Hippocampal Damage Research Articles

Photobiomodulation Therapy at 660 nm Inhibits Hippocampal Neuroinflammation in a Lipopolysaccharide-Challenged Rat Model

Background/Objectives: Neuroinflammation is associated with the progression of various brain diseases, and the management of neuroinflammation-induced neural damage is a crucial aspect of treating neurological disorders. This study investigated the anti-inflammatory efficacy of photobiomodulation therapy (PBMT) using 660 nm phototherapy in a rat model with lipopolysaccharide (LPS)-induced neuroinflammation. Methods: We induced inflammation in rat brains via intraperitoneal injection of LPS and subjected the treatment group to 660 nm phototherapy to examine its protective effect against hippocampal damage based on pathological, histological, and immunohistochemical tissue analyses. Results: The 660 nm treated rats showed a significant decrease in hippocampal structural damage and cell death compared to the LPS-treated group. We observed reduced expression of the inflammation markers GFAP, TNF-α, and IL-1β in the hippocampus of the treatment group, and an increase in SIRT1 expression across all hippocampal regions. Conclusions: This study presents a promising method for controlling neuroinflammation and providing neuroprotection and inflammation relief. PBMT represents a non-invasive therapeutic approach with minimal side effects ensured through the proper control of light irradiation.

Synthesis and biological evaluation of novel isobenzofuran-1(3H)-one derivatives as antidepressant agents

A series of novel isobenzofuran-1(3H)-one derivatives were designed and synthesized as antidepressants. Firstly, the serotonin reuptake inhibition of these compounds was tested in vitro, and most of them exhibited activity. Particularly, compounds 9d, 10a, and 10c demonstrated superior inhibitory effects and possibly avoided addiction via the μ-opioid receptor and CCK-B receptor. Secondly, the antidepressant effect of compound 10a was evaluated using chronic restraint stress (CRS)-induced mice. The results showed that compound 10a significantly improved CRS-induced depression-like behavior by increasing the neurotransmitters 5-HT in the cortex and THP2 expression in the hippocampus. Thirdly, compound 10a was further investigated and found to enhance CRS-induced hippocampal neuron damage recovery and elevate the expression of synaptic-associated proteins such as BDNF, TrkB, PSD95, and Spinophilin in CRS-induced mice. These findings suggested that novel isobenzofuran-1(3H)-one derivative showed efficacy in treating depression, with compound 10a emerging as a potential lead compound warranting further investigation.

Taurine Reverses Arsenic-Induced Inhibition of Hippocampal Neurogenesis and Depression-Like Behavior in Mice.

Arsenic exposure results in damage to the neurological system. We previously demonstrated the arsenic-induced inhibition of hippocampal neurogenesis and its reversibility after exposure is terminated. The present study aimed to reveal whether arsenic-induced inhibition of hippocampal neurogenesis was ameliorated when taurine was co-administered, and we also investigated depression-like behavioral changes using the forced swim test. Mice were randomly divided into four groups. The first group received distilled water only for 4 months (control group), the second group received 4.0 mg/L As2O3 via drinking water for 4 months (arsenic group), the third group received 4.0 mg/L As2O3 and taurine (150 mg/kg body weight, by gavage, twice a week) for 4 months (arsenic + taurine group), and the fourth group received taurine only by gavage for 4 months (taurine group). The percentage of new mature neurons decreased in the arsenic group compared with the control group (64% ± 0.90% vs. 76% ± 1.9%, p < 0.01); however, this percentage was reversed to control levels in the arsenic + taurine group (76% ± 1.4%, p > 0.05). In the forced swim test, the immobility time during the last 4 min was significantly increased in the arsenic group, but restored to control levels in the arsenic + taurine group. The possible mechanisms of this taurine amelioration of hippocampal damage were further investigated, and included a reduction in oxidative stress as indicated by carbonyl content, inflammation, and aquaporin1, 4, and 8 expressions, as well as an increase in Wnt3a and brain-derived neurotrophic factor expression in western blot analyses.

Epileptic seizures induced by pentylenetetrazole kindling accelerate Alzheimer-like neuropathology in 5×FAD mice

Clinical studies have shown that epileptic seizures worsen Alzheimer’s disease (AD) pathology and related cognitive deficits; however, the underlying mechanism is unclear. To assess the effects of seizures on the progression of AD, chronic temporal lobe epilepsy was induced in five familial AD mutation (5×FAD) mice by kindling with the chemoconvulsant pentylenetetrazole (PTZ) at 3–3.5 months of age. The amyloidogenic pathway, tauopathy, synaptic damage, neuronal death, neurological inflammatory response and associated kinase signaling pathway dysregulation were examined at 9 months of age. We found that APP, p-APP, BACE1, Aβ and kinase-associated p-tau levels were elevated after PTZ kindling in 5×FAD mice. In addition, PTZ kindling exacerbated hippocampal synaptic damage and neuronal cell death, as determined by scanning electron microscopy and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining, respectively. Finally, the levels of the neuroinflammation markers GFAP and Iba1, as well as the inflammatory cytokine IL-1β, were increased after PTZ insult. PTZ kindling profoundly exacerbated extracellular regulated kinase (ERK)-death-associated protein kinase (DAPK) signaling pathway overactivation, and acute ERK inhibitor treatment downregulated Aβ production and p-APP and p-tau levels in epileptic 5×FAD mice. In addition, long-term use of the antiseizure drug carbamazepine (CBZ) alleviated seizure-induced accelerated amyloid and tau pathology and ERK-DAPK overactivation in 5×FAD mice. Collectively, these results demonstrate that seizure-induced increases in AD-like neuropathology in 5×FAD mice are partially regulated by the ERK-DAPK pathway, suggesting that the ERK-DAPK axis could be a new therapeutic target for the treatment of AD patients with comorbid seizures.

Determination of Astrocyte Reaction Using Glial Fibrillary Acidic Protein (GFAP) Following Aluminium Chloride Induced Hippocampus Damage of Adult Wistar Male Rats Treated with Ethanolic Extracts of Carpolobia lutea at Different Doses

Background: Aluminium is a well-established neurotoxicant involved in the etiology of neurodegenerative diseases. Carpolobia lutea, commonly called cattle stick or poor man’s candle belongs to the plant family polygalaceae. It is a small tree native to West and Central tropical Africa and it is one of the medicinal plants that play a major role in the health care system of developing countries such as Nigeria. Aim of the Study: This study was aimed at investigating astrocyte reaction in aluminium chloride induced neurotoxicity in the hippocampus in adult male wistar rats treated with ethanolic extracts of C.lutea at different doses. Materials and Methods: Thirty wistar rats weighing 180-200 g were used for this study. The animals were randomized into five groups of six rats each. Group A rats received only animal feed. Groups B,C,D and E were given 100 mg/kg bw of aluminium chloride intraperitoneally five times a week for three weeks to induce neurotoxicity.In order to reverse the neurotoxicity,. Group C was treated with 10 mg/kg bw of donepezil as standard drug while group D and E were treated with 200 mg/kg and 400 mg/kg of Carpolobia lutea respectively for 14 days. Histopathological study was done on the hippocampus of the rat brain and thereafter hematoxylin and eosin staining were carried out. Immunohistochemical studies for GFAP was done using NovocasraTM Novolink TMpolymer detection system and appropriate primary monoclonal antibodies. Image J cell counter tool was used to note the number of GFAP positive cells across all groups. Results: The result from our histopatholological study shows that lower dose (200 mg/kg/bw) of ethanolic extract of the leaf of Carpolobia lutea have better protection on the cytoarchitecture of the CA1, CA3, and dentate gyrus of the hippocampus than 400 mg/kg/bw of the plant extract. From our study, it is evident that 200 mg/kg of Carpolobia lutea reduced the GFAP immunoreactivity in the hippocampus of AlCl3 induced neurotoxicity. When we compared the result of 200 mg/kg/bw of C. lutea with 10 mg/kg per body weight of donepezil (standard drug), it was observed that C. lutea had a slight reduced GFAP immunoreactivity than the standard drug(donepezil). The lower dose, 200 mg/kg of ethanolic extract of the leaf of Carpolobia lutea have a better neuroprotective benefit than the standard drug on the hippocampus Conclusion: In conlusion, 200 mg/kg of Carpolobia lutea have the tendencies of protecting the neurons in the hippocampus from degenerating as a result of aluminium chloride induced neurotoxicity compared to the standard drug (10 mg/kg donepezil).

20 (S)-Protopanaxadiol Alleviates DRP1-Mediated Mitochondrial Dysfunction in a Depressive Model In Vitro and In Vivo via the SIRT1/PGC-1α Signaling Pathway

Depression is a complex and common mental illness affecting physical and psychological health. Panax ginseng C. A. Mey is a traditional Chinese medicine with abundant pharmacological activity and applications in regulating mood disorders. 20 (S)-Protopanaxadiol is the major intestinal metabolite of ginsenoside and one of the active components in ginseng. In this study, we aimed to investigate the therapeutic effects of 20 (S)-Protopanaxadiol on neuronal damage and depression, which may involve mitochondrial dynamics. However, the mechanism underlying the antidepressant effects of 20 (S)-Protopanaxadiol is unelucidated. In the present study, we investigated the potential mechanisms underlying the antidepressant activity of 20 (S)-Protopanaxadiol by employing a corticosterone-induced HT22 cellular model and a chronic unpredicted mild stress (CUMS)-induced animal model in combination with a network pharmacology approach. In vitro, the results showed that 20 (S)-Protopanaxadiol ameliorated the corticosterone (CORT)-induced decrease in HT22 cell viability, decrease in 5-hydroxytryptamine (5-HT) levels, and increase in nitric oxide (NO) and malondialdehyde (MDA) levels. Furthermore, 20 (S)-Protopanaxadiol exerted improvement effects on the CORT-induced increase in HT22 cell mitochondrial reactive oxygen species, loss of mitochondrial membrane potential, and apoptosis. In vivo, the results showed that 20 (S)-Protopanaxadiol ameliorated depressive symptoms and hippocampal neuronal damage in CUMS mice, and sirtuin1 (SIRT1) and peroxisome proliferator-activated receptor-1-Alpha (PGC-1α) activity were activated in the hippocampus of mice, thereby alleviating mitochondrial dysfunction and promoting the clearance of damaged mitochondria. In both in vivo and in vitro models, after inhibiting SIRT1 expression, the protective effect of 20 (S)-Protopanaxadiol on mitochondria was significantly weakened, and dynamin-related protein 1 (DRP1)-mediated mitochondrial division was significantly reduced. These findings suggest that 20 (S)-Protopanaxadiol may exert neuroprotective and antidepressant effects by attenuating DRP1-mediated mitochondrial dysfunction and apoptosis by modulating the SIRT1/PGC-1α signaling pathway.

Huang-Pu-Tong-Qiao Formula Alleviates Hippocampal Neuron Damage by Inhibiting NLRP3 Inflammasome-mediated Pyroptosis in Alzheimer's Disease.

Huang-Pu-Tong-Qiao (HPTQ), a Traditional Chinese Medicine formula, has achieved remarkable efficacy in clinically treating Alzheimer's disease (AD). Pyroptosis refers to the inflammatory necrosis of cells, which contributes to AD pathological progression. However, it is unclear whether the therapeutic effect of HPTQ on AD is related to reducing pyroptosis. In this study, the network pharmacology analysis was used to predict the molecular mechanism of HPTQ in treating AD and validated our hypothesis through mice and cell experiments. APP/PS1 transgenic mice and Aβ25-35-injured HT22 cells were used as AD models in vivo and in vitro. The pharmacological effects and mechanisms of HPTQ on AD were evaluated by Morris water maze, Y-maze, transmission electron microscope, immunofluorescence, Hoechst/PI staining, western blot, and ELISA. Network pharmacology reveals the correlation between the therapeutic effect of HPTQ on AD and the NOD-like receptor signaling pathway. In APP/PS1 mice, HPTQ reduced the escape latency and maintained cell membrane integrity. In HT22 cells, 15% HPTQ-medicated serum and 10 µM MCC950 increased cell viability and decreased PI positive rate compared with the Model group. In addition, HPTQ treatment in AD animal and cell models reduced the protein expressions of NLRP3, ASC, cleaved caspase-1, GSDMD, GSDMD-N, IL-1β, and IL-18. The experimental results of MCC950 specifically inhibiting the NLRP3 expression suggested that HPTQ might reduce neuronal pyroptosis by reducing NLRP3 inflammasome. Network pharmacology and experimental validation suggested that HPTQ alleviated NLRP3 inflammasome-mediated neuronal pyroptosis in AD, which could provide valuable candidate drugs for AD clinical treatment.

House sparrows do not show a diel rhythm in double-strand DNA damage in erythrocytes.

DNA damage can be caused by a number of intrinsic and extrinsic factors. A recent study showed that free-living house sparrows (Passer domesticus) have higher DNA damage in the summer than the winter across five different tissues. This result was consistent when house sparrows were brought into captivity and exposed to comparable light cycles, with all other variables held constant. These results generated two hypotheses: (1) seasonal variation in DNA damage is related to circadian regulation and (2) seasonal variation in DNA damage is related to the total number of active hours. To investigate these hypotheses, we first quantified erythrocyte DNA damage in wild-caught house sparrows held in captivity on a 12L:12D light cycle at six points during the day to assess a diel or circadian rhythm but did not find one. We then performed a resonance experiment, in which birds experienced unnatural light cycles, and compared DNA damage in birds held on 6L:6D and 4.5L:7.5D resonance light cycles with their natural counterparts, 12L:12D and 9L:15D, respectively. We assessed corticosterone levels and DNA damage in blood before and after the resonance light cycles and DNA damage in abdominal fat, hippocampus, hypothalamus, and liver after the resonance light cycles. While our second experiment was not able to effectively test our hypotheses, we were able to demonstrate some interesting patterns. Throughout the resonance experiment, baseline corticosterone and testes size increased, consistent with the birds being photostimulated and preparing to breed. Surprisingly, the direction of change of DNA damage throughout the resonance photoperiod differed with tissue, which is not consistent with patterns during the breeding season in the wild. Our data indicate a potential uncoupling of the breeding physiology with the effect on DNA damage due to exposure to a resonance light cycle, which the birds may have interpreted as a skeleton photoperiod. Finally, though we were unable to fully disentangle the dynamics underlying seasonal DNA damage, we show that the previously documented patterns are not simply due to diel changes or the total amount of light exposure within a 24-hour period.

Curcumin triggers the Wnt/β-catenin pathway and shields neurons from injury caused by intermittent hypoxia

The objective of this study was to explore the molecular basis through which Curcumin (Cur) mitigates neuronal damage caused by obstructive sleep apnea (OSA). HT22 was used to simulate intermittent hypoxia (IH) injury and explore the effect of Cur on these cells. We evaluated the cell viability, cytotoxicity, apoptosis, proliferation, and Wnt/β-catenin (WβC) pathway. IWR-1 was used to block the pathway and investigate the protective mechanism of Cur. We constructed an in vivo model of IH to validate the results of the cellular experiments. IH accelerated apoptosis and cytotoxicity, suppressed proliferation, and decreased the activity of the WβC pathway. Cur can significantly improve cell viability, reduce apoptosis rate and cell toxicity, promote cell proliferation, and up-regulate the WβC. After blocking the WβC pathway, the proliferative effect of Cur was observably weakened. In vivo, IH caused hippocampal damage and inhibited WβC pathway activity in mice, which was ameliorated by Cur treatment. This implies that Cur could be a novel treatment option for neurological impairment brought on by OSA.

Neonatal overfeeding attenuates microgliosis and hippocampal damage in an infant rat model of pneumococcal meningitis.

Pneumococcal meningitis (PM) triggers apoptotic neuronal and progenitor cell death in the hippocampal dentate gyrus (DG), resulting in subsequent cognitive impairment. Microglia play a crucial role in PM-induced hippocampal damage. While the lasting effects of neonatal nutrition on health are well documented, the influence of early-life overfeeding on the host response to neuroinfections remains uncertain. This study aimed to examine whether neonatal overfeeding affects the outcome of PM in the hippocampus (HC). Overfeeding was induced by adjusting litter size immediately after birth. On the eleventh day of life, rats were intracisternally injected with Streptococcus pneumoniae or saline, followed by euthanasia after 24 hours for brain dissection. Histological analysis evaluated apoptosis in the DG and the extent of inflammatory infiltrate in the hippocampal fissure, while microgliosis was assessed by immunohistochemistry. The hippocampal transcriptome was analyzed using RNAseq, and the mRNA levels of specific inflammatory biomarkers were evaluated via RT-qPCR. Overfed rats exhibited 40.5% greater body mass compared to their normal-fed counterparts. Intriguingly, PM-induced apoptosis in the DG was 50% lower in overfed rats. This effect was accompanied by significant alterations in the hippocampal transcriptional profile, particularly the lack of activation of the Programmed cell death pathway in overfed infected animals. RT-qPCR analysis of Aif1 and examination of Iba1-immunostained cells revealed mild microgliosis in the HC of infected-overfed animals. This reduced microglial reaction may be attributed to the diminished activation of interferon signaling pathways, as disclosed by the transcriptome analysis, potentially preventing microglial priming. Additionally, evidence of reduced neuroinflammation in overfed rats with PM was observed through the milder activation of pathways associated with Toll-like receptors, interleukins, and chemokine signaling. Furthermore, overfed animals exhibited increased transcription of proinflammatory Il6 and anti-inflammatory Il10 genes, with the latter showing higher expression even in the absence of PM, suggesting a priming effect of overfeeding on hippocampal immune cells. This study sheds light on the complex interplay between early-life overfeeding, immune response, and neuroprotection in infant rats with PM. The findings demonstrate the neuroprotective impact of early-life overfeeding in the context of PM, linked to the modulation of microglial function.

Inhalation of H2/O2 (66.7 %/33.3 %) mitigates depression-like behaviors in diabetes mellitus complicated with depression mice via suppressing inflammation and preventing hippocampal damage

Diabetes mellitus complicated with depression (DD) is a prevalent psychosomatic disorder. It is characterized by severe cognitive impairment, and associated with high rates of disability and mortality. Although conventional treatment options are available, the efficacy of these regimens in managing DD remains limited. Molecular hydrogen (H2), a selective hydroxyl radical scavenger, has shown therapeutic potential in the treatment of various systemic diseases. This study aims to investigate the therapeutic effects of H2 on DD. A DD mouse model was established through intraperitoneal injection of streptozotocin (STZ, 150 mg/kg) and lipopolysaccharide (LPS, 0.5 mg/kg). Following the induction of DD, the mice were treated with H2/O2 (66.7 %/33.3 %)inhalation for 7 days. Behavioral assessments were conducted by standard behavioral tests, and the levels of inflammatory cytokines in peripheral blood serum and hippocampal tissue were measured using enzyme-linked immunosorbent assay (ELISA). Furthermore, magnetic resonance imaging (MRI) scans and immunofluorescence staining of the hippocampus were performed to evaluate hippocampal structural integrity. The results demonstrated that inhalation of H2/O2 (66.7 %/33.3 %) significantly ameliorated depressive behaviors and symptoms in DD mice, reversed hippocampal volume reduction, decreased inflammatory cytokine levels in peripheral blood serum and hippocampal tissue, and inhibited the activation of A1 astrocytes in the hippocampus. Our study suggests that H2/O2 (66.7 %/33.3 %) inhalation therapy may offer a promising treatment strategy for DD and its associated symptoms.

Protective Effect of Aloe-emodin on Cognitive Function in Copper-loaded Rats Based on The Inhibition of Hippocampal Neuron Ferroptosis.

Aloe-emodin (AE), a monomer derived from traditional Chinese medicine, has demonstrated remarkable efficacy in the clinical management of cognitive disorders. Ferroptosis (FPT), a specialized form of programmed cell death, plays a critical role in the pathological progression of various cognitive diseases. This study explored the therapeutic potential of AE in a rat model of Wilson's disease cognitive impairments (WDCI) and examined whether these effects are mediated through the silencing information regulator 1 (SIRT1)-regulated FPT signaling pathway. Employing techniques, such as the Morris water maze (MWM), Hematoxylin & eosin (H&E) staining, Transmission electron microscopy (TEM), Immunofluorescence (IF), assessments of oxidative stress markers, and measurements of FPT-related protein levels, we evaluated the extent of SIRT1-mediated FPT and the therapeutic efficacy of AE. The findings from the WD copper-loaded rat model experiments revealed that MWM, H&E, TEM, and IF outcomes indicated AE's potential to promote the restoration of learning and memory functions, ameliorate hippocampal neuronal morphological damage, and preserve cell membrane integrity. Results from western blot (WB) and ELISA analyses demonstrated that AE markedly upregulated the expression of SIRT1, nuclear factor erythroid-2-related factor 2 (Nrf2), solute carrier family 7 member 11 (SCL7A11), and glutathione peroxidase 4 (GPX4) proteins while simultaneously reversing the expression of oxidative stress markers such as malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD), and reactive oxygen species (ROS). Consequently, we posit that AE may attenuate WD copper-loaded rat model hippocampal neuronal FPT by activating the SIRT1-mediated signaling pathway. These findings suggested that AE mitigates WD copper-loaded rat model hippocampal neuronal damage through the activation of SIRT1-mediated FPT, thereby presenting a valuable candidate Chinese herbal monomer for the clinical treatment of WDCI.

Non-nutritive Sweetener Aspartame Disrupts Circadian Behavior and Causes Memory Impairment in Mice.

As a non-nutritive sweetener, aspartame is widely used in everyday life. However, its safety is highly controversial, especially its effects on neurobehavior. We evaluated the effects of chronic daily oral administration of aspartame-containing drinking water (at doses equivalent to 7-28% of the FDA-recommended human DIV) on memory and rhythm behaviors in mice and further investigated changes at the molecular level in the brains. Our results demonstrated that mice exposed to aspartame exhibited memory impairment. Disorders of hippocampal neurotransmitter metabolism and pathological damage may be responsible for the aspartame-induced memory impairment via inhibition of the BDNF/TrkB pathway. Furthermore, our findings suggested that disturbed clock gene expression in the hypothalamus after aspartame exposure led to altered rest-activity behavior, and this disruption of the circadian rhythm may exacerbate memory impairment. This study highlights the negative neurobehavioral effects of aspartame and provides valuable insights into its rational and safe use.

Effects of Vitamin C on Aluminum Chloride- Induced Neurotoxicity on the Hippocampal Cortex of Adult Wistar Male Rats

This study aimed to evaluate the neuroprotective effects of Vitamin C on aluminum chloride (AlCl₃)- induced brain damage, focusing on behavioral, biochemical, and histomorphological outcomes in a rodent model. Study Design: A total of 42 healthy male rats were randomly assigned to three groups: control, AlCl₃ -only, and AlCl₃ plus Vitamin C (500 mg/kg and 1000 mg/kg). The AlCl₃ groups received daily doses of AlCl₃, while the Vitamin C groups received concurrent Vitamin C supplementation. Methodology: Body weight, behavioral changes, biochemical markers of oxidative stress (MDA, SOD, GSH), and inflammation (TNF-α, IL-6) were assessed. Histomorphological analysis of the hippocampus was performed to evaluate structural damage. Behavioral assessments included locomotor and exploratory activity tests. Biochemical analyses measured oxidative stress and antioxidant enzyme activities. Results: AlCl₃ administration resulted in significant body weight loss, increased oxidative stress (elevated MDA, and SOD levels), and heightened inflammation (elevated TNF-α and IL-6). Behavioral tests showed increased excitatory activities, and increased anxiety levels as seen in increased rearing and grooming activities. Histomorphological examination revealed significant hippocampal damages as seen in the pale staining, shrunken pyramidal cells. Vitamin C co- administration mitigated these adverse effects, demonstrating reduced body weight loss, lower oxidative stress, decreased inflammation, and improved behavioral performance. Histological analysis indicated less hippocampal damage in the Vitamin C treated groups. Conclusion: As an antioxidant, Vitamin C effectively attenuates the neurotoxic effects of AlCl₃ by reducing oxidative stress and inflammation, and by protecting the hippocampal cellular integrity. These findings suggest that Vitamin C holds potential as a therapeutic agent for mitigating neurotoxicity induced by aluminum compounds.

Pathophysiological dynamics of acute myocardial infarction rats under chronic psychological stress at different time points

There is a lack of in-depth research on the impacts and changes in chronic psychological stress (CPS) on the cardiovascular system after acute myocardial infarction (AMI). This study aims to explore the comorbid mechanism and dynamic evolution of AMI exposed to CPS. 120 Wistar rats were randomly divided into Sham Operation group, Sham Operation + Chronic Unpredictable Mild Stress (CUMS) group, AMI group and AMI + CUMS group, with each group further divided into subgroups at days 7, 14, and 28. The AMI model was created by ligating the left anterior descending coronary artery, and CUMS model was used to induce CPS in rats. Behavioral changes were assessed through open field tests and sucrose preference tests. Cardiac function and structure were evaluated via echocardiography. The serum levels of TNFα, IL-6, NO, ET, CK-MB, cTNT, and ANP were measured using assay kits. Pathological changes in cardiac and brain tissues were observed under an optical microscope. Comparative analysis across different models revealed that CUMS significantly reduced behavioral activities in rats, with an interaction between CUMS and AMI affecting total distance (P < 0.05). Both CUMS and AMI significantly reduced cardiac function indicators, with their interaction effects on LVEF, LVFS, and CO (P < 0.05). AMI significantly altered cardiac structural parameters, particularly on day 28 (P < 0.05); while the impact of CUMS on cardiac structure was not significant, except for a notable reduction in LVAW/s on day 7 in AMI + CUMS group (P < 0.05). AMI caused significant changes in the serum biomarkers, while CUMS only significantly increased cTnT on day 7, ANP, TNFα, and IL-6 on day 14, and CK-MB on day 28, with their interaction effects on the three myocardial injury markers and TNFα (P < 0.05). Comparative analysis across different time points demonstrated that behavioral activity, cardiac function, CK-MB, cTnT, ANP, TNFα, and ET levels decreased significantly over time in the AMI model rats, while the left ventricular mass increased significantly (P < 0.05). Pathologically, compared with stress or AMI alone, the AMI + CUMS group exhibited more severe myocardia cellular degeneration and inflammatory infiltration, causing larger infract areas in myocardial tissue, as well as cell number decreases and morphological changes in hippocampal tissue. AMI with CPS exacerbates myocardial injury through sustained inflammation and endothelial dysfunction, leading to heart-brain pathology manifestations characterized by decreased cardiac function and hippocampal tissue damage.

Curcumin activates the Wnt/β-catenin signaling pathway to alleviate hippocampal neurogenesis abnormalities caused by intermittent hypoxia: A study based on network pharmacology and experimental verification

The purpose of this work was to investigate how curcumin (Cur) might enhance cognitive function and to gain a better understanding of the molecular mechanisms behind Cur’s impacts on neurogenesis deficits brought on by intermittent hypoxia (IH). Using network pharmacology, we explored possible targets for Cur’s obstructive sleep apnea (OSA) therapy. We established an IH model using C57BL/6 mice and c17.2 cells, and we assessed the influence of Cur on treatment outcomes as well as the effect of IH on cognitive function. Hippocampal damage and neurogenesis, as well as expression of core targets, were then examined. Network pharmacology analysis revealed that Cur has the potential for multi-target, multi-pathway therapy, with CTNNB1 and MYC as core target genes. The Morris water maze test showed that Cur (100 mg/kg, intragastrically) significantly improved cognitive dysfunction induced by IH. The hematoxylin and eosin (H&E) and Nissl staining indicated that Cur could alleviate damage to the hippocampus caused by IH. Immunohistochemistry, immunofluorescence, and western blotting results showed that Cur might promote neurogenesis and upregulate the expression of β-catenin and c-myc. In vitro, Cur (0.5 μM) has a protective effect on IH-induced neural stem cells (NSCs) injury and apoptosis and can restore the Wnt/β-catenin. Cur significantly increased the neurogenesis via the Wnt/β-catenin pathway, providing the scientific groundwork for the development of new treatment strategies for neurological damage linked to OSA.

Raloxifene Prevents Chemically-Induced Ferroptotic Neuronal Death In Vitro and In Vivo.

Ferroptosis, a regulated form of cell death characterized by excessive iron-dependent lipid peroxidation, can be readily induced in cultured cells by chemicals such as erastin and RSL3. Protein disulfide isomerase (PDI) has been identified as an upstream mediator of chemically induced ferroptosis and also a target for ferroptosis protection. In this study, we discovered that raloxifene (RAL), a selective estrogen receptor modulator known for its neuroprotective actions in humans, can effectively inhibit PDI function and provide robust protection against chemically induced ferroptosis in cultured HT22 neuronal cells. Specifically, RAL can bind directly to PDI both in vitro and in intact neuronal cells and inhibit its catalytic activity. Computational modeling analysis reveals that RAL can tightly bind to PDI through forming a hydrogen bond with its His256 residue, and biochemical analysis further shows that when PDI's His256 is mutated to Ala256, RAL loses its inhibition of PDI's catalytic activity. This inhibition of PDI by RAL significantly reduces the dimerization of both the inducible and neuronal nitric oxide synthases and the accumulation of nitric oxide, both of which have recently been shown to play a crucial role in mediating chemically induced ferroptosis through subsequent induction of ROS and lipid-ROS accumulation. In vivo behavioral analysis shows that mice treated with RAL are strongly protected against kainic acid-induced memory deficits and hippocampal neuronal damage. In conclusion, this study demonstrates that RAL is a potent inhibitor of PDI and can effectively prevent chemically induced ferroptosis in hippocampal neurons both in vitro and in vivo. These findings offer a novel estrogen receptor-independent mechanism for RAL's neuroprotective actions in animal models and humans.

Hippocampal iron overload and spatial reference memory impairment: Insights from a rat model

BackgroundBrain iron overload may induce neuronal death and lead to cognitive impairment. The hippocampus is a critical limbic structure involved in memory. This study aimed to investigate iron overload and its role in hippocampal damage and memory impairment using a rat model. MethodsYoung rats (2 weeks old) received intraperitoneal injections of high-dose iron solution (Group H, n = 10), low-dose iron solution (Group L, n = 10) and normal saline as control (Group D, n = 5). The Morris water maze (MWM) test was performed on all rats to evaluate their spatial reference memory by assessing their escape latency time and number of platform crossing. The iron content and neuronal damage in hippocampal tissue sections of the rats were assessed semi-quantitatively using diaminobenzidine (DAB)-enhanced Perl’s Prussian blue (PPB) staining, and their correlation with spatial reference memory performance was evaluated. ResultsThe escape latency in Group H was significantly longer compared to Groups L and D (P < 0.05). The number of platform crossings was significantly lower in Group H than in Group L or D (P < 0.001). The neuronal cells in Group H had more brown iron deposits than those of Groups L and D. There were significant correlations between the severity of structural damage in the hippocampal tissue and the number of platform crossings (P1 = 0.001 for Group H; P2 = 0.043 for Group L). ConclusionThis study showed an association between hippocampal iron-induced structural damage and spatial reference memory impairment in a rat model. This work should advance our understanding of hippocampal iron overload on cognitive functioning.

Overexpression of ATF4 Inhibits Ferroptosis to Alleviate Anxiety Disorders by Activating the TGF-β Signaling Pathway.

Anxiety disorders seriously impair patients' mental health and quality of life, with limited effectiveness of current treatments. Dysregulation of activating transcription factor 4 (ATF4) is involved in various mental diseases, but the research on its potential roles in alleviating anxiety disorders remains limited. ATF4 was screened out by bioinformatic analysis and its expression was verified in vivo. Mice were treated with 21 d of chronic restraint stress to establish the anxiety mice model. The anxiolytic effect of ATF4 was assessed by a battery of behavior tests and evaluation of hippocampal tissue damage after overexpressing ATF4. Ferroptosis-related indicators were detected by enzyme-linked immunosorbent assay and Western blotting. Then the transforming growth factor beta (TGF-β) signaling pathway was predicted as the downstream regulatory pathway of ATF4 by bioinformatic methods. Western blotting was conducted to detect the protein expression level of TGF-β1, small mothers against decapentaplegic 3 (Smad3), and phospho-Smad3 (p-Smad3). ATF4 was screened out as a ferroptosis-related anxiolytic gene after bioinformatics analysis and was down-regulated in the anxiety mice model. Mice with ATF4 overexpression spent more time in the open arms in the elevated plus-maze test, appeared more frequently in the central area in the open-field test, and decreased the immobility time in the forced swimming and tail suspension tests. Hippocampal tissue damage was alleviated, ferroptosis was suppressed, and the levels of TGF-β1 and p-Smad3/Smad3 were increased by AFT4 overexpression. ATF4 overexpression can repress ferroptosis to improve anxiety disorders by activating the TGF-β signaling pathway.

The nitration of SIRT6 aggravates neuronal damage during cerebral ischemia-reperfusion in rat

Ischemic stroke is a major cause of death and disability. The activation of neuronal nitric oxide synthase (nNOS) and the resulting production of nitric oxide (NO) via NMDA receptor-mediated calcium influx play an exacerbating role in cerebral ischemia reperfusion injury. The NO rapidly reacts with superoxide (O2-) to form peroxynitrite (ONOO-), a toxic molecule may modify proteins through tyrosine residue nitration, ultimately worsening neuronal damage. SIRT6 has been proven to be crucial in regulating cell proliferation, death, and aging in various pathological settings. We have previous reported that human SIRT6 tyrosine nitration decreased its intrinsic catalytic activity in vitro. However, the exact role of SIRT6 function in the process of cerebral ischemia reperfusion injury is not yet fully elucidated. Herein, we demonstrated that an increase in the nitration of SIRT6 led to reduce its enzymatic activity and aggravated hippocampal neuronal damage in a rat model of four-artery cerebral ischemia reperfusion. In addition, reducing SIRT6 nitration resulted in increase the activity of SIRT6, alleviating hippocampal neuronal damage. Moreover, SIRT6 nitration affected its downstream molecule activity such as PARP1 and GCN5, promoting the process of neuronal ischemic injury in rat hippocampus. Additionally, treatment with NMDA receptor antagonist MK801, or nNOS inhibitor 7-NI, and resveratrol (an antioxidant) diminished SIRT6 nitration and the catalytic activity of downstream molecules like PARP1 and GCN5, thereby reducing neuronal damage. Finally, in the biochemical regulation of SIRT6 activity, tyrosine 257 was essential for its activity and susceptibility to nitration. Replacing tyrosine 257 with phenylalanine in rat SIRT6 attenuated the death of SH-SY5Y neurocytes under oxygen-glucose deprivation (OGD) conditions. These results may offer further understanding of SIRT6 function in the pathogenesis of cerebral ischemic diseases.