Cemil Bayram

Background: Alterations in glutamatergic homeostasis have been implicated in Alzheimer’s disease, but the relationship between total hippocampal tissue glutamate and Alzheimer-like molecular alterations remains unclear. This study evaluated the early neuroprotective potential of gentisic acid (GA) and erucic acid (EA) in an intracerebroventricular streptozotocin (icv-STZ)-induced rat model of sporadic Alzheimer-like pathology. Methods: Sixty-four female Sprague–Dawley rats were randomly assigned to eight groups: control, sham, STZ, STZ + GA (100 or 200 mg/kg/day), STZ + EA (25 or 50 mg/kg/day), and STZ + memantine (10 mg/kg/day). Treatments began immediately after STZ and continued orally for 21 days. Behavioral performance was assessed by Morris water maze and passive avoidance tests. Total hippocampal tissue glutamate was quantified by LC–MS/MS. Neuronal degeneration was assessed histopathologically, whereas tau, amyloid-β, and AChE immunoreactivity and tau-, APP-, and AChE-related in situ hybridization signals were evaluated. Results: Compared with controls, STZ-treated rats exhibited poorer behavioral performance, higher total hippocampal tissue glutamate, greater neuronal degeneration, and increased molecular signals. GA and EA administration was associated with attenuation of these alterations, with generally stronger effects at higher doses. EA at 50 mg/kg/day showed the lowest mean total hippocampal tissue glutamate among treatment groups. GA at 200 mg/kg/day and EA at 50 mg/kg/day showed the most consistent preservation across behavioral, histopathological, and molecular endpoints. Conclusions: Early GA and EA administration was associated with neuroprotective effects in the icv-STZ model. Because treatment began immediately after STZ administration, the findings support early or preventive neuroprotection rather than reversal of established Alzheimer-like pathology. Total tissue glutamate measurements neither distinguish extracellular glutamate nor directly demonstrate glutamate-mediated excitotoxicity.

Parkinson’s disease (PD), the second most common neurodegenerative disorder, is characterized by α-synuclein aggregation and loss of dopaminergic neurons, and current treatments are symptomatic. Multiple intricate mechanisms contribute to the pathogenesis, and the effectiveness of single-target approaches is therefore limited. Current approaches highlight therapeutic candidates capable of simultaneously modulating multiple pathways. Recent clinical and experimental studies of sodium-glucose cotransporter inhibitors (SGLT2is), approved for the treatment of type 2 diabetes mellitus, have indicated their pleiotropic and neuroprotective potential. SGLT2i dapagliflozin has several features, including low molecular weight, blood-brain barrier permeability, and tolerability. This study investigated the effects of dapagliflozin on pathways implicated in the pathogenesis of PD in a 6-hydroxydopamine-induced experimental PD model in female Sprague-Dawley rats using in silico, histopathological, immunohistochemical, and biochemical methods. Dapagliflozin was administered by oral gavage at four different doses (2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, and 10 mg/kg) for 14 days. Motor deficits were evaluated by means of behavioral tests, and dapagliflozin was observed to alleviate motor dysfunction. Tyrosine hydroxylase expression increased in brain tissues, whereas A2AAR, TNF-α, and APAF-1 levels, as well as α-synuclein and caspase-3 expression, decreased. In molecular docking analyses, dapagliflozin showed notable binding affinity to PD-associated human target receptors. Our results suggest that dapagliflozin may exert potential neuroprotective effects via modulation of inflammatory, oxidative stress-related, and apoptosis-associated pathways and may represent a promising repurposing candidate for PD.

Aim: This study aimed to assess the modulatory effects of exercise on long-term high-fat diet (HFD)-induced variations in lipid parameters, cognitive performance, gut–brain peptides, and hippocampal histopathology in rats. Materials and Methods: Male Wistar albino rats were randomly divided into four experimental groups (n = 10 each): Sedentary-(SED), Exercise-(EX), High-Fat Diet-(HFD), and High-Fat-Diet + Exercise (HFD + EX). Exercise protocol was applied from the 4th weeks of experiment. The Morris Water Maze-(MWM) test was performed at the 4th, 8th, and 12th weeks of experiment to assess spatial learning. Serum levels of lipid profiles (triglyceride-(TG), total cholesterol-(TC), High Density Lipoprotein-(HDL), Low Density Lipoprotein-(LDL)) ghrelin, obestatin, and orexin A/B were measured. Hippocampal tissues were evaluated by hematoxylin–eosin and toluidine blue staining. Group comparisons were evaluated using both parametric (One-Way ANOVA) and non-parametric (Kruskal–Wallis H) statistical tests. Results: Through 6th week of the experiment, both HFD and HFD + EX groups showed lower body weight ( p < 0.05). and at 7th week of experiment, only the HFD + EX group remained lighter ( p < 0.05). TG, TC and LDL levels were increased in HFD (218.56 ± 57.43, 68.78 ± 12.43, 23.22 ± 4.60 mg/dL) and HFD + EX (159.22 ± 55.15, 70.78 ± 8.07, 26.9 ± 5.16 mg/dL) groups ( p < 0.05). Ghrelin was highest in the HFD + EX group (5.58 ± 1.00 ng/mL, p < 0.05), and obestatin levels were decreased in HFD (7.08 ± 0.85 ng/mL) and HFD + EX (7.11 ± 0.45 ng/mL) groups ( p < 0.001). Orexin A decreased in the HFD group (2713.38 ± 380.61 pg/mL, p < 0.05), and orexin B was highest in the EX group (7.23 ± 2.21 pg/mL, p < 0.01). MWM test revealed major increase in latency time in the HFD (59 s) group at 12th week of experiment ( p < 0.001). Histopathological analysis showed significant hippocampal degeneration, necrosis, and gliosis in HFD and HFD + EX groups ( p < 0.001). Conclusion: This study offers a comprehensive evaluation of long-term HFD exposure and exercise by jointly assessing metabolic outcomes, cognition, gut–brain peptides, and hippocampal histopathology—an approach seldom combined in a single design. The findings show that exercise offers limited neuroprotective and metabolic benefits but does not fully prevent HFD-induced hippocampal damage, highlighting a novel multidimensional perspective and pointing to the need for additional protective strategies.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss in the substantia nigra pars compacta, accompanied by oxidative stress and neuroinflammation. Novel multitarget neuroprotective strategies are required to overcome the limitations of current symptomatic treatments. The neuroprotective effects of Antrodia cinnamomea (AC) and citrate-stabilized silver nanoparticles (AgNPs), alone and in combination, were evaluated using a 6-hydroxydopamine (6-OHDA)–induced SH-SY5Y cell model and a unilateral 6-OHDA rat model. Sixty-three rats were divided into nine experimental groups. Cell viability, behavioral tests, LC–MS/MS analysis of dopamine and acetylcholine, oxidative stress and inflammatory biomarkers, histopathological assessment, immunohistochemistry, and Western blot analyses of TH, α-synuclein, PI3K, Bcl-2, Caspase-3, and agmatinase were performed. 6-OHDA significantly reduced cell viability, impaired motor performance, and induced dopaminergic neuronal degeneration. AC treatment, particularly in combination with AgNPs, markedly improved cell survival, ameliorated behavioral deficits, and preserved neuronal architecture. Combined treatment significantly decreased MDA, TNF-α, and IL-1β levels, while restoring GSH and SOD activities. LC–MS/MS analysis demonstrated partial recovery of dopamine and acetylcholine levels. Increased TH and PI3K expression, reduced α-synuclein and Caspase-3 levels, and normalization of Bcl-2 and agmatinase were observed following AC + AgNP treatment. AC conjugated with citrate-stabilized AgNPs exerts significant neuroprotective effects in experimental PD by concurrently modulating oxidative stress, neuroinflammation, and apoptotic pathways, highlighting its potential as a multitarget therapeutic strategy. Graphical Abstract

This study aims to evaluate the impact of tetracalcium phosphate (TTCP) applied directly to the fracture line in a rat femur fracture model. Thirty-three male Sprague-Dawley rats weighing 350 to 400 g were randomly and equally divided into three groups: normal control (NC), fracture control (PC), and TTCP treatment group. Standardized femur fractures were created in the PC and TTCP groups and fixed using intramedullary Kirschner wires. In the TTCP group, TTCP dissolved in distilled water was applied directly to the fracture line. All rats were sacrificed on postoperative Day 28. Radiological, histopathological, and biochemical analyses were performed to assess fracture healing. Radiological scoring revealed significantly higher fracture healing in the TTCP group compared to the PC group on Days 14 and 28 (p<0.05). Histopathological analyses showed reduced inflammation and fibrosis, and increased chondrocyte activity and neovascularization in the TTCP group. On Day 28, serum tumor necrosis factor-alpha (TNF-α) levels were significantly higher in the PC group compared to TTCP and NC, while TTCP values were comparable to NC. No adverse tissue reactions were observed in any group. The TTCP enhances fracture healing when applied directly to the fracture line, without causing soft tissue irritation or histologically detectable adverse reactions. Its biological activity and ease of application suggest that TTCP may be a promising adjunct in the treatment of complex fractures.

Parkinson’s disease (PD) is characterized by progressive dopaminergic neuronal loss, with oxidative stress and neuroinflammation as critical pathological mechanisms. The blood–brain barrier presents a significant challenge for therapeutic delivery, while current treatments provide only symptomatic relief without halting disease progression. This study investigated the neuroprotective effects of astaxanthin-loaded citrate-coated silver nanoparticles (AST-AgNPs), leveraging their potent antioxidant properties, anti-inflammatory capacity, and enhanced blood–brain barrier penetration. In vitro cytotoxicity analyses were performed using 6-hydroxydopamine (6-OHDA)-induced SH-SY5Y neuroblastoma cells, while in vivo experiments utilized a unilateral 6-OHDA-induced rat model. Following 14 days of treatment, comprehensive evaluations included behavioral assessments, biochemical analyses (MDA, GSH, SOD, TNF-α, IL-1β, IFN-γ), histopathology, immunohistochemistry (BrdU, tyrosine hydroxylase), and molecular analyses. Western blot measured CHOP, IRE1, ATF6, p-AKT, total AKT, caspase-3, and cleaved caspase-3, while RT-PCR quantified caspase-3, Bcl-2, Bax, PI3K, mTOR, Akt, CREB, and NF-κB-p65 expression. AST-AgNP treatment significantly ameliorated motor dysfunction, reduced neuroinflammation (TNF-α, IL-1β), improved oxidative stress parameters (MDA, GSH, SOD), and preserved dopaminergic neurons (all p < 0.05). Western blot revealed significant downregulation of ER stress markers (CHOP, IRE1, ATF6) and cleaved caspase-3, while restoring p-AKT and total AKT levels (p < 0.05). RT-PCR demonstrated decreased pro-apoptotic gene expression (caspase-3, NF-κB-p65) and increased anti-apoptotic Bcl-2 expression (p < 0.05). These findings demonstrate that AST-AgNPs provide neuroprotection through simultaneous modulation of ER stress and PI3K/Akt/mTOR pathways, representing a novel dual-pathway therapeutic strategy for PD addressing multiple pathological mechanisms through enhanced nanoparticle-mediated delivery. Graphical Abstract

Parkinson’s disease is a complex neurodegenerative disease that affects millions of people worldwide. The incidence and prevalence of Parkinson’s disease, the second most common neurodegenerative disease after Alzheimer’s disease, is gradually increasing. Although it is an important public health concern, the mechanisms related to Parkinson’s disease have not been fully elucidated. One of the main approaches to research on mechanisms and treatment related to Parkinson’s disease is the use of experimental models. In vitro and in vivo models enable the investigation of disease-related molecular and cellular processes and the testing of potential treatments. A variety of experimental models are used in Parkinson’s disease research, including toxin-induced models, genetic models, and transgenic models, each with their strengths and limitations. Experimental models come to the fore in research on Parkinson’s disease, which does not yet have a radical treatment. However, it is important to recognize that no experimental model truly represents all aspects of human Parkinson’s disease. For this reason, the findings obtained from the studies need to be supported by different test systems and interpreted carefully. Experimental models are invaluable in the quest to elucidate the mechanism of Parkinson’s disease and develop effective treatments.

Background: Cisplatin is a potent anticancer agent widely employed in chemotherapy. However, cisplatin leads to toxicity on non-targeted healthy organs, including the liver. We investigated the hepatoprotective mechanism of arbutin (ARB), a glycosylated hydroquinone, against cisplatin-induced hepatotoxicity. Methods: Rats were orally administered with ARB (ARB1 = 50 mg/kg; ARB2 = 100 mg/kg) for 14 consecutive days against hepatotoxicity induced by a single dose of cisplatin (10 mg/kg) on day 15. Three days after the intraperitoneal cisplatin injection, serum and liver tissue were collected for subsequent analyses. Results: Cisplatin triggered marked increases in serum AST, ALT, and ALP activities, hepatic malondialdehyde (MDA) and reactive oxygen species (ROS) coupled with a considerable diminution in hepatic activities of superoxide dismutase (SOD), catalase (CAT) and the concentration of reduced glutathione (GSH). The gene expressions of interleukin-1β (IL-1β), tumor necrosis factor (TNF-α), and IL-6 were notably increased. The pre-administration of ARB1 and ARB2 reduced AST, ALT and ALP in serum and restored SOD, CAT, GSH, ROS, MDA and cytokine levels which was also evidenced by alleviated hepatic lesions. Further, cisplatin-induced prominent alterations in the gene expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), iNOS, NF-κB, Bax, Bcl-2, caspase-3 and 8-OHdG in the liver. Interestingly, ARB protected the liver and mitigated the cisplatin-induced alterations in serum AST, ALT, ALP, and reduced hepatic redox markers, 8-OdG, inflammatory markers and gene expressions. Conclusion: The findings demonstrate that ARB is a potential protective adjuvant against cisplatin-induced hepatotoxicity via inhibition of hepatic oxidative stress, inflammation, and apoptosis.

Background: Mitochondrial dysfunction and metabolic abnormalities are acknowledged as significant factors in the onset of neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). Our research has demonstrated that the use of combined metabolic activators (CMA) may alleviate metabolic dysfunctions and stimulate mitochondrial metabolism. Therefore, the use of CMA could potentially be an effective therapeutic strategy to slow down or halt the progression of PD and AD. CMAs include substances such as the glutathione precursors (L-serine and N-acetyl cysteine), the NAD+ precursor (nicotinamide riboside), and L-carnitine tartrate. Methods: Here, we tested the effect of two different formulations, including CMA1 (nicotinamide riboside, L-serine, N-acetyl cysteine, L-carnitine tartrate), and CMA2 (nicotinamide, L-serine, N-acetyl cysteine, L-carnitine tartrate), as well as their individual components, on the animal models of AD and PD. We assessed the brain and liver tissues for pathological changes and immunohistochemical markers. Additionally, in the case of PD, we performed behavioral tests and measured responses to apomorphine-induced rotations. Findings: Histological analysis showed that the administration of both CMA1 and CMA2 formulations led to improvements in hyperemia, degeneration, and necrosis in neurons for both AD and PD models. Moreover, the administration of CMA2 showed a superior effect compared to CMA1. This was further corroborated by immunohistochemical data, which indicated a reduction in immunoreactivity in the neurons. Additionally, notable metabolic enhancements in liver tissues were observed using both formulations. In PD rat models, the administration of both formulations positively influenced the behavioral functions of the animals. Interpretation: Our findings suggest that the administration of both CMA1 and CMA2 markedly enhanced metabolic and behavioral outcomes, aligning with neuro-histological observations. These findings underscore the promise of CMA2 administration as an effective therapeutic strategy for enhancing metabolic parameters and cognitive function in AD and PD patients.