Alkaloids in Uncaria rhynchophylla improves AD pathology by restraining CD4+ T cell-mediated neuroinflammation via inhibition of glycolysis in APP/PS1 mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Uncaria rhynchophylla (Miq.) Miq.ex Havil. was a classical medicinal plant exhibiting the properties of extinguishing wind, arresting convulsions, clearing heat and pacifying the liver. Clinically, it could be utilized for the treatment of central nervous system-related diseases, such as Alzheimer's disease. U. rhynchophylla (UR) and its major ingredient alkaloid compounds (URA) have been proved to exert significant neuroprotective effects. However, the potential mechanism aren't fully understood. AIM OF THE STUDY: This study systematically examined the therapeutic effects of URA on AD pathology in APP-PS1 mice, and revealed the potential mechanism of action. MATERIALS AND METHODS: The cognitive ability was evaluated by morris water maze test in APP-PS1 mice. The H&E staining was used to observe the tissue pathological changes. The ELISA kits were used to detect the level of inflammatory factors. The flow cytometry was used to analyze the percentage of CD4+ effector T cells (Teffs) in spleen. The immunofluorescent staining was performed to count the Teffs and microglia in brain. The protein expression was analyzed by western blot. In vitro, the lymphocyte proliferation induced by ConA was performed by CCK-8 kits. The IFN-γ, IL-17, and TNF-α production were detected by ELISA kits. The effects of URA on glycolysis and the involvement of PI3K/Akt/mTOR signaling pathway was analyzed by Lactic Acid assay kit and western blot in ConA-induced naive T cell. RESULTS: URA treatment improved AD pathology effectively as demonstrated by enhanced cognitive ability, decreased Aß deposit and Tau phosphorylation, as well as reduced neuron apoptosis. Also, the neuroinflammation was significantly alleviated as evidenced by decreased IFN-γ, IL-17 and increased IL-10, TGF-ß. Notably, URA treatment down-regulated the percentage of Teffs (Th1 and Th17) in spleen, and reduced the infiltration of Teffs and microglia in brain. Meanwhile, the Treg cell was up-regulated both in spleen and brain. In vitro, URA was capable of attenuating the spleen lymphocyte proliferation and release of inflammatory factors provoked by ConA. Interestingly, glycolysis was inhibited by URA treatment as evidenced by the decrease in Lactic Acid production and expression of HK2 and GLUT1 via regulating PI3K/Akt/mTOR signaling pathway in ConA-induced naive T cell. CONCLUSION: This study proved that URA could improve AD pathology which was possibly attributable to the restraints of CD4+ T cell mediated neuroinflammation via inhibiting glycolysis.

Salvianolic acid A inhibits ferroptosis and protects against intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a common cerebral vascular disease with high incidence, disability, and mortality. Ferroptosis is a regulated type of iron-dependent, non-apoptotic programmed cell death. There is increasing evidence that ferroptosis may lead to neuronal damage mediated by hemorrhagic stroke mediated neuronal damage. Salvianolic acid A (SAA) is a natural bioactive polyphenol compound extracted from salvia miltiorrhiza, which has anti-inflammatory, antioxidant, and antifibrosis activities. SAA is reported to be an iron chelator that inhibits lipid peroxidation and provides neuroprotective effects. However, whether SAA improves neuronal ferroptosis mediated by hemorrhagic stroke remains unclear. The study aims to evaluate the therapeutic effect of SAA on Ferroptosis mediated by Intracerebral hemorrhage and explore its potential mechanisms. We constructed in vivo and in vitro models of intracerebral hemorrhage in rats. Multiple methods were used to analyze the inhibitory effect of SAA on ferroptosis in both in vivo and in vitro models of intracerebral hemorrhage in rats. Then, network pharmacology is used to identify potential targets and mechanisms for SAA treatment of ICH. The SAA target ICH network combines SAA and ICH targets with protein-protein interactions (PPIs). Find the specific mechanism of SAA acting on ferroptosis through molecular docking and functional enrichment analysis. In rats, SAA (10 mg/kg in vivo and 50 µM in vitro, p < 0.05) alleviated dyskinesia and brain injury in the ICH model by inhibiting ferroptosis (p < 0.05). The molecular docking results and functional enrichment analyses suggested that AKT (V-akt murine thymoma viral oncogene homolog) could mediate the effect of SAA. NRF2 (Nuclear factor erythroid 2-related factor 2) was a potential target of SAA. Our further experiments showed that salvianolic acid A enhanced the Akt /GSK-3ß/Nrf2 signaling pathway activation in vivo and in vitro. At the same time, SAA significantly expanded the expression of GPX4, XCT proteins, and the nuclear expression of Nrf2, while the AKT inhibitor SH-6 and the Nrf2 inhibitor ML385 could reduce them to some extent. Therefore, SAA effectively ameliorated ICH-mediated neuronal ferroptosis. Meanwhile, one of the critical mechanisms of SAA inhibiting ferroptosis was activating the Akt/GSK-3ß/Nrf2 signaling pathway.

Efficacy of Citicoline Delivered via Brain Extracellular Space against Experimental Acute Ischemic Stroke in Rats.

Objective: Citicoline can be used to reduce acute ischemic stroke injury via venous infusion, however, its protective effects in the brain extracellular space remain largely unknown. Herein, we investigated the brain protective effects of citicoline administered via the brain extracellular space and sought precise effective dosage range that can protect against ischemic injury after experimental ischemic stroke in rats. Methods: Fifty-six Sprague-Dawley rats were randomly divided into control, intraperitoneal (IP), caudate-putamen (CPu)-25, CPu-40, CPu-50, CPu-60 and CPu-75 groups based on the infusion site and concentration of citicoline. Two hours after the administration of citicoline, the rats were subjected to a permanent middle cerebral artery occlusion to mimic acute ischemic stroke. Then, the brain infarct volume in rats after stroke was measured and their neurological deficiency was evaluated to explain the protective effects and effective dosage range of citicoline. Results: Compared to the control and IP groups, brain infarct volume of rats in CPu-40, CPu-50, and CPu-60 groups is significant smaller. Furthermore, the brain infarct volume of rats in CPu-50 is the least. Conclusions: Here, we showed that citicoline can decrease the brain infarct volume, thus protecting the brain from acute ischemic stroke injury. We also found that the appropriate effective citicoline dose delivered via the brain extracellular space is 50 mM. Our study provides novel insights into the precise treatment of acute ischemic stroke by citicoline via the brain extracellular space, further guiding the treatment of brain disease.

Neuroprotective Effects of [Formula: see text]-Terpinene in Rats with Acute Cerebral Ischemia: Modulation of Inflammation, Apoptosis, and Oxidation.

The study aimed to assess 𝛾-Terpinene's (𝛾-TER) neuroprotective potential in acute cerebral ischemia, characterized by reduced cerebral blood flow in rats. Middle cerebral artery occlusion (MCAO), a standard method for inducing cerebral ischemia, was employed in male Wistar rats. 𝛾-TER at varying doses (5, 10, and 15 mg/kg) were intraperitoneally administered during reperfusion onset. Neurological outcomes, cerebral infarct size, edema, and enzymatic activities (SOD, GPx, and catalase) in the brain were evaluated using diverse techniques. The study examined gene expression and pathways associated with neuroinflammation and apoptosis using Cytoscape software, identifying the top 10 genes involved. Pro-inflammatory and pro-apoptotic factors were assessed through real-time PCR and ELISA, while apoptotic cell rates were measured using the TUNEL and Flow cytometry assay. Immunohistochemistry assessed apoptosis-related proteins like Bax and bcl-2 in the ischemic area. 𝛾-TER, particularly at doses of 10 and 15 mg/kg, significantly reduced neurological deficits and cerebral infarction size. The 15 mg/kg dose mitigated TNF-α, IL-1ß, Bax, and caspase-3 gene and protein levels in the cortex, hippocampus, and striatum compared to controls. Furthermore, Bcl-2 levels increased in these regions. 𝛾-TER show cased neuroprotective effects by suppressing inflammation, apoptosis, and oxidation. In conclusion, 𝛾-TER, possessing natural anti-inflammatory and anti-apoptotic properties, shields the brain against ischemic damage by reducing infarction, edema, oxidative stress, and inflammation. It modulates the expression of crucial genes and proteins associated with apoptosis in diverse brain regions. These findings position 𝛾-TER as a potential therapeutic agent for ischemic stroke.

Menaquinone-4 alleviates hypoxic-ischemic brain damage in neonatal rats by reducing mitochondrial dysfunction via Sirt1-PGC-1α-TFAM signaling pathway.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is a major contributor to neonatal mortality and neurodevelopmental disorders, but currently there is no effective therapy drug for HIE. Mitochondrial dysfunction plays a pivotal role in hypoxic-ischemic brain damage(HIBD). Menaquinone-4 (MK-4), a subtype of vitamin K2 prevalent in the brain, has been shown to enhance mitochondrial function and exhibit protective effects against ischemia-reperfusion injury. However, the impact and underlying molecular mechanism of MK-4 in HIE have not been fully elucidated. METHODS: In this study, we established the neonatal rats HIBD model in vivo and oxygen-glucose deprivation and reperfusion (OGD/R) of primary neurons in vitro to explore the neuroprotective effects of MK-4 on HI damage, and illuminate the potential mechanism. RESULTS: Our findings revealed that MK-4 ameliorated mitochondrial dysfunction, reduced oxidative stress, and prevented HI-induced neuronal apoptosis by activating the Sirt1-PGC-1α-TFAM signaling pathway through Sirt1 mediation. Importantly, these protective effects were partially reversed by EX-527, a Sirt1 inhibitor. CONCLUSION: Our study elucidated the potential therapeutic mechanism of MK-4 in neonatal HIE, suggesting its viability as an agent for enhancing recovery from HI-induced cerebral damage in newborns. Further exploration into MK-4 could lead to novel interventions for HIE therapy.

Oridonin exerts anticonvulsant profile and neuroprotective activity in epileptic mice by inhibiting NLRP3-mediated pyroptosis.

BACKGROUND: Epilepsy is a chronic disabling disease poorly controlled by available antiseizure medications. Oridonin, a bioactive alkaloid with anti-inflammatory properties and neuroprotective effects, can inhibit the increased excitability of neurons caused by glutamate accumulation at the cellular level. However, whether oridonin affects neuronal excitability and whether it has antiepileptic potential has not been reported in animal models or clinical studies. METHOD: Pentylenetetrazol was injected into mice to create a model of chronic epilepsy. Seizure severity was assessed using the Racine scale, and the duration and latency of seizures were observed. Abnormal neuronal discharge was detected using electroencephalography, and neuronal excitability was assessed using calcium imaging. Damage to hippocampal neurons was evaluated using Hematoxylin-Eosin and Nissl staining. The expression of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and other pyroptosis-related proteins was determined using western blotting and immunofluorescence. A neuronal pyroptosis model was established using the supernatant of BV2 cells treated with lipopolysaccharide and adenosine triphosphate to stimulate hippocampal neurons. RESULTS: Oridonin (1 and 5 mg/kg) reduced neuronal damage, increased the latency of seizures, and shortened the duration of fully kindled seizures in chronic epilepsy model mice. Oridonin decreased abnormal discharge during epileptic episodes and suppressed increased neuronal excitability. In vitro experiments showed that oridonin alleviated pyroptosis in hippocampal HT22 neurons. CONCLUSION: Oridonin exerts neuroprotective effects by inhibiting pyroptosis through the NLRP3/caspase-1 pathway in chronic epilepsy model mice. It also reduces pyroptosis in hippocampal neurons in vitro, suggesting its potential as a therapy for epilepsy.

Protective effect of equol intake on bladder dysfunction in a rat model of bladder outlet obstruction.

OBJECTIVES: This study evaluates the impact of equol, a metabolite of soy isoflavone, on bladder dysfunction in rats with bladder outlet obstruction (BOO). In addition, we investigate its potential as a neuroprotective agent for the obstructed bladder and discuss its applicability in managing overactive bladder (OAB). METHODS: Eighteen male Sprague-Dawley rats were divided into three groups (six rats per group) during the rearing period. The Sham and C-BOO groups received an equol-free diet, while the E-BOO group received equol supplementation (0.25 g/kg). At 8 weeks old, rats underwent BOO surgery, followed by continuous cystometry after 4 weeks of rearing. The urinary oxidative stress markers (8-hydroxy-2'-deoxyguanosine and malondialdehyde) were measured, and the bladder histology was analyzed using hematoxylin-eosin, Masson's trichrome, and immunohistochemical staining (neurofilament heavy chain for myelinated nerves, peripherin for unmyelinated nerves, and malondialdehyde). RESULTS: Equol reduced BOO-induced smooth muscle layer fibrosis, significantly prolonged the micturition interval (C-BOO: 193 s, E-BOO: 438 s) and increased the micturition volume (C-BOO: 0.54 mL, E-BOO: 1.02 mL) compared to the C-BOO group. Equol inhibited the increase in urinary and bladder tissue malondialdehyde levels. While the C-BOO group exhibited reduced peripherin alone positive nerve fibers within the smooth muscle layer, equol effectively attenuated this decline. CONCLUSIONS: Equol reduces lipid peroxidation and smooth muscle layer fibrosis in the bladder and exhibited neuroprotective effects on bladder nerves (peripheral nerves) and prevented the development of bladder dysfunction associated with BOO in rats. Consumption of equol is promising for the prevention of OAB associated with BOO.

Beneficial effects of metformin treatment on memory impairment.

Memory issues are a prevalent symptom in different neurodegenerative diseases and can also manifest in certain psychiatric conditions. Despite limited medications approved for treating memory problems, research suggests a lack of sufficient options in the market. Studies indicate that a significant percentage of elderly individuals experience various forms of memory disorders. Metformin, commonly prescribed for type 2 diabetes, has shown neuroprotective properties through diverse mechanisms. This study explores the potential of metformin in addressing memory impairments. The current research gathered its data by conducting an extensive search across electronic databases including PubMed, Web of Science, Scopus, and Google Scholar. Previous research suggests that metformin enhances brain cell survival and memory function in both animal and clinical models by reducing oxidative stress, inflammation, and cell death while increasing beneficial neurotrophic factors. The findings of the research revealed that metformin is an effective medication for enhancing various types of memory problems in numerous studies. Given the rising incidence of memory disorders, it is plausible to utilize metformin, which is an affordable and accessible drug. It is often recommended as a treatment to boost memory.

The Molecular Biological Mechanism of Hydrogen Therapy and Its Application in Spinal Cord Injury.

Hydrogen, which is a novel biomedical molecule, is currently the subject of extensive research involving animal experiments and in vitro cell experiments, and it is gradually being applied in clinical settings. Hydrogen has been proven to possess anti-inflammatory, selective antioxidant, and antiapoptotic effects, thus exhibiting considerable protective effects in various diseases. In recent years, several studies have provided preliminary evidence for the protective effects of hydrogen on spinal cord injury (SCI). This paper provides a comprehensive review of the potential molecular biology mechanisms of hydrogen therapy and its application in treating SCI, with an aim to better explore the medical value of hydrogen and provide new avenues for the adjuvant treatment of SCI.

Design, synthesis and neuroprotective biological evaluation of novel HDAC6 inhibitors incorporating benzothiadiazinyl systems as cap groups.

Histone deacetylase 6 (HDAC6), as the key regulatory enzyme, plays an important role in the development of the nervous system. More and more studies indicate that HDAC6 has become a promising therapeutic target for CNS diseases. Herein we designed and synthesized a series of novel HDAC6 inhibitors with benzothiadiazinyl systems as cap groups and evaluated their activity in vitro and in vivo. Among them, compound 3 exhibited superior selective inhibitory activity against HDAC6 (IC50 = 5.1 nM, about 30-fold selectivity over HDAC1). The results of docking showed that compound 3 can interact well with the key amino acid residues of HDAC6. Compound 3 showed lower cytotoxicity (20 µM to SH-SY5Y cells, inhibition rate = 25.75%) and better neuroprotective activity against L-glutamate-induced SH-SY5Y cell injury model in vitro. Meanwhile, compound 3 exhibited weak cardiotoxicity (10 µM hERG inhibition rate = 17.35%) and possess good druggability properties. Especially, compound 3 could significantly reduce cerebral infarction from 49.87% to 32.18%, and similar with butylphthalide in MCAO model, indicating potential clinical application prospects for alleviating ischemic stroke-induced brain infarction.

The Benzoylpiperidine Fragment as a Privileged Structure in Medicinal Chemistry: A Comprehensive Review.

The phenyl(piperidin-4-yl)methanone fragment (here referred to as the benzoylpiperidine fragment) is a privileged structure in the development of new drugs considering its presence in many bioactive small molecules with both therapeutic (such as anti-cancer, anti-psychotic, anti-thrombotic, anti-arrhythmic, anti-tubercular, anti-parasitic, anti-diabetic, and neuroprotective agents) and diagnostic properties. The benzoylpiperidine fragment is metabolically stable, and it is also considered a potential bioisostere of the piperazine ring, thus making it a feasible and reliable chemical frame to be exploited in drug design. Herein, we discuss the main therapeutic and diagnostic agents presenting the benzoylpiperidine motif in their structure, covering articles reported in the literature since 2000. A specific section is focused on the synthetic strategies adopted to obtain this versatile chemical portion.

Protection of Si Nanowires against Aß Toxicity by the Inhibition of Aß Aggregation.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of amyloid beta (Aß) plaques in the brain. Aß1-42 is the main component of Aß plaque, which is toxic to neuronal cells. Si nanowires (Si NWs) have the advantages of small particle size, high specific surface area, and good biocompatibility, and have potential application prospects in suppressing Aß aggregation. In this study, we employed the vapor-liquid-solid (VLS) growth mechanism to grow Si NWs using Au nanoparticles as catalysts in a plasma-enhanced chemical vapor deposition (PECVD) system. Subsequently, these Si NWs were transferred to a phosphoric acid buffer solution (PBS). We found that Si NWs significantly reduced cell death in PC12 cells (rat adrenal pheochromocytoma cells) induced by Aß1-42 oligomers via double staining with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and fluorescein diacetate/propyl iodide (FDA/PI). Most importantly, pre-incubated Si NWs largely prevented Aß1-42 oligomer-induced PC12 cell death, suggesting that Si NWs exerts an anti-Aß neuroprotective effect by inhibiting Aß aggregation. The analysis of Fourier Transform Infrared (FTIR) results demonstrates that Si NWs reduce the toxicity of fibrils and oligomers by intervening in the formation of ß-sheet structures, thereby protecting the viability of nerve cells. Our findings suggest that Si NWs may be a potential therapeutic agent for AD by protecting neuronal cells from the toxicity of Aß1-42.

Indole-Based Compounds in the Development of Anti-Neurodegenerative Agents.

Neurodegeneration is a gradual decay process leading to the depletion of neurons in both the central and peripheral nervous systems, ultimately resulting in cognitive dysfunctions and the deterioration of brain functions, alongside a decline in motor skills and behavioral capabilities. Neurodegenerative disorders (NDs) impose a substantial socio-economic strain on society, aggravated by the advancing age of the world population and the absence of effective remedies, predicting a negative future. In this context, the urgency of discovering viable therapies is critical and, despite significant efforts by medicinal chemists in developing potential drug candidates and exploring various small molecules as therapeutics, regrettably, a truly effective treatment is yet to be found. Nitrogen heterocyclic compounds, and particularly those containing the indole nucleus, which has emerged as privileged scaffold, have attracted particular attention for a variety of pharmacological applications. This review analyzes the rational design strategy adopted by different research groups for the development of anti-neurodegenerative indole-based compounds which have the potential to modulate various molecular targets involved in NDs, with reference to the most recent advances between 2018 and 2023.

Comparing the biological activity and composition of Cerebrolysin with other peptide preparations.

Neurological disorders, ranging from acute forms such as stroke and traumatic brain injury to neurodegenerative diseases like dementia, are the leading cause of disability-adjusted life years (DALYs) worldwide. A promising approach to address these conditions and promote nervous system regeneration is the use of the neuropeptide preparation Cerebrolysin, which has been shown to be effective in both clinical and preclinical studies. Despite claims of similar clinical efficacy and safety by several peptide preparations, concerns regarding their generic composition and efficacy have been previously raised. Based on these reports, we analyzed the peptide composition and neurotrophic activity of several peptide preparations allegedly similar to Cerebrolysin and approved in some countries for treating neurological diseases. Our results demonstrate that these preparations lack relevant biological activity and that the peptide composition is significantly different from Cerebrolysin. peptide.

Protecting effects of 4-octyl itaconate on neonatal hypoxic-ischemic encephalopathy via Nrf2 pathway in astrocytes.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the most common neurological problems occurring in the perinatal period. However, there still is not a promising approach to reduce long-term neurodevelopmental outcomes of HIE. Recently, itaconate has been found to exhibit anti-oxidative and anti-inflammatory effects. However, the therapeutic efficacy of itaconate in HIE remains inconclusive. Therefore, this study attempts to explore the pathophysiological mechanisms of oxidative stress and inflammatory responses in HIE as well as the potential therapeutic role of a derivative of itaconate, 4-octyl itaconate (4OI). METHODS: We used 7-day-old mice to induce hypoxic-ischemic (HI) model by right common carotid artery ligation followed by 1 h of hypoxia. Behavioral experiments including the Y-maze and novel object recognition test were performed on HI mice at P60 to evaluate long-term neurodevelopmental outcomes. We employed an approach combining non-targeted metabolomics with transcriptomics to screen alterations in metabolic profiles and gene expression in the hippocampal tissue of the mice at 8 h after hypoxia. Immunofluorescence staining and RT-PCR were used to evaluate the pathological changes in brain tissue cells and the expression of mRNA and proteins. 4OI was intraperitoneally injected into HI model mice to assess its anti-inflammatory and antioxidant effects. BV2 and C8D1A cells were cultured in vitro to study the effect of 4OI on the expression and nuclear translocation of Nrf2. We also used Nrf2-siRNA to further validate 4OI-induced Nrf2 pathway in astrocytes. RESULTS: We found that in the acute phase of HI, there was an accumulation of pyruvate and lactate in the hippocampal tissue, accompanied by oxidative stress and pro-inflammatory, as well as increased expression of antioxidative stress and anti-inflammatory genes. Treatment of 4OI could inhibit activation and proliferation of microglial cells and astrocytes, reduce neuronal death and relieve cognitive dysfunction in HI mice. Furthermore, 4OI enhanced nuclear factor erythroid-2-related factor (Nfe2l2; Nrf2) expression and nuclear translocation in astrocytes, reduced pro-inflammatory cytokine production, and increased antioxidant enzyme expression. CONCLUSION: Our study demonstrates that 4OI has a potential therapeutic effect on neuronal damage and cognitive deficits in HIE, potentially through the modulation of inflammation and oxidative stress pathways by Nrf2 in astrocytes.

Exploiting Natural Niches with Neuroprotective Properties: A Comprehensive Review.

Natural products from mushrooms, plants, microalgae, and cyanobacteria have been intensively explored and studied for their preventive or therapeutic potential. Among age-related pathologies, neurodegenerative diseases (such as Alzheimer's and Parkinson's diseases) represent a worldwide health and social problem. Since several pathological mechanisms are associated with neurodegeneration, promising strategies against neurodegenerative diseases are aimed to target multiple processes. These approaches usually avoid premature cell death and the loss of function of damaged neurons. This review focuses attention on the preventive and therapeutic potential of several compounds derived from natural sources, which could be exploited for their neuroprotective effect. Curcumin, resveratrol, ergothioneine, and phycocyanin are presented as examples of successful approaches, with a special focus on possible strategies to improve their delivery to the brain.

Positive Effect of 6-Gingerol on Functional Plasticity of Microglia in a rat Model of LPS-induced Depression.

Neuroinflammation has emerged as a crucial factor in the development of depression. Despite the well-known anti-inflammatory properties of 6-gingerol, its potential impact on depression remains poorly understood. This study aimed to investigate the antidepressant effects of 6-gingerol by suppressing microglial activation. In vivo experiments were conducted to evaluate the effect of 6-gingerol on lipopolysaccharide (LPS)-induced behavioral changes and neuroinflammation in rat models. In vitro studies were performed to examine the neuroprotective properties of 6-gingerol against LPS-induced microglial activation. Furthermore, a co-culture system of microglia and neurons was established to assess the influence of 6-gingerol on the expression of synaptic-related proteins, namely synaptophysin (SYP) and postsynaptic density protein 95 (PSD95), which are influenced by microglial activation. In the in vivo experiments, administration of 6-gingerol effectively alleviated LPS-induced depressive behavior in rats. Moreover, it markedly suppressed the activation of rat prefrontal cortex (PFC) microglia induced by LPS and the activation of the NF-κB/NLRP3 inflammatory pathway, while also reducing the levels of inflammatory cytokines IL-1ß and IL-18. In the in vitro experiments, 6-gingerol mitigated nuclear translocation of NF-κB p65, NLRP3 activation, and maturation of IL-1ß and IL-18, all of which were induced by LPS. Furthermore, in the co-culture system of microglia and neurons, 6-gingerol effectively restored the decreased expression of SYP and PSD95. The findings of this study demonstrate the neuroprotective effects of 6-gingerol in the context of LPS-induced depression-like behavior. These effects are attributed to the inhibition of microglial hyperactivation through the suppression of the NF-κB/NLRP3 inflammatory pathway.

Quetiapine attenuates cadmium neurotoxicity by suppressing oxidative stress, inflammation, and pyroptosis.

BACKGROUND: Cadmium (Cd) is a heavy metal with extremely harmful toxic effects on the brain. Quetiapine (QTP) has unique neuroprotective effects with anti-inflammatory and antioxidant actions. However, its neuroprotective effect against Cd-induced neurotoxicity has not been previously studied. METHODS: QTP was administered in 10 and 20 mg/kg doses, while Cd was given in a dose of 6.5 mg/kg. RESULTS: In our study, QTP dose-dependently attenuated neuronal injury by downregulating p-tau and ß-amyloid. QTP potently attenuates histological abrasions induced by Cd. QTP counteracted oxidative injury by decreasing neuronal MDA and increased GSH levels mediated by downregulating Keap1 and upregulating Nrf2 and HO-1. QTP mitigated inflammation by decreasing MPO and NO2 and neuronal cytokines TNF-α and IL-1ß and upregulating IL-10 levels mediated by NF-κB downregulation. Additionally, QTP counteracted Cd-induced pyroptosis by downregulating caspase-1, ASC, and NLRP3 protein levels. CONCLUSION: In conclusion, QTP mitigates neurotoxicity induced by Cd through suppression of inflammation, pyroptosis, and oxidative stress by controlling the NF-κB, Keap1/Nrf2, and pyroptosis signals.

Emerging ferroptosis inhibitors as a novel therapeutic strategy for the treatment of neonatal hypoxic-ischemic encephalopathy.

Neonatal hypoxia-ischemia encephalopathy (NHIE), an oxygen deprivation-mediated brain injury due to birth asphyxia or reduced cerebral blood perfusion, often leads to lifelong sequelae, including seizures, cerebral palsy, and mental retardation. NHIE poses a significant health challenge, as one of the leading causes of neonatal morbidity and mortality globally. Despite this, available therapies are limited. Numerous studies have recently demonstrated that ferroptosis, an iron-dependent non-apoptotic regulated form of cell death characterized by lipid peroxidation (LPO) and iron dyshomeostasis, plays a role in the genesis of NHIE. Moreover, recently discovered compounds have been shown to exert potential therapeutic effects on NHIE by inhibiting ferroptosis. This comprehensive review summarizes the fundamental mechanisms of ferroptosis contributing to NHIE. We focus on various emerging therapeutic compounds exhibiting characteristics of ferroptosis inhibition and delineate their pharmacological benefits for the treatment of NHIE. This review suggests that pharmacological inhibition of ferroptosis may be a potential therapeutic strategy for NHIE.

Lead optimization based design, synthesis, and pharmacological evaluation of quinazoline derivatives as multi-targeting agents for Alzheimer's disease treatment.

The complexity and multifaceted nature of Alzheimer's disease (AD) have driven us to further explore quinazoline scaffolds as multi-targeting agents for AD treatment. The lead optimization strategy was utilized in designing of new series of derivatives (AK-1 to AK-14) followed by synthesis, characterization, and pharmacological evaluation against human cholinesterase's (hChE) and ß-secretase (hBACE-1) enzymes. Amongst them, compounds AK-1, AK-2, and AK-3 showed good and significant inhibitory activity against both hAChE and hBACE-1 enzymes with favorable permeation across the blood-brain barrier. The most active compound AK-2 revealed significant propidium iodide (PI) displacement from the AChE-PAS region and was non-neurotoxic against SH-SY5Y cell lines. The lead molecule (AK-2) also showed Aß aggregation inhibition in a self- and AChE-induced Aß aggregation, Thioflavin-T assay. Further, compound AK-2 significantly ameliorated Aß-induced cognitive deficits in the Aß-induced Morris water maze rat model and demonstrated a significant rescue in eye phenotype in the Aꞵ-phenotypic drosophila model of AD. Ex-vivo immunohistochemistry (IHC) analysis on hippocampal rat brains showed reduced Aß and BACE-1 protein levels. Compound AK-2 suggested good oral absorption via pharmacokinetic studies and displayed a good and stable ligand-protein interaction in in-silico molecular modeling analysis. Thus, the compound AK-2 can be regarded as a lead molecule and should be investigated further for the treatment of AD.