynur; Ozer, Vildan

Purpose: This study aimed to biochemically and histopathologically evaluate the protective and therapeutic effects of elamipretide and methylprednisolone on methanol poisoning-induced brain, optic nerve, and retinal toxicity. Method: In this study, 40 male Wistar Albino rats were divided into six groups: healthy control (HC), methotrexate (MTX, 0.3 mg/kg/d for 7 d), methotrexate + methanol (MTX-M, 0.3 mg/kg/d for 7 d + methanol 3 g/kg on Day 8), methotrexate + methanol + methylprednisolone (MTX-M-MPZ, 0.3 mg/kg/d for 7 d + methanol 3 g/kg on Day 8 + MPZ 1 mg/kg/d for 3 d), methotrexate + methanol + elamipretide (MTX-M-E, 0.3 mg/kg/d for 7 d + methanol 3 g/kg on Day 8 + elamipretide 5 mg/kg/d for 3 d), and methotrexate + methanol + methylprednisolone + elamipretide (MTX-M-MPZ-E, 0.3 mg/kg/d for 7 d + methanol 3 g/kg on Day 8 + MPZ 1 mg/kg/d + Elamipretide 5 mg/kg/d for 3 d). The rats were euthanized 8 h after the last drug administration. Histopathological and biochemical evaluations were performed on serum, caudatoputamen, and ocular tissues. Retinal degeneration was assessed using a scoring system where higher scores indicate less degeneration, with a score of 5 representing normal structure and 1 reflecting severe degeneration. Results: In the MTX-M-MPZ-E group, the retinal degeneration score was higher than in MTX-M group (p = 0.002). The apoptosis index in the retina was highest in MTX-M group, while it was lower in MTX-M-MPZ-E group compared to MTX-M group (p = 0.018). In addition, the apoptosis index in the caudatoputamen was lower in MTX-M-MPZ-E group compared to MTX-M group (p = 0.009). Conclusion: Combined elamipretide and methylprednisolone treatment improved optic nerve and retinal degeneration, reduced neuronal degeneration in the caudatoputamen, decreased oxidative stress and lipid peroxidation, and reduced apoptosis in the retina and caudatoputamen.

Özcan, Delil; Özçelik, Fatih; Mammadov, Renad; Aktaş, Mehmet; Altındağ, Fikret; Alkan, Abdurrahman Alpaslan; Karapapak, Murat; Altuner, Durdu; Süleyman, Halis

Purpose: Favipiravir (FAV) used against COVID-19 is an antiviral drug that causes adverse reactions, such as hyperuricaemia, liver damage, and hematopoetic toxicity. The aim of the study was to investigate the systemic and ocular side-effects of FAV in rats, for the first time.Materials and methods: A total of 18 albino male Wistar rats were used in the study. The rats were divided into 3 groups as the healthy group (HG), the group given 50 mg/kg/day favipiravir (FAV50), and the group given 200 mg/kg/d favipiravir (FAV200). These doses were given to the experimental groups for one week. At the end of the experiment histopathological examinations were performed on the conjunctiva and sclera of the eye. In addition, malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), interleukin-1β (IL-1β), and tumor necrosis factor alpha (TNF-α) levels were measured in blood samples taken from rats. Results: Compared to HG, the MDA (1.37 ± 0.61 vs. 4.82 ± 1.40 µmol/mL), IL-1β (2.52 ± 1.14 vs. 6.67 ± 1.99 pg/mL), and TNF-α levels (3.28 ± 1.42 vs. 8.53 ± 3.06 pg/mL) of the FAV200 group were higher. The levels of tGSH (7.58 ± 1.98 vs. 2.50 ± 0.98 nmol/mL) and SOD (13.63 ± 3.43 vs. 3.81 ± 1.43 U/mL) the FAV200 group were lower than the HG (p < 0.05, for all). The degree of damage to the cornea and sclera of the FAV200 group was quite high according to HG (p < 0.001). Conclusions: FAV can cause damage to rat conjunctiva and sclera by increasing oxidant stress and inflammation at high dose.

Bayrakçeken, Kemal; Ucgul, Rukiye Kilic; Coban, Taha; Yazıcı, Gulce; Suleyman, Halis

Objective: This study aims to investigate possible preventive effect of ATP on optic nerve damage caused by amiodarone in rats. Material and method: Thirty albino male Wistar rats weighing between 265 and 278 g were used in the study. Before the experiment, the rats were housed at 22 °C in a 12-h light/dark cycle under appropriate condition. The rats were equally divided into five groups of six animals each: healthy group, 50 mg/kg amiodarone (AMD-50), 100 mg/kg amiodarone (AMD-100), 25 mg/kg ATP + 50 mg/kg amiodarone (ATAD-50), and 25 mg/kg ATP + 100 mg/kg amiodarone (ATAD-100). At the end of 14th day, the animals were sacrificed using cardiac puncture under deep thiopental anaesthesia, and optic nerve tissues were harvested to measure superoxide dismutase (SOD), total glutathione (tGSH), malondialdehyde (MDA), and catalase (CAT) levels. Results: The MDA levels were found to be significantly higher in the AMD-50 and AMD-100 groups compared to the healthy group (p ˂ 0.001). There was also a significant difference between the AMD-50 and ATAD-50 groups, and between the AMD-100 and ATAD-100 groups regarding MDA levels (p ˂ 0.001). tGSH, SOD, and CAT levels were significantly lower in the AMD-50 and AMD-100 groups compared to the healthy group (p ˂ 0.001). ATP was found to partially inhibit amiodarone-induced optic neuropathy. Conclusion: The biochemical and histopathological results of this study demonstrated that amiodarone at high doses caused more severe optic neuropathy inducing oxidative damage, but ATP could relatively antagonise these negative effects on the optic nerve. Therefore, we believe that ATP may be beneficial in preventing amiodarone-induced optic neuropathy.

Akbaş, Nergis; Akbaş, Emin Murat; Süleyman, Zeynep; Çiçek, Betül; Ağgül, Ahmet Gökhan; Mokhtare, Behzad; Süleyman, Halis

Purpose: Ribociclib is a CDK4/6 inhibitor approved for the treatment of breast cancer; it inhibits the activity of CDK4/6 by competitively binding to adenosine 5'-triphosphate (ATP) binding sites. Although generally well-tolerated, ribociclib has been connected to a number of serious dermatologic complications. This study explored the effects of ATP on ribociclib-induced skin damage. Materials and methods: Using a rat model, ATP 25 mg/kg was injected intraperitoneally in the ATP + Ribociclib (ATR) group (n = 6). Distilled water as solvent was applied to the healthy control (HC) group (n = 6) and ribociclib (RCB) group (n = 6). One hour after ATP and solvent administration, ribociclib (200 mg/kg) suspension prepared in distilled water was administered to the stomach by gavage (ATR and RCB groups). This was repeated once a day for 15 d. After that period, biochemical markers were studied in the skin tissues and histopathological evaluations were conducted. Results: In the histopathological evaluation of the RCB group, dermal necrosis, degeneration in hair follicles, and pycnosis in keratinocytes were observed. Only mild degeneration was observed in the ATR group; the HC group had a normal histological appearance. The malondialdehyde (MDA) values were significantly higher and the superoxide dismutase (SOD), catalase (CAT), and total glutathione (tGSH) levels were significantly lower in the RCB group in comparison to the HC group (p <.001). ATP reduced the ribociclib-induced increases in the MDA values and decreased the SOD, CAT, and tGSH levels in the ATR group (p <.001). Conclusion: ATP may be useful in the treatment of ribociclib-induced skin damage.

Gore Karaali, Muge; Karaali, Soner; Demir, Damla; Yazıcı, Gulce Naz; Coban, Abdulkadir; Mammadov, Renad; Suleyman, Bahadır; Suleyman, Halis

Purpose: Bevacizumab is a recombinant humanized monoclonal antibody that specifically binds to vascular endothelial growth factor (VEGF). Cutaneous side effects of bevacizumab are seen with substantial frequency and may require the interruption of the treatment. The aim of the study was to conduct a biochemical and histopathological investigation of the effects of carvacrol against the possible oxidative skin damage caused by bevacizumab in rats. Materials and methods: A total of 18 adult male Wistar albino rats were randomly assigned to three groups as healthy (H group; n = 6), bevacizumab alone (B group; n = 6), and carvacrol + bevacizumab (CB group; n = 6). Carvacrol was injected intraperitoneally (IP) at a dose of 50 mg/kg in the CB group. Sterile salt solution (0.9% NaCl) was used as a solvent for the H and B groups. One hour after the administration of carvacrol and solvent, bevacizumab at a dose of 10 mg/kg IP was administered to the CB and B groups. Bevacizumab was given once daily for a total of two doses, 15 days apart. Carvacrol was administered once daily for one month. After that period, all animals were sacrificed and their skin tissues removed. Malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GPO), catalase (CAT), superoxide dismutase (SOD), total oxidant status (TOS), and total antioxidant status (TAS) levels in rats’ skin tissues were biochemically evaluated. The parameters were measured with spectrophotometric method by using a microplate reader (BioTek, Winooski, VT, USA). The skin tissues were also examined histopathologically by the pathologist (blind) for the study groups. Results: The MDA and TOS levels of the H and CB groups were significantly lower than the B group (p < 0.05). The mean scores of the other biochemical levels (GSH, GPO, CAT, SOD, TAS) in the H group were significantly higher than in the B and CB groups. Pathological examination of H group was normal. In B group epidermal atrophy, abnormal keratin accumulation, degenerated hair follicles, edoema and inflammatory cells accumulation in the dermis were observed. In the CB group, these findings were significantly improved. Conclusion: The positive effect of carvacrol against possible local oxidative skin damage due to bevacizumab in rats was demonstrated. In addition, more detailed studies are required to clarify the mechanism of the protective effect of carvacrol against bevacizumab-induced skin toxicity. The effect should be evaluated through further human studies, as well as studies using different doses of carvacrol.

Ahiskali, Ibrahim; Ferah Okkay, Irmak; Mammadov, Renad; Okkay, Ufuk; Keskin Cimen, Ferda; Kurt, Nezahat; Suleyman, Halis

Aim: To investigate the effect of taxifolin on cisplatin-induced oxidative and proinflammatory optic nerve damage in rats. Methods: A total of 18 albino Wistar male rats were assigned into 3 groups, as follows; Group 1: Control group, Group 2: Only cisplatin administered group for 14 days (Cisplatin group), and Group 3: Taxifolin + cisplatin administered group for 14 days (CIS + TAX group). Serum malondialdehyde (MDA), total Glutathione (tGSH), Nuclear Factor-Kappa B (NF-ƘB), Total Oxidative Status (TOS) and Total Antioxidant Status (TAS) levels were collected from the left eyes of rats. Rats’ right eyes were enucleated for histopathological evaluations of optic nerves. Results: NF-ƘB, MDA and TOS levels were statistically significantly higher (p < 0.001) in cisplatin group when compared to other 2 groups, the tGSH and TAS levels of which were statistically significantly lower (p < 0.001). Regarding these parameters, in cisplatin group NF-ƘB, MDA and TOS levels were statistically significantly increased with cisplatin administration and giving taxifolin concomitantly with cisplatin prevented this elevation. On the other hand, tGSH and TAS levels were statistically significantly decreased with cisplatin administration and routine simultaneous application of taxifolin with cisplatin prevented this decrease. In histopathological findings, haemorrhage was observed in the perineum of the injured optic nerves in the cisplatin treated group. And also edoema and degeneration in nerve fascicles in damaged optic nerves were seen in the cisplatin group. In the taxifolin treated group histopathological examinations were close to normal appearance, except mild edoema in nerve fascicles. Conclusion: Cisplatin causes oxidative stress on the rat optic nerves, and these changes lead to significant histopathological damage. Taxifolin, which we used to prevent oxidative damage to the optic nerves caused by cisplatin, has been emphasized as a powerful antioxidant agent in many previous scientific investigations. Concomitant administration of taxifolin may prevent these adverse effects of cisplatin, as well as histopathological damage. Further studies are needed to fully determine the effects of cisplatin and taxifolin on the eye.

Agcayazi, Sümeyye Burcu; Ugurlu, Adem; Ucak, Turgay; Tasli, Nurdan Gamze; Karakurt, Yucel; Icel, Erel; Keskin Cimen, Ferda; Süleyman, Halis

Aim: To investigate the effects of resveratrol on oxidative stress and inflammation parameters and histological alterations in cisplatin-induced optic nerve damage in a mouse model. Material and Method: Thirty-six albino Wistar male rats were divided into three groups as control, 5 mg/kg cisplatin-administered (Cis) and 5 mg/kg cisplatin + 25 mg/kg resveratrol-administered (Cis + Res) animals. At the end of the experimental period, the rats were sacrificed with high-dose (50 mg/kg) thiopental sodium, and their optic nerves were dissected. Malondialdehyde (MDA), total glutathione (tGSH), total oxidant status (TOS), total antioxidant status (TAS), tumour necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-KB) levels, and histopathological findings were assessed using the optic nerve tissues. Results: In the Cis + Res group, the MDA, TOS, OSI, TNF-a and NFK-B levels were significantly lower and the tGSH and TAS levels were significantly higher compared with the Cis group (P = 0.001). In histological evaluations, there were dilated and congested blood vessels, destruction, oedema, degeneration, haemorrhage, and proliferating capillaries indicating the presence of inflammation and damage only in the Cis-administered group. However, in the Cis + Res group, the histological findings were very similar to the healthy controls. Conclusion: Resveratrol is a promising neuroprotective agent for cisplatin-induced optic nerve toxicity with its anti-oxidant and anti-inflammatory effects. Further investigations are needed to evaluate the possible therapeutic effects on other optic nerve toxicities.

Sunar, Mukadder; Yazici, Gulce Naz; Mammadov, Renad; Kurt, Nezahat; Arslan, Yusuf Kemal; Süleyman, Halis

Aim: In this study, it was aimed to investigate the effect of coenzyme Q10 (CoQ10) on cisplatin-induced oxidative retinal damage in rats biochemically and histopathologically. Materials and methods: Thirty male Wistar albino rats were divided into 3 groups randomly: untreated control (C group), only 2.5 mg/kg cisplatin daily administrated group for 2 weeks (CP group), 2.5 mg/kg cisplatin + 20 mg/kg orally CoQ10 daily administrated group for 2 weeks (CoQC group). At the end of experimental period, blood samples obtained before sacrification for the biochemical examination of serum malondialdehyde (MDA), total glutathione (tGSH), total oxidant system (TOS), total antioxidant systemic (TAS) levels and after eyes were removed for examined histopathology. Results: As a result of our study, severe histopathological damage was detected in the retinal tissue of the cisplatin group with serum malondialdehyde (MDA) and total oxidant system (TOS) levels were high and total glutathione (tGSH) and total antioxidant systemic (TAS) levels were low. However, it was observed that the histopathological damage associated with cisplatin was decreased in the retinal tissue of the CoQ10 group, which inhibited the increase in blood serum MDA/TOS levels and decrease in tGSH/TAS levels. Conclusion: The biochemical and histopathological results of our study were compatible with each other, so we concluded that the damage to the rat retinal tissue caused by cisplatin may be reversible with coenzyme.

Okkay, Ufuk; Ferah Okkay, Irmak; Aydin, Ismail Cagri; Bayram, Cemil; Ertugrul, Muhammed Sait; Gezer, Arzu; Hacimuftuoglu, Ahmet

Aim: Cisplatin is a widely used and highly effective anti-cancer agent and one of the limiting side effects of cisplatin is ocular toxicity. Achillea millefolium, also known as yarrow, is a plant that has been used for many years to treat various health problems including chemotherapy-related toxicities. Methods: The present investigation was designed to evaluate the biochemical, molecular and histopathological effects of Achillea Millefolium on cisplatin-induced oxidative and inflammatory ocular damage in rats. Twenty-four adult male rats were assigned randomly to four groups (n = 6) as (1) control, (2) cisplatin (7 mg/kg, intraperitoneally), (3) Cisplatin + Achillea millefolium (200 mg/kg, orally for 14 consecutive days), (4) Cisplatin + Achillea millefolium (400 mg/kg, orally for 14 consecutive days). Levels of total antioxidant capacity and total oxidant status, SOD, MDA, IL-1β, and IL-10 were measured in ocular tissue. The mRNA expressions of TNF-α, nuclear factor kappa B and Caspase-3 were evaluated. Also, ocular sections were evaluated histopathologically. Results: Achillea Millefolium upregulated ocular antioxidant enzymes and downregulated inflammation. The SOD activity and total antioxidant capacity increased whereas total oxidant status and MDA levels decreased significantly at high dose group. High dose Achillea millefolium treatment reduced the IL-1β concentrations, whereas IL-10 levels increased significantly in that group. Moreover, we observed that Achillea millefolium restored ocular histopathological structure and significantly suppressed apoptosis by reducing the expression of Caspase-3. Conclusion: Collectively, our results suggest that Achillea millefolium have protective effects against cisplatin-induced ocular toxicity and is a promising adjuvant therapy with the potential to prevent cisplatin related ocular toxicity.

Icel, Erel; Suleyman, Halis; Yazici, Gulce Naz; Bakan, Nuri; Sunar, Mukadder

Purpose: Acute methanol exposure leads to systemic intoxication and toxic optic neuropathy. In this experimental study, we aimed to determine the protective effects of intravenous administration of ATP in methanol-induced optic neuropathy. Materials and methods: A total of 18 male albino Wistar rats weighing between 267 and 282 g were used for the experiment. The animals were divided into three groups as healthy control (HC), methanol (M), and methanol + ATP (M-ATP) groups. Distilled water was given to the healthy control group (n = 6) as the solvent, while 20% methanol was administered orally to the rats in M (n = 6) and M-ATP (n = 6) groups at a dose of 3 g/kg. Four hours after the administration of 20% methanol orally to the M-ATP group, ATP was injected intraperitoneally at a dose of 4 mg/kg. Eight hours after ATP injection, the animals were sacrificed by high-dose (50 mg/kg) thiopental anaesthesia and biochemical and histopathological examinations were performed on the removed optic nerve tissues. Malondialdehyde (MDA), total glutathione (tGSH), total oxidant status (TOS) and total anti-oxidant status (TAS) were analysed with biochemical tests. Results: MDA, TOS and OSI were significantly higher and tGSH and TAS levels were significantly lower in methanol administered group compared with the healthy controls or M-ATP group (p: 0.001). There was not any significant difference between healthy controls and M-ATP group regarding the oxidative stress parameters. There was a significant destruction and increase in thickness and astrocyte numbers and edema-vacuolization in methanol administered group compared with the healthy controls or M-ATP group (p: 0.001). Conclusion: Intravenous ATP administration had a significant positive effect on the oxidative stress parameters and optic nerve structure in methanol-intoxicated rats. Antioxidant therapies should be considered in future studies as a possible therapy for methanol-induced toxic optic neuropathy.