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.

Newly synthesized derivatives with a thiosemicarbazide group reduce the viability of cancer cell lines. Acute toxicity assessment in Zebrafish (Danio rerio) early life stages.

Due to the variability and ability of tumor to mutate, as well as the heterogeneity of tumor tissue, such drugs are sought that would act selectively and multidirectionally on the cancer cell. Therefore, two newly synthesized semicarbazide structured substances were evaluated for anticancer properties in our study: 1a and 1b. In order to evaluate the cytotoxicity and selectivity of the tested compounds, MTT and Neutral Red uptake assay on cell lines (HEK293, LN229, 769-P, HepG2 and NCI-H1563) and cell cycle analysis were performed. Acute toxicity and cardiotoxicity were also evaluated in the zebrafish model. The tested compounds (1a, 1b) showed cytotoxic activity, with the greatest selectivity noted against the glioblastoma multiforme cell line (LN229). However, compound 1b showed stronger selective activity than 1a. Both of compounds were shown to significantly affect the M phase of the cell cycle. Whereas, the conducted toxicological examination of newly synthesized thiosemicarbazide derivates showed, that direct exposition of Danio rerio embryos to compound 1a, but not 1b, causes a concentration-dependent increase in developmental malformations, indicating possible teratogenic effects.

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.

Evaluation of developmental toxicity in zebrafish embryos and antiproliferative potential against human tumor cell lines of new derivatives containing 4-nitrophenyl group.

The aim of the studies was to evaluate the antiproliferative potential against human tumor cell lines of newly synthetized derivatives containing 4-nitrophenyl group, as well as its impact on developmental toxicity in zebrafish model. We selected 1-(4-nitrobenzoyl)-4-ethylsemicarbazide (APS-1) and 1-[(4-nitrophenyl)acetyl]-4-hexyl-thiosemicarbazide (APS-18) for research. The antiproliferative properties of semicarbazide derivatives were assessed against human cancer cell lines derived from hepatocellular adenocarcinoma (HepG2), renal cell carcinoma (769-P), non-small cell lung cancer (NCI-H1563) and glioblastoma multiforme (LN229) in comparison to the physiological human embryonic kidney (HEK-293) cell line. The influence of the tested substances on the cell cycle and apoptosis was also evaluated. Fish embryo acute toxicity test (FET) was performed based on OECD Guidelines (Test No. 236), and was carried out for the first 5 days post fertilization. The following concentrations of APS-1 and APS-18 were tested: 125-2000 µM and 0.125-1000 µM, respectively. The presented studies on the antiproliferative properties of the new semicarbazide derivatives showed that the compounds APS-1 and APS-18 reduce the viability of human tumor lines. Particularly noteworthy is the strong and selective antiproliferative activity of APS-18 against all neoplastic cell lines, in particular against glioblastoma. Against this tumor line, the compound APS-1 showed an effective inhibitory effect. In the FET we noted that the direct exposure of zebrafish embryos to APS-1 and APS-18 in used range of concentration did not cause morphological abnormalities, including cardiotoxicity. On basis of obtained outcomes it could be concluded that APS-1 and APS-18 may constitute models for further research, design and synthesis of new, safer drugs with more favorable anticancer properties.

Amaryllidaceae, Lycopodiaceae Alkaloids and Coumarins-A Comparative Assessment of Safety and Pharmacological Activity.

The study aimed to evaluate the safety and pharmacological activity Amaryllidaceae, Lycopodiaceae alkaloids and coumarins obtained from Narcissus triandrus L., Lycopodium clavatum L., Lycopodium annotinum L., Huperzia selago L. and Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav. In the in vivo studies. The influence of the tested compounds on the central nervous system of rats was assessed in behavioral tests (locomotor activity, Y-maze, passive avoidance). In order to investigate the mechanisms of action, biochemical determinations were performed (AChE activity, BChE activity, IL-1ß, IL-6 concentration). In order to assess safety, the concentrations of AST, ALT, GGT and urea and creatinine were determined. The results of the conducted studies indicate a high safety profile of the tested compounds. Behavioral tests showed that they significantly improved rodent memory in a passive avoidance test. The results of biochemical studies showed that by reducing the activity of AChE and BChE and lowering the concentration of IL-1ß and IL-6, the coumarin-rich Angelica dahurica extract shows the most promising potential for future therapeutic AD strategies.

Parent experience of caring for neonates with seizures.

OBJECTIVE: Neonates with seizures have a high risk of mortality and neurological morbidity. We aimed to describe the experience of parents caring for neonates with seizures. DESIGN: This prospective, observational and multicentre (Neonatal Seizure Registry) study enrolled parents of neonates with acute symptomatic seizures. At the time of hospital discharge, parents answered six open-ended response questions that targeted their experience. Responses were analysed using a conventional content analysis approach. RESULTS: 144 parents completed the open-ended questions (732 total comments). Four themes were identified. Sources of strength: families valued medical team consensus, opportunities to contribute to their child's care and bonding with their infant. Uncertainty: parents reported three primary types of uncertainty, all of which caused distress: (1) the daily uncertainty of the intensive care experience; (2) concerns about their child's uncertain future and (3) lack of consensus between members of the medical team. Adapting family life: parents described the many ways in which they anticipated their infant's condition would lead to adaptations in their family life, including adjusting their family's lifestyle, parenting approach and routine. Many parents described financial and work challenges due to caring for a child with medical needs. Emotional and physical toll: parents reported experiencing anxiety, fear, stress, helplessness and loss of sleep. CONCLUSIONS: Parents of neonates with seizures face challenges as they adapt to and find meaning in their role as a parent of a child with medical needs. Future interventions should target facilitating parent involvement in clinical and developmental care, improving team consensus and reducing the burden associated with prognostic uncertainty.

Associations between Infant and Parent Characteristics and Measures of Family Well-Being in Neonates with Seizures: A Cohort Study.

OBJECTIVE: To characterize and determine risk factors for key dimensions of well-being at hospital discharge in families of neonates with acute symptomatic seizures. STUDY DESIGN: This prospective, observational cohort study enrolled 144 parent-infant dyads among neonates with acute symptomatic seizures from 9 pediatric hospitals in the Neonatal Seizure Registry. One parent per family completed a discharge survey, which included measures of anxiety and depression, health-related quality of life, and impact on the family. Multivariable regression analyses adjusted for site were constructed to examine parent and infant characteristics associated with well-being. RESULTS: At discharge, 54% of parents reported symptoms of anxiety and 32% reported symptoms of depression. Parents of infants with hypoxic-ischemic encephalopathy reported more depression and worse quality of life than parents of infants with other seizure etiologies. Parental quality of life was also lower with greater infant age at discharge. A higher level of maternal education was associated with greater impact on the family. All these differences were medium to large effect sizes, ranging from 0.52 to 0.78. CONCLUSIONS: Symptoms of anxiety and depression are common in parents of infants with neonatal seizures, and several parent and infant characteristics are associated with poorer parental quality of life and family well-being. These findings are a call to action to improve mental health screening and services for parents of infants with neonatal seizures.

Altered expression of genes involved in brain energy metabolism as adaptive responses in rats exposed to chronic variable stress; changes in cortical level of glucogenic and neuroactive amino acids.

Brain metabolism is closely associated with neuronal activity and enables the accurate synthesis and function of neurotransmitters. Although previous studies have demonstrated that chronic stress is associated with the overproduction of reactive oxygen species (ROS), which leads to oxidative stress and the disruption of glucose metabolism, the molecular mechanisms and cerebral gluconeogenesis in depression have not yet been completely elucidated. In order to examine this subject, the present study evaluated changes in the expression of selected genes involved in the glycolytic pathway and the levels of glucogenic and neuroactive amino acids in the brain of rats exposed to chronic variable stress. Male Wistar rats (50­55 days old, weighing 200­250 g) were divided into two groups: control and stressed, and the rats in the stressed group were exposed to stress conditions for 40 days. Depressive­like states were observed and recorded by measuring the body weight and forced swim test (FST). The mRNA levels of Slc2a3 (coding GLUT3) and Tfam (activator of mitochondrial transcription and a participant in mitochondrial genome replication) were markedly increased, while a decrease in the expression of Ldhb and GAPDH was also observed. These modifications were associated with the redirection of glucose metabolism to appropriate defensive pathways under chronic stress conditions, and an increased ability to maintain mitochondrial function as potential adaptive responses. A marked reduction of glucogenic and neuroactive amino acids levels indicate the support of energy metabolism by stimulation of the gluconeogenesis pathway. The findings of the present study provide a novel insight into the molecular and biochemical events that impact the development of depression under chronic stress conditions, and they may identify novel targets for therapeutic intervention.

α-Tocopherol Ameliorates Redox Equilibrium and Reduces Inflammatory Response Caused by Chronic Variable Stress.

Chronic exposure to stress factors contributes to the development of depression by generating excess of reactive oxygen species which leads to oxidative stress and inflammatory processes. The aim of the study was to assess the potential protective properties of α-tocopherol supplementation on the rats exposed to chronic variable stress (CVS). Male Wistar rats (50-55 days old, weighing 200-250 g) were divided into three groups (n=10): control, stressed, and stressed and receiving (+)-α-tocopherol solution in a dose of 100 mg/kg/day. Rats in the stressed groups were exposed to CVS for 40 days. Markers of redox disorders (glutathione reduced and oxidized levels, GSH/GSSG ratio, glutathione peroxidase, glutathione reductase activities, total antioxidant status, and lipid peroxidation) and inflammatory response (IL-1ß, IL6, and TNF-α) were determined in the blood. Additionally, molecular biomarkers of depression (expression of Fkbp5 and Tph2) were studied in hippocampus. The biochemical analysis was inconclusive about the presence of oxidative stress in the blood of rats exposed to CVS. However, changes in all parameters suggest presence of redox equilibrium disorders. Similarly, activation of inflammatory processes was observed as a result of CVS. Molecular effects of environmental stress in hippocampus were also observed. Generally, α-tocopherol ameliorated redox equilibrium disorders, tempered inflammatory response, and protected from changes in determined molecular markers of depression.