Hippocampal Damage Research Articles

Prolactin deficiency drives diabetes-associated cognitive dysfunction by inducing microglia-mediated synaptic loss.

Diabetes-associated cognitive dysfunction, characterized by hippocampal synaptic loss as an early pathological feature, seriously threatens patients' quality of life. Synapses are dynamic structures, and hormones play important roles in modulating the formation and elimination of synapses. The pituitary, the master gland of the body, releases several hormones with multiple roles in hippocampal synaptic regulation. In this study, we aimed to explore the relationship between pituitary hormones and cognitive decline in diabetes. A total of 744 patients with type 2 diabetes (T2DM) (445 men and 299 postmenopausal women) who underwent serum pituitary hormone level assessments, comprehensive cognitive evaluations and MRI scans were enrolled. Dynamic diet interventions were applied in both chow diet-fed mice and high-fat diet (HFD)-fed diabetic mice. The cognitive performance and hippocampal pathology of prolactin (PRL)-knockout mice, neuronal prolactin receptor(PRLR)-specific knockout mice and microglial PRLR-specific knockout mice were assessed. Microglial PRLR-specific knockout mice were fed an HFD to model diabetes. Diabetic mice received an intracerebroventricular infusion of recombinant PRL protein or vehicle. This clinical study revealed that decreased PRL levels were associated with cognitive impairment and hippocampal damage in T2DM patients. In diabetic mice, PRL levels diminished before hippocampal synaptic loss and cognitive decline occurred. PRL loss could directly cause cognitive dysfunction and decreased hippocampal synaptic density. Knockout of PRLR in microglia, rather than neurons, induced hippocampal synaptic loss and cognitive impairment. Furthermore, blockade of PRL/PRLR signaling in microglia exacerbated abnormal microglial phagocytosis of synapses, further aggravating hippocampal synaptic loss and cognitive impairment in diabetic mice. Moreover, PRL infusion reduced microglia-mediated synaptic loss, thereby alleviating cognitive impairment in diabetic mice. PRL is associated with cognitive dysfunction and hippocampal damage in T2DM patients. In diabetes, a decrease in PRL level drives hippocampal synaptic loss and cognitive impairment by increasing microglia-mediated synapse engulfment. Restoration of PRL levels ameliorates cognitive dysfunction and hippocampal synaptic loss in diabetic mice.

Deciphering the Therapeutic Efficacy and Underlying Mechanisms of Dendrobium officinale Polysaccharides in the Intervention of Alzheimer's Disease Mice: Insights from Metabolomics and Microbiome.

As a traditional drug-food homologous plant, Dendrobium officinale is widely recognized for its nutritional and medicinal value. Specifically, D. officinale polysaccharide (DOP) has garnered attention as a potential prebiotic for its protective effects on gut microbiota and the nervous system. However, the underlying mechanism by which DOP improves cognitive dysfunction in Alzheimer's disease (AD) remains unclear. This study intends to elucidate the beneficial effects of DOP on AD mice from the perspectives of metabolomics and the intestinal microbiome. The results showed that DOP significantly ameliorated cognitive dysfunction, attenuated hippocampal neuronal damage and Aβ plaque deposition, and restored intestinal barrier integrity in AD mice. The antibiotic-cocktail-induced germ-free mouse model confirmed that the neuroprotective effect of DOP was dependent on gut microbiota. Further investigations demonstrated that DOP influenced the composition of gut microbiota and restored its diversity. Additionally, DOP reshaped metabolic profile disorders in AD mice and increased the short-chain fatty acids (SCFAs) content. Correlation analysis further highlighted that specific gut microbiota was associated with the metabolism of AD mice. In conclusion, this study sheds light on the positive impact of DOP in reshaping the gut microbiota and enhancing cognitive function, offering important perspectives for the possible advancement and utilization of DOP.

Intergenerational crosstalk of brain-gut axis in parental Nd2O3 exposure-induced offspring neurotoxicity and cognitive dysfunction: a mechanistic study

IntroductionRare earth elements (REEs) are widely used in plenty of fields. REEs have significant neurotoxicity and it may adversely affect the development of cognitive. For example, neodymium will causing neurological damage through penetrate the blood–brain barrier (BBB). However, whether it disrupts the balance of brain-gut axis (BGA) crosstalk and affects the intestinal microecology disorder of host is still unclear. This study investigated the neural damage on children caused by maternal exposure to Neodymium oxide (Nd2O3) during pregnancy, and its involved mechanism of BGA injury.MethodsWe used rat model to investigated the mechanisms of the offspring’s neural damage that Nd2O3 exposure in pregnancy. To verify the neural damage of offspring rats, we examed BBB-related factors, such like glutamate and ROS levels in brain tissue, behavioral tests, hippocampal and cortical damage, as well as changes in gut microbiota, intestinal mucosal barrier, and SCFAs in the intestine. Also, we observed some specific indicators of intestinal immune barrier function and gut nerve-related indicators.ResultsMaternal Nd2O3 exposure reduced the content of offspring tight junction proteins, increased BBB permeability, leading to Nd accumulation and brain tissue inflammation, affecting offspring’s neural development and weakening their spatial learning ability. Nd2O3 also disrupted BBB integrity by regulating SCFAs and BGA. Probiotic intervention in the offspring rats exposed to 2% Nd2O3 showed significant recovery of inflammation in both brain and colon tissues, and reduced BBB permeability.ConclusionMaternal exposure to Nd2O3 affects the offspring’s BGA, targeting brain and colon tissues, increasing BBB permeability, affecting neural development, causing damage to the intestinal mucosa, and impacting children’s gut development. Probiotics can alleviate these effects. These findings provide valuable insights into understanding the neurodevelopmental and intestinal developmental toxicity of Nd2O3 and its prevention and treatment. It also calls for a comprehensive assessment of the health risks of susceptible populations to Nd2O3, such as pregnant women. It may providing theoretical basis for preventing and controlling neodymium-induced harm in children by examing the repair mechanism of the damage through probiotic intervention.

Mitochondrial transplantation following cardiopulmonary resuscitation improves neurological function in rats by inducing M2-type MG/MΦ polarization.

Explore the effects of mitochondrial transplantation (MT) after cardiopulmonary resuscitation (CPR) on the polarization of microglia/macrophages (MG/MΦ) and neurological function. Seventy-five Sprague-Dawley rats were randomly divided into five groups: sham, normal saline (NS), vehicle, mitochondria (Mito), and non-functional mitochondria (N-Mito) group. Rats in sham group underwent surgical procedures without cardiac arrest, while the other four groups underwent cardiac arrest and CPR, and then received NS, respiration buffer, mitochondrial suspension or non-functional mitochondria, immediately after the restoration of spontaneous circulation (ROSC). The number of mitochondria in the hippocampus, the morphology and structure of mitochondria in MG/MΦ, the phenotype of MG/MΦ, and hippocampal tissue injury, neuroinflammation, and neuronal apoptosis were detected on days 1 and 3 after ROSC. Neurodeficit score (NDS) was performed on days 1, 3, 7, 15 and 30 after ROSC. Compared with other groups, the number of mitochondria in the hippocampus was increased, and the morphology and structure of mitochondria in MG/MΦ were significantly improved in the Mito group. Our results show higher expression of M2-type markers in MG/MΦ and decreased hippocampal tissue damage in the Mito group. Levels of NSE and S100β in serum, and TNF-α, IL-6 in the hippocampus were decreased, while the levels of TGF-β and IL-10 were increased in the Mito group. Apoptosis rate of neurons in the Mito group was decreased and the NDS of the Mito group was higher than the other groups. Exogenous MT can improve neurological function after CPR by promoting the polarization of MG/MΦ to M2-type cells, and this could be a potential method for brain protection after CPR.

Exploration of Astragaloside IV in multiple organ dysfunction syndrome and hippocampus damage through network pharmacological analysis

Background: This study aims to investigate the potential therapeutic effect of Astragaloside IV on the hippocampus in multiple organ dysfunction syndrome (MODS) and its underlying mechanisms. Methods: Targets related to "Multiple Organ Dysfunction Syndrome," "Hippocampus," and "Astragaloside IV" were collected from the GeneCards database. Co-existing intersection targets were identified using a Venn diagram via the bioinformatics platform. A protein interaction network was constructed using the String database, and core targets were screened with the cytoHubba plug-in of Cytoscape software. GO functional enrichment and KEGG pathway enrichment analyses were performed using the DAVID database, and a "disease-site-drug-key target-KEGG pathway" network map was constructed to reveal the mechanisms of Astragaloside IV. Results: Two intersection targets were identified, and the protein interaction network showed their interactions. GO and KEGG analyses indicated that these targets are mainly involved in biological processes and pathways such as efferocytosis. The "disease-site-drug-key targets-KEGG pathway" network map further clarified that Astragaloside IV may treat MODS by affecting specific signaling pathways. Conclusion: Astragaloside IV may exert a therapeutic effect on the hippocampus in MODS by influencing pathways such as efferocytosis, offering new perspectives and potential targets for future research.

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.

Scalp acupuncture alleviates remote hippocampal damage in MCAO rats by inhibiting neuroinflammation: A TMT-based proteomics analysis

While mounting evidence suggests that scalp acupuncture (SA) may be effective in alleviating neurological deficits in patients with acute ischemic stroke (IS), its effect on remote hippocampal damage in acute IS and the underlying mechanisms remain elusive. Thus, proteomics analysis was conducted to identify potential targets of SA therapy in acute IS. SA significantly reduced cerebral infarct volume and attenuated neuronal damage in the ischemic penumbra and hippocampus, as well as alleviated neurological deficits in rats with middle cerebral artery occlusion (MCAO). Moreover, 74 upregulated and 50 downregulated proteins were identified in the MCAO group compared to the sham group, whilst 52 up-regulated and 50 down-regulated proteins were identified in the SA group compared to the MCAO group. Bioinformatics analysis indicated that SA may exert neuroprotective effects by modulating the acute inflammatory response and microglial activation. Additionally, SA down-regulated the expression levels of Iba-1, TNF-α, IL-1β, and IL-6, while up-regulating those of IL-4 and IL-10. Likewise, it downregulated the expression levels of three key proteins identified via proteomics analysis (Kng1, Brd9, and Magl) that may mediate the anti-inflammatory effects of SA. Overall, these results indicate that SA attenuates neuronal damage in the hippocampus and ischemic penumbra and ameliorates neurological deficits. Proteomic analysis suggested that this effect is related to the modulation of the acute inflammatory response. SA attenuated remote hippocampal damage after IS by inhibiting microglia activation and neuroinflammation. Lastly, Kng1, Brd9, and Magl were identified as potential targets that mediate the anti-inflammatory effects of SA.

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.