Neuronal Oxidative Stress Research Articles

Evaluation of terpenes rich Hura crepitans extract on glucose regulation and diabetic complications in STZ-induced diabetic rats

The continual increase in global diabetic statistics portends decreased productivity and life spans, thus making it a disease of concern requiring more effective and safe therapeutic options. While several reports on antidiabetic plants, including Hura crepitans, are available, there is still a dearth of information on the holistic antidiabetic properties of H. crepitans and its associated complications. This study evaluated the antidiabetic potential of methanolic extract of Hura crepitans using in vitro, in vivo, and in silico approaches. The extract revealed a dose-dependent in vitro effect, with a 47.97 % and 65.34 % decrease in the fasting blood sugar levels of streptozotocin (STZ) induced diabetic rats at 150 and 300 mg/kg BW, respectively. Likewise, the extract increased serum and pancreatic insulin levels, and significantly ameliorated neuronal oxidative stress and inflammation by reducing the expression levels of cholinesterase, NF-κB, and COX-2 in the brain of hyperglycemic rats. Serum dyslipidemia, liver, and kidney biomarker indices, and hematological alterations in diabetic rats were also significantly attenuated by the extract. Several constituents, mainly terpenes, were identified in the extract. To further predict the drug-likeness, pharmacokinetics, and binding properties of the compounds, in silico analysis was conducted. Ergosta-2,24-dien-26-oicacid,18-(acetyloxy)-5,6-epoxy-4, 22-dihydroxy-1-oxo-,delta.-lactone-4.beta., displayed the highest docking scores for acetylcholinesterase, butyrylcholinesterases, alpha-amylase, and nuclear factor-kB with values of −12.4, −10.9, −10.3, and −9.4 kcal/mol, while ergost-25-ene-6,12-dione,3,5-dihydroxy-, (3.beta.,5.alpha.) topped for cyclooxygenase-2 (-9.0 kcal/mol). The top-ranked compounds also presented significant oral drug-likeness, pharmacokinetics, and safety properties. Altogether, our data provide preclinical evidence of the potential of Hura crepitans in ameliorating diabetes and its associated complications.

Molecular mechanisms of enteric neuropathies in high-fat diet feeding and diabetes.

Obesity and diabetes are associated with altered gastrointestinal function and with the development of abdominal pain, nausea, diarrhea, and constipation among other symptoms. The enteric nervous system (ENS) regulates gastrointestinal motility. Enteric neuropathies defined as damage or loss of enteric neurons can lead to motility disorders. Here, we review the molecular mechanisms that drive enteric neurodegeneration in diabetes and obesity, including signaling pathways leading to neuronal cell death, oxidative stress, and microbiota alteration. We also highlight potential approaches to treat enteric neuropathies including antioxidant therapy to prevent oxidative stress-induced damage and the use of stem cells.

Oxidative Stress in Cerebral Ischemia/Reperfusion Injury

Oxidative stress in cerebral ischemia/reperfusion injury (CIRI) involves reactive oxygen and nitrogen species (ROS and RNS). Despite efficient antioxidant pathways in the brain, hypoxia triggers the production of oxygen free radicals and downregulates ATP, which leads to oxidative stress. Sources of free radicals during CIRI include Ca<sup>2+</sup>-dependent enzymes, phospholipid degradation and mitochondrial enlargement. Upon reperfusion, the abrupt increase of oxygen triggers a massive radical production via enzymes like xantin oxidase (XO), phospholipase A2 (PLA2) and oxide synthases (OS). These enzymes play an essential role in neuronal damage by excitotoxicity, lipoperoxidation, nitrosylation, inflammation and programmed cell death (PCD). Endothelial nitric oxide synthase (eNOS) decreases as compared to neuronal nitric oxide synthase (nNOS). This is associated with neuronal damage, endothelial inflammation, apoptosis and oxidative stress. Strategies promoting activation of eNOS while inhibiting nNOS could offer neuroprotective benefits in CIRI. Understanding and targeting these pathways could mitigate brain damage in ischemia/reperfusion events. Clinically, tissue plasminogen activator (t-PA) has been shown to restore cerebral blood flow. However, serious side effects have been described, including hemorrhagic transformation. Different treatments are currently under investigation to avoid I/R injury. Baicalin has been reported as a potential agent that could improve t-PA adverse effects, which have to do with peroxynitrite synthesis and matrix metalloproteinase (MMP) expression. In this review, CIRI and interventions in oxidative stress are addressed. Special attention is paid to efficient antioxidant mechanisms in the brain and the production of free radicals, especially nNOS-derived nitric oxide (NO). The primary purpose is to describe accessible radical pathways with the activity of Ca<sup>2+</sup>-dependent oxidative enzymes, leading to membrane phospholipids and mitochondrial breakdown. <strong>Key</strong><strong>w</strong><strong>ords</strong>Oxidative stress; cerebral ischemia/reperfusion; nitric oxide; reactive oxygen species; nitric oxide synthase

Ginkgo biloba extract inhibits hippocampal neuronal injury caused by mitochondrial oxidative stress in a rat model of Alzheimer's disease.

Ginkgo biloba extracts (GBE) have been shown to effectively improve cognitive function in patients with Alzheimer's disease (AD). One potential therapeutic strategy for AD is to prevent loss of adult hippocampal neurons. While recent studies have reported that GBE protects against oxidative stress in neurons, the underlying mechanisms remain unclear. In this study, an AD-like rat model was established via bidirectional injection of amyloid beta 25-35 (Aβ25-35; 20 μg) in the hippocampal CA1 region. Learning and memory abilities of experimental rats were AD assessed in response to oral administration of 7.5 g/L or 15 g/L Ginkgo biloba extract 50 (GBE50) solution and the peroxidation phenomenon of hippocampal mitochondria determined via analysis of mitochondrial H2O2 and several related enzymes. Levels of the oxidative stress-related signaling factor cytochrome C (Cyto C), apoptosis-related proteins (Bax, Bcl-2 and caspase-3) and caspase-activated DNase (CAD) were further detected via western blot. 8-Hydroxydeoxyguanosine (8-OHdG), the major product of DNA oxidative stress, was evaluated to analyze DNA status. Our results showed elevated H2O2 levels and monoamine oxidase (MAO) activity, and conversely, a decrease in the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the hippocampus of AD rats. Administration of GBE50 regulated the activities of these three enzymes and induced a decrease in H2O2. GBE50 exerted regulatory effects on abnormally expressed apoptotic proteins in the AD rat hippocampus, enhancing the expression of Bcl-2, inhibiting release of Cyto C from mitochondria, and suppressing the level of caspase-3 (excluding cleaved caspase-3). Furthermore, GBE50 inhibited DNA damage by lowering the generation of 8-OHdG rather than influencing expression of CAD. The collective findings support a protective role of GBE50 in hippocampal neurons of AD-like animals against mitochondrial oxidative stress.

LncRNA ILF3-AS1 mediates oxidative stress and inflammation through miR-504-3p/HMGB1 axis in a cellular model of temporal lobe epilepsy.

Temporal lobe epilepsy (TLE), a prevalent neurological disorder, is associated with hippocampal oxidative stress and inflammation. A recent study reveals that the long noncoding RNA ILF3 divergent transcript (ILF3-AS1) level is elevated in the hippocampus of TLE patients; however, the functional roles of ILF3-AS1 in TLE and underlying mechanisms deserve further investigation. Hence, this study aimed to elucidate whether ILF3-AS1 is involved in the pathogenesis of TLE by regulating oxidative stress and inflammation and to explore its underlying mechanism in vitro. Human hippocampal neurons were subjected to a magnesium-free (Mg2+-free) solution to establish an in vitro model of TLE. The potential binding sites between ILF3-AS1 and miRNA were predicted by TargetScan/Starbase and confirmed by dual luciferase reporter assay. Cell viability and damage were assessed by cell counting kit-8 and lactate dehydrogenase assay kits, respectively. Levels of reactive oxygen species, malondialdehyde, and superoxide dismutase were determined by commercial kits. Levels of Interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-alpha were quantified by enzyme-linked immunosorbent assay. The expressions of gene and protein were determined by quantitative real-time polymerase chain reaction and Western blot analysis. In Mg2+-free-treated hippocampal neurons, both ILF3-AS1 and HMGB1 were highly up-regulated, whereas miR-504-3p was down-regulated. ILF3-AS1 knockdown ameliorated Mg2+-free-induced cellular damage, oxidative stress, and inflammatory response. Bioinformatics analysis revealed that miR-504-3p was a target of ILF3-AS1 and was negatively regulated by ILF3-AS1. MiR-504-3p inhibitor blocked the protection of ILF3-AS1 knockdown against Mg2+-free-induced neuronal injury. Further analysis presented that ILF3-AS1 regulated HMGB1 expression by sponging miR-504-3p. Moreover, HMGB1 overexpression reversed the protective functions of ILF3-AS1 knockdown. Our findings indicate that ILF3-AS1 contributes to Mg2+-free-induced hippocampal neuron injuries, oxidative stress, and inflammation by targeting the miR-504-3p/HMGB1 axis. These results provide a novel mechanistic understanding of ILF3-AS1 in TLE and suggest potential therapeutic targets for the treatment of epilepsy.

Administration of low dose intranasal ketamine exerts a neuroprotective effect on whole brain irradiation injury model in wistar rats.

Exposure to ionizing radiation leads to oxidative stress and neuroinflammation, resulting in neurocognitive impairments. Adverse effects are also associated with glutamate-induced excitotoxicity due to alterations in the composition of glutamate receptors. Ketamine, which is a noncompetitive NMDA glutamate receptor antagonist, has been stated to exert an impact on glutamatergic receptors. This study aims to reveal the possible alleviating or preventive effects of ketamine, which maintains glutamate homeostasis and decreases neurodegeneration, in a radiation-induced neurotoxicity model. Twenty-one female Wistar Queryrats were included in the study and 14 of these underwent whole brain irradiation (IR) with a 20 Gray single dose. Animals were allocated into three groups. Group 1: Normal control; Group 2: Placebo / IR + Saline; Group 3: IR + Ketamine. Ketamine was administered in addition to IR to rats in Group 3. The one-way ANOVA statistical test was used to compare groups. The value of p < 0.05 was considered statistically significant. When administered in addition to irradiation, ketamine treatment significantly increased scores in the three-chamber sociability test, open field test, and passive avoidance learning test. It also raised neuron counts in the hippocampal CA1 and CA3 regions as well as in Purkinje cells, and enhanced levels of brain-derived neurotrophic factor and tyrosine receptor kinase-B. Furthermore, ketamine administration resulted in decreased levels of glial fibrillary acidic protein, malondialdehyde, and tumor necrosis factor-alpha, indicating a reduction in neuroinflammation and oxidative stress. Ketamine exerted a significant protective impact on radiation-induced neurocognitive impairments and enhanced social-memory capacity by reducing neuronal loss, oxidative stress, and neuroinflammation. Our findings suggest that ketamine is beneficial in the treatment or prevention of neurodegeneration via the regulation of the BDNF/TrkB signaling pathway besides decreasing neuroinflammation and blocking NMDA receptors.

Protective effect of crocin-loaded nanoparticles in rats following epileptic seizures: Biochemical, behavioral and histopathological outcomes

Epilepsy is a condition resulting from complex interactions involving excessive neuronal electrical activity and oxidative stress, which can lead to chronic neurological conditions. This study evaluates crocin encapsulated in SLNC for neuroprotective and countering pentylenetetrazole (PTZ) -induced oxidative damage. The rats were pre-treated with SLNC and FC (25, 50 mg/kg/day; P.O.) for 28 days before being induced with PTZ. Various standard tests were conducted to assess their behavioral functions, such as Y-maze, Open field test (OFT), and elevated plus maze (EPM) tests. ELISA measured brain tissue catalase activity (CAT) and nitric oxide status (NO). The expression of Nuclear factor kappa B (NF-κB) and the number of dendrite spines were examined through Immunohistochemical and Golgi–Cox staining, respectively. The Pretreating rats with SLNC plus PTZ significantly boosted memory and reduced anxiety levels in Y-maze, OFT, and EPM tests. In addition, it decreased NO levels and increased CAT levels. SLNC also showed a significant decrease in NF-κB expression and an increase in neurons and the number of spines. The positive effects of SLNC in improving memory and learning deficits after PTZ injection can be attributed to its anti-inflammatory and anti-oxidative effects.

RNA-Seq and metabolomic analysis reveal dynamic response mechanism to hypoxia in the pearl oyster Pinctada fucata martensii

Hypoxia is becoming a stressor in aquatic environments due to human activities and climate change. To reveal the dynamic response mechanisms of pearl oyster, this study investigated transcriptomic and metabolomic changes in pearl oyster (Pinctada fucata martensii) exposed to hypoxia for 2 and 25 days. In total, 488 differentially expressed genes (DEGs) were detected between 2 and 25 days of hypoxia stress. The identified DEGs were primarily associated with Gene Ontology (GO) terms such as "histone H4 acetylation", "DNA methylation", "histone (H3-K9/H4-K20/H3-K27/H3-K4) trimethylation", "positive regulation of ATPase activity", "myosin complex", “microtubule-based processes", "actin cytoskeleton", and "glutathione peroxidase activity", as well as KEGG pathways such as "neuroactive ligand-receptor interactions", "ECM-receptor interactions", and "apoptosis". We also identified 77 significantly differential metabolites (SDMs), which were associated with 32 metabolic pathways, including arginine and proline metabolism, glycerophospholipid metabolism, aminoacyl-tRNA biosynthesis, and sphingolipid metabolism. Integrated DEGs and SDMs analyses showed that pearl oysters were found to suffer from reduced biomineralization, hindered cytoskeletal reorganization, decreased neuronal excitability, apoptosis, immune inhibition, and oxidative stress after 25 days of hypoxic stress. Overall, these results help to elucidate the complex responses of pearl oysters to hypoxic conditions.

A Biocompatible Hydrogen-Bonded Organic Framework (HOF) as Sonosensitizer and Artificial Enzyme for In-Depth Treatment of Alzheimer's Disease.

Current phototherapeutic approaches for Alzheimer's disease (AD) exhibit restricted clinical outcomes due to the limited physical penetration and comprised brain microenvironment of noninvasive nanomedicine. Herein, a hydrogen-bonded organic framework (HOF) based sonosensitizer is designed and synthesized. Mn-TCPP, a planar molecule where Mn2+ ion is chelated in the core with a large p-conjugated system and 4 carboxylate acid groups, has been successfully used as building blocks to construct an ultrasound-sensitive HOF (USI-MHOF), which can go deep in the brain of AD animal models. The both in vitro and in vivo studies indicate that USI-MHOF can generate singlet oxygen (1O2) and oxidize β-amyloid (Aβ) to inhibit aggregation, consequently attenuating Aβ neurotoxicity. More intriguingly, USI-MHOF exhibits catalase (CAT)- and superoxide dismutase (SOD)-like activities, mitigating neuron oxidative stress and reprograming the brain microenvironment. For better crossing the blood-brain barrier (BBB), the peptide KLVFFAED (KD8) has been covalently grafted to USI-MHOF for improving BBB permeability and Aβ selectivity. Further, in vivo experiments demonstrate a significant reduction of the craniocerebral Aβ plaques and improvement of the cognition deficits in triple-transgenic AD (3×Tg-AD) mice models following deep-penetration ultrasound treatment. The work provides the first example of an ultrasound-responsive biocompatible HOF as non-invasive nanomedicine for in-depth treatment of AD.

Targeting Oxidative Stress in Neurodegenerative Disorders: A Novel Role for PCSK9 Inhibition?

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that regulates cholesterol levels by lysosomal low-density lipoprotein receptor (LDLR) degradation and has recently been associated with the production of neuronal oxidative stress and age-associated cardiovascular dysfunction. Since increased oxidative stress and vascular dysfunction are implicated in the pathology of aging and various neurodegenerative disorders, targeting PCSK9 may offer a promising therapeutic avenue for addressing these conditions. While the precise mechanisms through which PCSK9 contributes to vascular and neuronal oxidative stress in the brain remain elusive, preclinical studies have highlighted a neuroprotective effect linked to PCSK9 inhibition. This inhibition has shown promise in reducing oxidative stress, mitigating neuroinflammation, and alleviating neuropathological changes, thus underscoring the therapeutic potential of this approach in addressing neurodegenerative conditions.

The Role of Gut Microbiota in the Neuroprotective Effects of Selenium in Alzheimer's Disease.

The objective of the present review was to provide a timely update on the molecular mechanisms underlying the beneficial role of Se in Alzheimer's disease pathogenesis, and discuss the potential role of gut microbiota modulation in this neuroprotective effect. The existing data demonstrate that selenoproteins P, M, S, R, as well as glutathione peroxidases and thioredoxin reductases are involved in regulation of Aβ formation and aggregation, tau phosphorylation and neurofibrillary tangles formation, as well as mitigate the neurotoxic effects of Aβ and phospho-tau. Correspondingly, supplementation with various forms of Se in cellular and animal models of AD was shown to reduce Aβ formation, tau phosphorylation, reverse the decline in brain antioxidant levels, inhibit neuronal oxidative stress and proinflammatory cytokine production, improve synaptic plasticity and neurogenesis, altogether resulting in improved cognitive functions. In addition, most recent findings demonstrate that these neuroprotective effects are associated with Se-induced modulation of gut microbiota. In animal models of AD, Se supplementation was shown to improve gut microbiota biodiversity with a trend to increased relative abundance of Lactobacillus, Bifidobacterium, and Desulfivibrio, while reducing that of Lachnospiracea_NK4A136, Rikenella, and Helicobacter. Moreover, the relative abundance of Se-affected taxa was significantly associated with Aβ accumulation, tau phosphorylation, neuronal oxidative stress, and neuroinflammation, indicative of the potential role of gut microbiota to mediate the neuroprotective effects of Se in AD. Hypothetically, modulation of gut microbiota along with Se supplementation may improve the efficiency of the latter in AD, although further detailed laboratory and clinical studies are required.

Impact of Cyclosporine A on Cognitive Functions and Neuronal Oxidative Stress, Apoptosis and Inflammatory Markers in Rats

Cyclosporine A (CYP-A), a potent immunosuppressive agent, significantly impacts organ transplantation and the treatment of autoimmune disorders, and its ability to control autoimmune reactions and prevent organ rejection has made it indispensable in contemporary medicine. However, its negative effects, such as nephrotoxicity, neurotoxicity, and hepatotoxicity, limit its usefulness. The study investigated the effects of CYP-A on cognitive and neurological functions in rats over a fifteen-day period. Four groups of six rats each were treated with normal saline (control) or varying doses of CYP-A (20, 50, and 100 mg/kg). Behavioural assessments included the elevated plus maze (EPM) and novel object recognition (NOR) tests used to evaluate memory capabilities and recognition memory respectively, and the Y-maze assessed the exploration of a new environment and navigational skills. Post-experiment, brain tissues were analyzed for apoptosis, neuroinflammation, and oxidative stress markers to assess potential neurotoxicity. Histopathological analysis was also performed to provide further insights into CYP-A's effects on brain tissue. Compared to the control rats, there were significant changes in the memory parameters with two higher doses (50 and 100 mg/kg). The findings indicated that MDA, TNF-α, NF-κB, PGE2, and Caspase-3 levels increased significantly in the CYP-A 100 treatment compared to the control animals. However, a significant drop was observed in CAT, and GSH when comparing the CYP-A 100 group to the control rats. Conversely, comparable alterations were also noted in MDA, TNF-α, PGE2, Bcl-2, Bax, and Caspase-3 levels between the CYP-A 100 and other treatment groups (20 or 50 mg/kg). Moreover, the histopathological analysis revealed that as compared to the control rats, CYP-A at three different dose levels (20, 50, or 100 mg/kg, p.o.) exhibited various changes. It was noticed that as the dose levels of CYP-A increased, there was a corresponding increase in brain tissue architectural changes. Precisely, the group treated with 100 mg/kg exhibited severe haemorrhages, inflammation, necrosis, and congestion compared to the control animals. In conclusion, CYP-A induces neurotoxicity, leading to oxidative stress, neuroinflammation, apoptosis, and cognitive deficits. Understanding the underlying mechanisms of this neurotoxicity is crucial to mitigating the adverse effects of CYP-A and improving patient outcomes. Further research is needed to develop targeted therapies and enhance the safe use of CYP-A.

Computational modeling of neuronal nitric oxide synthase biochemical pathway: A mechanistic analysis of tetrahydrobiopterin and oxidative stress

Neuronal cell dysfunction plays an important role in neurodegenerative diseases. Oxidative stress can disrupt the redox balance within neuronal cells and may cause neuronal nitric oxide synthase (nNOS) to uncouple, contributing to the neurodegenerative processes. Experimental studies and clinical trials using nNOS cofactor tetrahydrobiopterin (BH4) and antioxidants in neuronal cell dysfunction have shown inconsistent results. A better mechanistic understanding of complex interactions of nNOS activity and oxidative stress in neuronal cell dysfunction is needed. In this study, we developed a computational model of neuronal cell using nNOS biochemical pathways to explore several key mechanisms that are known to influence neuronal cell redox homeostasis. We studied the effects of oxidative stress and BH4 synthesis on nNOS nitric oxide production and biopterin ratio (BH4/total biopterin). Results showed that nNOS remained coupled and maintained nitric oxide production for oxidative stress levels less than 230 nM/s. The results showed that neuronal oxidative stress above 230 nM/s increased the degree of nNOS uncoupling and introduced instability in the nitric oxide production. The nitric oxide production did not change irrespective of initial biopterin ratio of 0.05–0.99 for a given oxidative stress. Oxidative stress resulted in significant reduction in BH4 levels even when nitric oxide production was not affected. Enhancing BH4 synthesis or supplementation improved nNOS coupling, however the degree of improvement was determined by the levels of oxidative stress and BH4 synthesis. The results of our mechanistic analysis indicate that there is a potential for significant improvement in neuronal dysfunction by simultaneously increasing BH4 levels and reducing cellular oxidative stress.

Early oxidative stress and DNA damage in Aβ-burdened hippocampal neurons in an Alzheimer’s-like transgenic rat model

Oxidative stress is a key contributor to AD pathology. However, the earliest role of pre-plaque neuronal oxidative stress, remains elusive. Using laser microdissected hippocampal neurons extracted from McGill-R-Thy1-APP transgenic rats we found that intraneuronal amyloid beta (iAβ)-burdened neurons had increased expression of genes related to oxidative stress and DNA damage responses including Ercc2, Fancc, Sod2, Gsr, and Idh1. DNA damage was further evidenced by increased neuronal levels of XPD (Ercc2) and γH2AX foci, indicative of DNA double stranded breaks (DSBs), and by increased expression of Ercc6, Rad51, and Fen1, and decreased Sirt6 in hippocampal homogenates. We also found increased expression of synaptic plasticity genes (Grin2b (NR2B), CamkIIα, Bdnf, c-fos, and Homer1A) and increased protein levels of TOP2β. Our findings indicate that early accumulation of iAβ, prior to Aβ plaques, is accompanied by incipient oxidative stress and DSBs that may arise directly from oxidative stress or from maladaptive synaptic plasticity.

The role of the AMPK/ERK1/2 signaling pathway in neuronal oxidative stress damage following cerebral ischemia-reperfusion

Cerebral ischemia-reperfusion injury involves a series of pathophysiological processes that occur when blood supply is restored after cerebral vascular obstruction, leading to neuronal damage. The AMPK/ERK1/2 signaling pathway has been identified as crucial in this process, although the exact mechanisms underlying the induction of ischemia-reperfusion injury remain unclear. In this study, we investigated the involvement of the AMPK/ERK1/2 signaling pathway in neuronal oxidative stress damage following cerebral ischemia-reperfusion by establishing animal and cell models. Our experimental results demonstrated that cerebral ischemia-reperfusion leads to oxidative stress damage, including cell apoptosis and mitochondrial dysfunction. Moreover, further experiments showed that inhibition of AMPK and ERK1/2 activity, using U0126 and Compound C respectively, could alleviate oxidative stress-induced cellular injury, improve mitochondrial morphology and function, reduce reactive oxygen species levels, increase superoxide dismutase levels, and suppress apoptosis. These findings clearly indicate the critical role of the AMPK/ERK1/2 signaling pathway in regulating oxidative stress damage and cerebral ischemia-reperfusion injury. The discoveries in this study provide a theoretical basis for further research and development of neuroprotective therapeutic strategies targeting the AMPK/ERK1/2 signaling pathway.

Protective Effect of Arzanol against H2O2-Induced Oxidative Stress Damage in Differentiated and Undifferentiated SH-SY5Y Cells.

Oxidative stress can damage neuronal cells, greatly contributing to neurodegenerative diseases (NDs). In this study, the protective activity of arzanol, a natural prenylated α-pyrone-phloroglucinol heterodimer, was evaluated against the H2O2-induced oxidative damage in trans-retinoic acid-differentiated (neuron-like) human SH-SY5Y cells, widely used as a neuronal cell model of neurological disorders. The pre-incubation (for 2 and 24 h) with arzanol (5, 10, and 25 μM) significantly preserved differentiated SH-SY5Y cells from cytotoxicity (MTT assay) and morphological changes induced by 0.25 and 0.5 mM H2O2. Arzanol reduced the generation of reactive oxygen species (ROS) induced by 2 h oxidation with H2O2 0.5 mM, established by 2',7'-dichlorodihydrofluorescein diacetate assay. The 2 h incubation of differentiated SH-SY5Y cells with H2O2 determined a significant increase in the number of apoptotic cells versus control cells, evaluated by propidium iodide fluorescence assay (red fluorescence) and NucView® 488 assay (green fluorescence). Arzanol pre-treatment (2 h) exerted a noteworthy significant protective effect against apoptosis. In addition, arzanol was tested, for comparison, in undifferentiated SH-SY5Y cells for cytotoxicity and its ability to protect against H2O2-induced oxidative stress. Furthermore, the PubChem database and freely accessible web tools SwissADME and pkCSM-pharmacokinetics were used to assess the physicochemical and pharmacokinetic properties of arzanol. Our results qualify arzanol as an antioxidant agent with potential neuroprotective effects against neuronal oxidative stress implicated in NDs.

Oral administration of crocin-loaded solid lipid nanoparticles inhibits neuroinflammation in a rat model of epileptic seizures by activating SIRT1 expression.

Epilepsy is a group of chronic neurological diseases caused by a complex set of neuronal hyper electrical activities and oxidative stress of neurons. Crocin is a natural bioactive agent of saffron with different pharmacological properties and low bioavailability. This study aimed to evaluate crocin-loaded solid lipid nanoparticles (SLNC) for neuroprotection activity and efficacy against pentylenetetrazol (PTZ)- induced epilepsy. The rats were pretreated with SLNC and pure-crocin (PC; 25 and 50 mg/kg/day; P.O.) for 28 days before PTZ induction. Behavioral functions were evaluated by passive avoidance learning (PAL) tasks. Then, total antioxidant capacity (TAC), malondialdehyde (MDA), and pro-inflammatory factors were measured in the brain tissue using ELISA kits. Gene expression levels were analyzed with real-time polymerase chain reaction and immunohistochemical assay was used to assess the protein expression of sirtuin1 SIRT 1). SLNC was prepared with an average particle size of 98.25 nm and 98.33% encapsulation efficiency. Memory deficit improved in rats treated with SLNC. Administering SLNC at 25 and 50 mg/kg significantly reduced MDA and proinflammatory cytokines while increasing TAC. Additionally, administering SLNC before treatment increased the levels of SIRT1, peroxisome proliferator-activated receptor coactivator 1α, cAMP-regulated enhancer binding protein, and brain-derived neurotrophic factor. Furthermore, SLNC administration resulted in the downregulation of caspase-3 and inflammation factor expression. Overall, the obtained results showed that SLNC has better protective effects on oxidative stress in neurons, neurocognitive function, and anti-apoptotic and neuromodulatory activity than PC, suggesting that it is a promising therapeutic strategy for inhibiting seizures.

Naringenin mitigates nanoparticulate-aluminium induced neuronal degeneration in brain cortex and hippocampus through downregulation of oxidative stress and neuroinflammation

Alumunium usage and toxicity has been a global concern especially an increased use of nanoparticulated aluminum (Al-NPs) products from the environment and the workplace. Al degrades in to nanoparticulate form in the environment due to the routine process of bioremediation in human body. Al-NPs toxicity plays key role in the pathophysiology of neurodegeneration which is characterised by the development of neurofibrillary tangles and neuritic plaques which correlates to the Alzheimer's disease. This study evaluated the Al-NPs induced neurodegeneration and causative behavioral alterations due to oxidative stress, inflammation, DNA damage, β-amyloid aggregation, and histopathological changes in mice. Furthermore, the preventive effect of naringenin (NAR) as a potent neuroprotective flavonoid against Al-NPs induced neurodegeneration was assessed. Al-NPs were synthesized and examined using FTIR, XRD, TEM, and particle size analyzer. Mice were orally administered with Al-NPs (6 mg/kg b.w.) followed by NAR treatment (10 mg/kg b.w. per day) for 66 days. The spatial working memory was determined by novel object recognition, T-maze, Y-maze, and Morris Water Maze tests. We measured nitric oxide, advanced oxidation of protein products, protein carbonylation, lipid peroxidation, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, reduced glutathione, oxidised glutathione, and acetylcholine esterase, as well as cytokines analysis, immunohistochemistry, and DNA damage. Al-NPs significantly reduced the learning memory power, increased oxidative stress, reduced antioxidant enzymatic activity, increased DNA damage, altered the levels of cytokines, and increased β-amyloid aggregation in the cortex and hippocampus regions of the mice brain. These neurobehavioral impairments, neuronal oxidative stress, and histopathological alterations were significantly attenuated by NAR supplementation. In conclusion, Al-NPs may be potent neurotoxic upon exposure and that NAR could serve as a potential preventive measure in the treatment and management of neuronal degeneration.

Therapeutic Potential of Nitrogen-Doped Rutin-Bound Glucose Carbon Dots for Alzheimer's Disease.

The blood-brain barrier (BBB) prevents the use of many drugs for the treatment of neurological disorders. Recently, nitrogen-doped carbon dots (NCDs) have emerged as promising nanocarriers to cross BBB. The primary focus of our study was to evaluate the effectiveness of NCDs for the symptomatic treatment of Alzheimer's disease (AD). In this study, we developed and characterized NCDs bound to rutin, a flavonoid with known benefits for AD. Despite its benefits, the transportation of rutin via NCDs for AD therapy has not been explored previously. We characterized the particles using FTIR and UV-visible spectroscopy followed by atomic force microscopy. Once the design was optimized and validated, we performed in vivo testing via a hemolytic assay to optimize the dosage. Preliminary in vitro testing was performed in AlCl3-induced rat models of AD whereby a single dose of 10 mg/kg NCDs-rutin was administered intraperitoneally. Interestingly, this single dose of 10 mg/kg NCDs-rutin produced the same behavioral effects as 50 mg/kg rutin administered intraperitoneally for 1 month. Similarly, histological and biomarker profiles (SOD2 and TLR4) also presented significant protective effects of NCDs-rutin against neuronal loss, inflammation, and oxidative stress. Hence, NCDs-rutin are a promising approach for the treatment of neurological diseases.

Ameliorative effect of vanillic acid against scopolamine-induced learning and memory impairment in rat via attenuation of oxidative stress and dysfunctional synaptic plasticity

Alzheimer’s disease (AD) is characterized by cognitive impairment, loss of learning and memory, and abnormal behaviors. Scopolamine (SCOP) is a non-selective antagonist of muscarinic acetylcholine receptors that exhibits the behavioral and molecular hallmarks of AD. Vanillic acid (VA), a phenolic compound, is obtained from the roots of a traditional plant called Angelica sinensis, and has several pharmacologic effects, including antimicrobial, anti-inflammatory, anti-angiogenic, anti-metastatic, and antioxidant properties. Nevertheless, VA’s neuroprotective potential associated with the memory has not been thoroughly investigated. Therefore, this study investigated whether VA treatment has an ameliorative effect on the learning and memory impairment induced by SCOP in rats. Behavioral experiments were utilized to assess the learning and memory performance associated with the hippocampus. Using western blotting analysis and assay kits, the neuronal damage, oxidative stress, and acetylcholinesterase activity responses of hippocampus were evaluated. Additionally, the measurement of long-term potentiation was used to determine the function of synaptic plasticity in organotypic hippocampal slice cultures. In addition, the synaptic vesicles’ density and the length and width of the postsynaptic density were evaluated using electron microscopy. Consequently, the behavioral, biochemical, electrophysiological, and ultrastructural analyses revealed that VA treatment prevents learning and memory impairments caused by SCOP in rats. The study’s findings suggest that VA has a neuroprotective effect on SCOP-induced learning and memory impairment linked to the hippocampal cholinergic system, oxidative damage, and synaptic plasticity. Therefore, VA may be a prospective therapeutic agent for treating AD.