Natural Products for Preventing and Managing Anthracycline-Induced Cardiotoxicity: A Comprehensive Review.

Doxorubicin (DOX) is an anthracycline anticancer agent that is highly effective in the treatment of solid tumors. Given the multiplicity of mechanisms involved in doxorubicin-induced cardiotoxicity, it is difficult to identify a precise molecular target for toxicity. The findings of a literature review suggest that natural products may offer cardioprotective benefits against doxorubicin-induced cardiotoxicity, both in vitro and in vivo. However, further confirmatory studies are required to substantiate this claim. It is of the utmost importance to direct greater attention towards the intricate signaling networks that are of paramount importance for the survival and dysfunction of cardiomyocytes. Notwithstanding encouraging progress made in preclinical studies of natural products for the prevention of DOX-induced cardiotoxicity, these have not yet been translated for clinical use. One of the most significant obstacles hindering the development of cardioprotective adjuvants based on natural products is the lack of adequate bioavailability in humans. This review presents an overview of current knowledge on doxorubicin DOX-induced cardiotoxicity, with a focus on the potential benefits of natural compounds and herbal preparations in preventing this adverse effect. As literature search engines, the browsers in the Scopus, PubMed, Web of Science databases and the ClinicalTrials.gov register were used.

Antidepressant effects of selective adenosine receptor antagonists targeting the A1 and A2A receptors administered jointly with NMDA receptor ligands: behavioral, biochemical and molecular investigations in mice.

BACKGROUND: The objective of the study was to ascertain the antidepressant potential of the co-administration of NMDA receptor ligands and selective adenosine A1 and A2A receptor antagonists. METHODS: The forced swim test (FST) and spontaneous locomotor activity test were carried out in adult male naïve mice. Before the behavioral testing, animals received DPCPX (a selective adenosine A1 receptor antagonist, 1 mg/kg) or istradefylline (a selective adenosine A2A receptor antagonist, 0.5 mg/kg) in combination with L-701,324 (a potent NMDA receptor antagonist, 1 mg/kg), D-cycloserine (a partial agonist at the glycine recognition site of NMDA receptor, 2.5 mg/kg), CGP 37849 (a competitive NMDA receptor antagonist, 0.3 mg/kg) or MK-801 (a non-competitive NMDA receptor antagonist, 0.05 mg/kg). Additionally, serum BDNF level and the mRNA level of the Adora1, Comt, and Slc6a15 genes in the murine prefrontal cortex were determined. RESULTS: The obtained results showed that DPCPX and istradefylline administered jointly with NMDA receptor ligands (except for DPCPX + D-cycloserine combination) produced an antidepressant effect in the FST in mice without enhancement in spontaneous motility of animals. An elevation in BDNF concentration was noted in the D-cycloserine-treated group. Adora1 expression increased with L-701,324, DPCPX + D-cycloserine, and DPCPX + CGP 37849, while D-cycloserine, CGP 37849, and MK-801 led to a decrease. Comt mRNA levels dropped with DPCPX + L-701,324, istradefylline + L-701,324/CGP 37849 but increased with D-cycloserine, MK-801, CGP 37849 and DPCPX + MK-801/ CGP 37849. Slc6a15 levels were reduced by D-cycloserine, DPCPX + L-701,324 but rose with DPCPX + CGP 37849/MK-801 and istradefylline + D-cycloserine/MK-801/CGP 37849. CONCLUSION: Our study suggests that selective antagonists of adenosine receptors may enhance the antidepressant efficacy of NMDA receptor ligands highlighting a potential synergistic interaction between the adenosinergic and glutamatergic systems. Wherein, A2A receptor antagonists are seen as more promising candidates in this context. Given the intricate nature of changes in BDNF levels and the expression of Adora1, Comt, and Slc6a15 seen after drug combinations exerting antidepressant properties, further research and integrative approaches are crucial understand better the mechanisms underlying their antidepressant action.

Restoring Brain Pathways Involved in Diabetes-Associated Neurocognitive Disorders: The Potential of Dipeptidyl Peptidase 4 Inhibitors as a Therapeutic Strategy.

Diabetes, a widespread chronic metabolic disease, is projected to affect 783 million people globally by 2045. Recent studies emphasize the neuroprotective potential of dipeptidyl peptidase 4 (DPP4i) inhibitors, pointing toward a promising avenue for intervention in addressing cognitive challenges associated with diabetes. Due to limited data on the effect of DPP4i on brain pathways involved in diabetes-related neurocognitive disorders, the decision was made to conduct this study to fill existing knowledge gaps on this topic. The primary aim of our study was to evaluate the potential of DPP4 inhibitors (DPP4i) in preventing cognitive decline in mice with type 2 diabetes (T2D), placing special emphasis on gaining insight into the complex molecular mechanisms underlying this action. We examined drug efficacy in modulating neurotrophic factors, calcium levels, and the expression of key genes (HIF1α, APP, Arc) crucial for neural plasticity. Conducting cognitive assessments with the hole board and passive avoidance tests, we discerned a remarkable influence of short-term gliptin usage on the limiting progress of cognitive dysfunction in diabetic mice. The administration of DPP4 inhibitors led to heightened neurotrophin levels, increased HIF1α in the prefrontal cortex, and a significant elevation in Arc mRNA levels. Our findings reveal that DPP4 inhibitors effectively limit the progression of diabetes-related cognitive disorders. This breakthrough discovery not only opens new research avenues but also constitutes a potential starting point for creating innovative strategies for the treatment of central nervous system disorders focused on improving cognitive abilities.

Pathological Changes and Metabolic Adaptation in the Myocardium of Rats in Response to Chronic Variable Mild Stress.

Chronic variable mild stress (CVS) in rats is a well-established paradigm for inducing depressive-like behaviors and has been utilized extensively to explore potential therapeutic interventions for depression. While the behavioral and neurobiological effects of CVS have been extensively studied, its impact on myocardial function remains largely unexplored. To induce the CVS model, rats were exposed to various stressors over 40 days. Behavioral assessments confirmed depressive-like behavior. Biochemical analyses revealed alterations in myocardial metabolism, including changes in NAD+ and NADP+, and NADPH concentrations. Free amino acid analysis indicated disturbances in myocardial amino acid metabolism. Evaluation of oxidative DNA damage demonstrated an increased number of abasic sites in the DNA of rats exposed to CVS. Molecular analysis showed significant changes in gene expression associated with glucose metabolism, oxidative stress, and cardiac remodeling pathways. Histological staining revealed minor morphological changes in the myocardium of CVS-exposed rats, including increased acidophilicity of cells, collagen deposition surrounding blood vessels, and glycogen accumulation. This study provides novel insights into the impact of chronic stress on myocardial function and metabolism, highlighting potential mechanisms linking depression and cardiovascular diseases. Understanding these mechanisms may aid in the development of targeted therapeutic strategies to mitigate the adverse cardiovascular effects of depression.

2,4-dinitrophenol enhances cisplatin and etoposide cytotoxic activity on prostate cancer cell line.

INTRODUCTION AND OBJECTIVE: Including additional compounds that disturb the energy metabolism of cancer cells in advanced cancer therapy regimens may be an approach to overcome the problem of drug resistance and the therapeutic effectiveness of classic chemotherapeutics. One of the compounds that decouple oxidative phosphorylation, and thus alter the activity of energy-producing pathways, is 2,4-DNP (2,4- dinitrophenol). OBJECTIVE: The aim of the study was to assess the ability of the 2,4-DNP to sensitize prostate cancer cells to the action of cisplatin and etoposide, or to intensify their action. MATERIAL AND METHODS: The research was carried out on three prostate cancer cell lines (LNCaP, PC-3, DU-145. To assess the effect of cisplatin or etoposide with 2,4-DNP on prostate cancer cells, MTT assay, analysis of the cell cycle and apoptosis detection was performed. Oxidative stress was investigated by CellRox fluorescence staining and expression of genes related to antioxidant defence. In addition, analysis was conducted of the expression of genes related to cell cycle inhibition, transporters associated with multi-drug resistance and DNA repair. RESULTS: The study showed that the simultaneous incubation of 2,4-DNP with cisplatin or etoposide enhances the cytotoxic effect of the chemotherapeutic agent only in LNCaP cells (oxidative phenotype). CONCLUSIONS: The enhanced cytotoxic effect of chemotherapeutics by 2,4-DNP may be the result of disturbed redox balance, reduced ability of cells to repair DNA, and the oxidative metabolic phenotype of prostate cancer cells.

Assessment of the Impact of Carvedilol Administered Together with Dexrazoxan and Doxorubicin on Liver Structure and Function, Iron Metabolism, and Myocardial Redox System in Rats.

Late cardiotoxicity is a formidable challenge in anthracycline-based anticancer treatments. Previous research hypothesized that co-administration of carvedilol (CVD) and dexrazoxane (DEX) might provide superior protection against doxorubicin (DOX)-induced cardiotoxicity compared to DEX alone. However, the anticipated benefits were not substantiated by the findings. This study focuses on investigating the impact of CVD on myocardial redox system parameters in rats treated with DOX + DEX, examining its influence on overall toxicity and iron metabolism. Additionally, considering the previously observed DOX-induced ascites, a seldom-discussed condition, the study explores the potential involvement of the liver in ascites development. Compounds were administered weekly for ten weeks, with a specific emphasis on comparing parameter changes between DOX + DEX + CVD and DOX + DEX groups. Evaluation included alterations in body weight, feed and water consumption, and analysis of NADPH2, NADP+, NADPH2/NADP+, lipid peroxidation, oxidized DNA, and mRNA for superoxide dismutase 2 and catalase expressions in cardiac muscle. The iron management panel included markers for iron, transferrin, and ferritin. Liver abnormalities were assessed through histological examinations, aspartate transaminase, alanine transaminase, and serum albumin level measurements. During weeks 11 and 21, reduced NADPH2 levels were observed in almost all examined groups. Co-administration of DEX and CVD negatively affected transferrin levels in DOX-treated rats but did not influence body weight changes. Ascites predominantly resulted from cardiac muscle dysfunction rather than liver-related effects. The study's findings, exploring the impact of DEX and CVD on DOX-induced cardiotoxicity, indicate a lack of scientific justification for advocating the combined use of these drugs at histological, biochemical, and molecular levels.

Mirabegron, a Selective ß3-Adrenergic Receptor Agonist, as a Potential Anti-Obesity Drug.

Obesity is becoming a global health epidemic. Brown and "beige" adipose tissue may produce heat, leading to energy expenditure enhancement and weight loss. Mirabegron, a selective ß3-adrenergic receptor agonist, has been found to be effective as a brown adipose tissue activator, a "beige" cells stimulator and a metabolic homeostasis controller in animal and human studies. Although in animal studies, administration of mirabegron led to obesity improvement, significant weight loss in obese patients after mirabegron treatment has not been demonstrated so far, which may be associated with the too-short duration of the trials and the small number of participants in the studies. In humans, the most effective treatment for adipose tissue stimulation was high doses of mirabegron; however, cardiovascular side effects may limit the use of such doses, so the long-term safety must be evaluated. In cases of tachycardia or blood pressure elevation, the co-administration of a ß1-adrenergic receptor blocker may be useful. It should be checked whether smaller doses of mirabegron, taken for a longer time, will be sufficient to stimulate brown and "beige" adipose tissue, leading to weight loss. The introduction of mirabegron into obesity treatment in the future will require long-term trials with larger numbers of subjects, to assess mirabegron efficacy, tolerability, and safety.

The Lack of Synergy between Carvedilol and the Preventive Effect of Dexrazoxane in the Model of Chronic Anthracycline-Induced Cardiomyopathy.

The anticancer efficacy of doxorubicin (DOX) is dose-limited because of cardiomyopathy, the most significant adverse effect. Initially, cardiotoxicity develops clinically silently, but it eventually appears as dilated cardiomyopathy with a very poor prognosis. Dexrazoxane (DEX) is the only FDA-approved drug to prevent the development of anthracycline cardiomyopathy, but its efficacy is insufficient. Carvedilol (CVD) is another product being tested in clinical trials for the same indication. This study's objective was to evaluate anthracycline cardiotoxicity in rats treated with CVD in combination with DEX. The studies were conducted using male Wistar rats receiving DOX (1.6 mg/kg b.w. i.p., cumulative dose: 16 mg/kg b.w.), DOX and DEX (25 mg/kg b.w. i.p.), DOX and CVD (1 mg/kg b.w. i.p.), or a combination (DOX + DEX + CVD) for 10 weeks. Afterward, in the 11th and 21st weeks of the study, echocardiography (ECHO) was performed, and the tissues were collected. The addition of CVD to DEX as a cardioprotective factor against DOX had no favorable advantages in terms of functional (ECHO), morphological (microscopic evaluation), and biochemical alterations (cardiac troponin I and brain natriuretic peptide levels), as well as systemic toxicity (mortality and presence of ascites). Moreover, alterations caused by DOX were abolished at the tissue level by DEX; however, when CVD was added, the persistence of DOX-induced unfavorable alterations was observed. The addition of CVD normalized the aberrant expression of the vast majority of indicated genes in the DOX + DEX group. Overall, the results indicate that there is no justification to use a simultaneous treatment of DEX and CVD in DOX-induced cardiotoxicity.

Mitochondrial DNA Changes in Respiratory Complex I Genes in Brain Gliomas.

Mitochondria are organelles necessary for oxidative phosphorylation. The interest in the role of mitochondria in the process of carcinogenesis results from the fact that a respiratory deficit is found in dividing cells, especially in cells with accelerated proliferation. The study included tumor and blood material from 30 patients diagnosed with glioma grade II, III and IV according to WHO (World Health Organization). DNA was isolated from the collected material and next-generation sequencing was performed on the MiSeqFGx apparatus (Illumina). The study searched for a possible relationship between the occurrence of specific mitochondrial DNA polymorphisms in the respiratory complex I genes and brain gliomas of grade II, III and IV. The impact of missense changes on the biochemical properties, structure and functioning of the encoded protein, as well as their potential harmfulness, were assessed in silico along with their belonging to a given mitochondrial subgroup. The A3505G, C3992T, A4024G, T4216C, G5046A, G7444A, T11253C, G12406A and G13604C polymorphisms were assessed as deleterious changes in silico, indicating their association with carcinogenesis.

Disruption of mitochondrial function augments the radiosensitivity of prostate cancer cell lines.

INTRODUCTION: Ionizing radiation is one of the most widely used therapeutic methods in the treatment of prostate cancer, but the problem is developing radioresistance of the tumour. There is evidence that metabolic reprogramming in cancer is one of the major contributors to radioresistance and mitochondria play a crucial role in this process. OBJECTIVE: The aim of the study was to assess the influence of oxidative phosphorylation uncoupling to radiosensitivity of prostate cancer cells differing in metabolic phenotype. MATERIAL AND METHODS: LNCaP, PC-3 and DU-145 cells were exposed to X-rays and simultaneously treated with 2,4-dinitrophenol (2,4-DNP). The radiosensitive of cell lines was determined by cell clonogenic assay and cell cycle analysis. The cytotoxic effect was evaluated with MTT and CVS (Crystal violet staining) assay, apoptosis detection and cell cycle analysis. The phenotype of the cells was determined by glucose uptake and lactate release, ATP level measurement as well as basal reactive oxygen species level and mRNA expression of genes related to oxidative stress defence. RESULTS: The synergistic effect of 2,4-dinitrophenol and X-ray was observed only in the case of the LNCaP cell line. CONCLUSIONS: Phenotypic analysis indicates that this may be due to the highest dependence of these cells on oxidative phosphorylation and sensitivity to disruption of their redox status.

Molecular and neural roles of sodium-glucose cotransporter 2 inhibitors in alleviating neurocognitive impairment in diabetic mice.

Diabetes causes a variety of molecular changes in the brain, making it a real risk factor for the development of cognitive dysfunction. Complex pathogenesis and clinical heterogeneity of cognitive impairment makes the efficacy of current drugs limited. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) gained our attention as drugs with potential beneficial effects on the CNS. In the present study, these drugs ameliorated the cognitive impairment associated with diabetes. Moreover, we verified whether SGLT2i can mediate the degradation of amyloid precursor protein (APP) and modulation of gene expression (Bdnf, Snca, App) involved in the control of neuronal proliferation and memory. The results of our research proved the participation of SGLT2i in the multifactorial process of neuroprotection. SGLT2i attenuate the neurocognitive impairment through the restoration of neurotrophin levels, modulation of neuroinflammatory signaling, and gene expression of Snca, Bdnf, and App in the brain of diabetic mice. The targeting of the above-mentioned genes is currently seen as one of the most promising and developed therapeutic strategies for diseases associated with cognitive dysfunction. The results of this work could form the basis of a future administration of SGLT2i in diabetics with neurocognitive impairment.

2,4-Dinitrophenol as an Uncoupler Augments the Anthracyclines Toxicity against Prostate Cancer Cells.

One of the strategies for the treatment of advanced cancer diseases is targeting the energy metabolism of the cancer cells. The compound 2,4-DNP (2,4-dinitrophenol) disrupts the cell energy metabolism through the ability to decouple oxidative phosphorylation. The aim of the study was to determine the ability of 2,4-DNP to sensitize prostate cancer cells with different metabolic phenotypes to the action of known anthracyclines (doxorubicin and epirubicin). The synergistic effect of the anthracyclines and 2,4-DNP was determined using an MTT assay, apoptosis detection and a cell cycle analysis. The present of oxidative stress in cancer cells was assessed by CellROX, the level of cellular thiols and DNA oxidative damage. The study revealed that the incubation of LNCaP prostate cancer cells (oxidative phenotype) with epirubicin and doxorubicin simultaneously with 2,4-DNP showed the presence of a synergistic effect for both the cytostatics. Moreover, it contributes to the increased induction of oxidative stress, which results in a reduced level of cellular thiols and an increased number of AP sites in the DNA. The synergistic activity may consist of an inhibition of ATP synthesis and the simultaneous production of toxic amounts of ROS, destroying the mitochondria. Additionally, the sensitivity of the LNCaP cell line to the anthracyclines is relatively higher compared to the other two (PC-3, DU-145).

The N-Substituted-4-Methylbenzenesulphonyl Hydrazone Inhibits Angiogenesis in Zebrafish Tg(fli1: EGFP) Model.

One of the most important therapies of malignant neoplasms, which are the second cause of death worldwide, is focused on the inhibition of pathological angiogenesis within the tumor. Therefore, the searching for the efficacious and relatively inexpensive small-molecule inhibitors of this process is essential. In this research, the anti-angiogenic potential of N-substituted-4-methylbenzenesulphonyl hydrazone, possessing antiproliferative activity against cancer cells, was tested. For this purpose, an intersegmental vessel (ISV) angiogenesis assay was performed using 6 hpf (hours post fertilization), 12 hpf and 24 hpf embryos of zebrafish transgenic strain, Tg(fli1: EGFP). They were incubated with different concentrations of tested molecule and after 24 h the development of intersegmental vessels of the trunk was analysed. In turn, the acute toxicity study in the zebrafish model was mainly conducted on strain AB, using the OECD-approved and recommended fish embryo acute toxicity test (FET) procedure. The results showed the moderate toxicity of N-[(3-chloro-4-methoxyphenyl)methylidene]-4-methylbenzenesulphonohydrazide in above-mentioned model with the LC50 value calculated at 23.04 mg/L. Moreover, newly synthesized molecule demonstrated the anti-angiogenic potential proved in Tg(fli1: EGFP) zebrafish model, which may be promising for the therapy of neoplastic tumors as well as other diseases related to pathological angiogenesis, such as age-related macular degeneration and diabetic retinopathy.

Regulation of Neuroinflammatory Signaling by PPARγ Agonist in Mouse Model of Diabetes.

Many relevant studies, as well as clinical practice, confirm that untreated diabetes predisposes the development of neuroinflammation and cognitive impairment. Having regard for the fact that PPARγ are widely distributed in the brain and PPARγ ligands may regulate the inflammatory process, the anti-inflammatory potential of the PPARγ agonist, pioglitazone, was assessed in a mouse model of neuroinflammation related with diabetes. In this regard, the biochemical and molecular indicators of neuroinflammation were determined in the hippocampus and prefrontal cortex of diabetes mice. The levels of cytokines (IL-1ß, IL-6, and TNF) and the expression of genes (Tnfrsf1a and Cav1) were measured. In addition, behavioral tests such as the open field test, the hole-board test, and the novel object recognition test were conducted. A 14-day treatment with pioglitazone significantly decreased IL-6 and TNFα levels in the prefrontal cortex and led to the downregulation of Tnfrsf1a expression and the upregulation of Cav1 expression in both brain regions of diabetic mice. Pioglitazone, by targeting neuroinflammatory signaling, improved memory and exploratory activity in behavioral tests. The present study provided a potential theoretical basis and therapeutic target for the treatment of neuroinflammation associated with diabetes. Pioglitazone may provide a promising therapeutic strategy in diabetes patients with muffled of behavioral activity.

Alteration in the Expression of Genes Involved in Cerebral Glucose Metabolism as a Process of Adaptation to Stressful Conditions.

Exposure to chronic stress leads to disturbances in glucose metabolism in the brain, and changes in the functioning of neurons coexisting with the development of depression. The detailed molecular mechanism and cerebral gluconeogenesis during depression are not conclusively established. The aim of the research was to assess the expression of selected genes involved in cerebral glucose metabolism of mice in the validated animal paradigm of chronic stress. To confirm the induction of depression-like disorders, we performed three behavioral tests: sucrose preference test (SPT), forced swim test (FST), and tail suspension test (TST). In order to study the cerebral glucose metabolism of the brain, mRNA levels of the following genes were determined in the prefrontal cortex of mice: Slc2a3, Gapdh, Ldha, Ldhb, and Pkfb3. It has been shown that exogenous, chronic administration of corticosterone developed a model of depression in behavioral tests. There were statistically significant changes in the mRNA level of the Slc2a3, Ldha, Gapdh, and Ldhb genes. The obtained results suggest changes in cerebral glucose metabolism as a process of adaptation to stressful conditions, and may provide the basis for introducing new therapeutic strategies for chronic stress-related depression.

The novel adamantane derivatives as potential mediators of inflammation and neural plasticity in diabetes mice with cognitive impairment.

Diabetes is a chronic disease leading to memory difficulties and deterioration of learning abilities. The previous studies showed that modulation of inflammatory pathways in the diabetic brain may reduce dysfunction or cell death in brain areas which are important for control of cognitive function. In the present study, we investigated the neuroprotective actions of newly synthesized adamantane derivatives on diabetes-induced cognitive impairment in mice. Our study relied on the fact that both vildagliptin and saxagliptin belong to DPP4 inhibitors and, contain adamantanyl group. Efficacy of tested compounds at reversing diabetes-induced different types of memory impairment was evaluated with the use of selected behavioural tests. The following neuroinflammatory indicators were also analyzed: neuroinflammatory indicators and the expression of genes involved in the inflammatory response of brain (Cav1, Bdnf). Our study demonstrated that new adamantane derivatives, similarly to DPP4 inhibitors, can restrict diabetes-induced cognitive deficits. We demonstrated that the overexpression of GLP-1-glucagon-like peptide as well as Bdnf, Cav1 genes translate into central blockade of pro-inflammatory synthesis of cytokines and significantly improvement on memory performance in diabetes mice. Newly synthesized adamantane derivatives might have important roles in prevention and treatment of cognitive impairment by inflammatory events in patients with diabetes or related diseases.

Common Factors of Alzheimer's Disease and Rheumatoid Arthritis-Pathomechanism and Treatment.

The accumulation of amyloid plaques, or misfolded fragments of proteins, leads to the development of a condition known as amyloidosis, which is clinically recognized as a systemic disease. Amyloidosis plays a special role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, and rheumatoid arthritis (RA). The occurrence of amyloidosis correlates with the aging process of the organism, and since nowadays, old age is determined by the comfort of functioning and the elimination of unpleasant disease symptoms in the elderly, exposure to this subject is justified. In Alzheimer's disease, amyloid plaques negatively affect glutaminergic and cholinergic transmission and loss of sympathetic protein, while in RA, amyloids stimulated by the activity of the immune system affect the degradation of the osteoarticular bond. The following monograph draws attention to the over-reactivity of the immune system in AD and RA, describes the functionality of the blood-brain barrier as an intermediary medium between RA and AD, and indicates the direction of research to date, focusing on determining the relationship and the cause-effect link between these disorders. The paper presents possible directions for the treatment of amyloidosis, with particular emphasis on innovative therapies.

The Role of Molecular and Inflammatory Indicators in the Assessment of Cognitive Dysfunction in a Mouse Model of Diabetes.

The brain is the most vulnerable organ to glucose fluctuations, as well as inflammation. Considering that cognitive impairment might occur at the early stage of diabetes, it is very important to identify key markers of early neuronal dysfunction. Our overall goal was to identify neuroinflammatory and molecular indicators of early cognitive impairment in diabetic mice. To confirm cognitive impairment in diabetic mice, series of behavioral tests were conducted. The markers related to cognitive decline were classified into the following two groups: Neuroinflammatory markers: IL-1ß, IL-6, tumor necrosis factor-α (TNF-α) and genetic markers (Bdnf, Arc, Egr1) which were estimated in brain regions. Our studies showed a strong association between hyperglycemia, hyperinsulinemia, neuroinflammation, and cognitive dysfunction in T2DM mice model. Cognitive impairment recorded in diabetes mice were associated not only with increased levels of cytokines but also decreased Arc and Egr1 mRNA expression level in brain regions associated with learning process and memory formation. The results of our research show that these indicators may be useful to test new forms of treatment of early cognitive dysfunction associated not only with diabetes but other diseases manifesting this type of disorders. The significant changes in Arc and Egr1 gene expression in early stage diabetes create opportunities it possible to use them to track the progression of CNS dysfunction and also to differential disease diagnosis running with cognitive impairment.

The Interaction of Selective A1 and A2A Adenosine Receptor Antagonists with Magnesium and Zinc Ions in Mice: Behavioural, Biochemical and Molecular Studies.

The purpose of the study was to investigate whether the co-administration of Mg2+ and Zn2+ with selective A1 and A2A receptor antagonists might be an interesting antidepressant strategy. Forced swim, tail suspension, and spontaneous locomotor motility tests in mice were performed. Further, biochemical and molecular studies were conducted. The obtained results indicate the interaction of DPCPX and istradefylline with Mg2+ and Zn2+ manifested in an antidepressant-like effect. The reduction of the BDNF serum level after co-administration of DPCPX and istradefylline with Mg2+ and Zn2+ was noted. Additionally, Mg2+ or Zn2+, both alone and in combination with DPCPX or istradefylline, causes changes in Adora1 expression, DPCPX or istradefylline co-administered with Zn2+ increases Slc6a15 expression as compared to a single-drug treatment, co-administration of tested agents does not have a more favourable effect on Comt expression. Moreover, the changes obtained in Ogg1, MsrA, Nrf2 expression show that DPCPX-Mg2+, DPCPX-Zn2+, istradefylline-Mg2+ and istradefylline-Zn2+ co-treatment may have greater antioxidant capacity benefits than administration of DPCPX and istradefylline alone. It seems plausible that a combination of selective A1 as well as an A2A receptor antagonist and magnesium or zinc may be a new antidepressant therapeutic strategy.

Beneficial effects of combined administration of fluoxetine and mitochondria-targeted antioxidant at in behavioural and molecular studies in mice model of depression.

Chronic or recurrent stress is associated with reactive oxygen species (ROS) overproduction and can lead to oxidative damage, which plays important roles in neurodegenerative diseases. Mito - TEMPO is an antioxidant targeted at mitochondria. The aim of the presented study was to assess antidepressant and antioxidant efficacy of Mito - TEMPO administered alone or with fluoxetine in mice exposed to chronic stress. The evaluation of the antidepressant-like activity was based on forced swimming test (FST) and tail suspension test (TST). In order to evaluate the antioxidant potential, the level of mRNA expression of Adora1, Ogg1, Msra, Nrf2 and Tfam in the hippocampus of mice was determined. Behavioural research data showed the antidepressant effect of fluoxetine and Mito - TEMPO administered to mice alone and in combination. The molecular research results indicate a significant impact of chronic stress on the oxidation-reduction balance and an antioxidant effect of Mito - TEMPO. The results obtained in the study suggest that Mito - TEMPO protects DNA against oxidative damage and may be beneficial in the way of cellular function improvement under the conditions of chronic stress. Adora1, Msra, Nrf2 and Tfam genes may be involved in mediating the antioxidant effect of the combined treatment with fluoxetine and Mito - TEMPO.