da Silva Lemos I, de Vasconcelos FFP, da Silva Lodetti G
… +6 more, Alano CG, Rigo FK, Scussel R, Baia FH, Rico EP, Streck EL
Neurotox Res
· 2025 Oct · PMID 41117875
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Tyrosinemia type II (Richner-Hanhart syndrome) is a rare disorder caused by mutations in the TAT gene, leading to elevated blood tyrosine and impaired metabolism. It presents with oculocutaneous symptoms, retinal tyrosin...Tyrosinemia type II (Richner-Hanhart syndrome) is a rare disorder caused by mutations in the TAT gene, leading to elevated blood tyrosine and impaired metabolism. It presents with oculocutaneous symptoms, retinal tyrosine crystals, and neurological issues. Elevated tyrosine disrupts brain metabolism, neurotransmitters, and neurotrophic factors, causing neuroinflammation and affecting brain function. The exact mechanism of neurological damage is unclear, and the impact of dietary intervention on cognition is uncertain. While rodent models are commonly used, zebrafish are emerging as a cost-effective, genetically similar alternative for studying tyrosinemia type II. Thus, this study aims to determine whether acute exposure of zebrafish to elevated tyrosine concentrations can reproduce early central nervous system alterations associated with tyrosinemia type II. Zebrafish were exposed via immersion to 1 mM or 2 mM tyrosine for 1-24 h, with a total of 180 animals used across assays. Behavioral analysis was conducted using the novel tank test, and cholinergic and oxidative stress markers were assessed. Brain tyrosine levels were measured centrally. Exposure to 1 mM tyrosine for 24 h resulted in the highest brain accumulation, suggesting a non-linear dose-response. Behavioral testing revealed decreased locomotor activity and exploratory behavior, and ChAT activity was reduced in both exposure groups. No significant changes were observed in oxidative stress or protein damage. These findings indicate that acute tyrosine exposure induces early behavioral and cholinergic alterations without detectable oxidative stress, supporting the use of zebrafish as a preliminary model to study early neurochemical disturbances such in tyrosinemia type II. Further studies should explore different life stages, sex-specific responses, chronic exposure, and precise tyrosine kinetics, including potential non-linear effects due to the LAT1 transporter, to clarify mechanisms underlying neurotoxicity and improve translational relevance.
Cecchini MS, Bourckhardt GF, de Melo MS
… +1 more, Nazari EM
Neurotox Res
· 2025 Oct · PMID 41111098
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Mitochondrial dynamics, including fusion and fission, are essential for neural cell function and survival during central nervous system development. These processes are vital for eye formation, which requires high energy...Mitochondrial dynamics, including fusion and fission, are essential for neural cell function and survival during central nervous system development. These processes are vital for eye formation, which requires high energy to support cellular events, such as proliferation, differentiation, and apoptosis. However, different conditions can disrupt the normal development of the eye, such as hyperhomocysteinemia (HHcy), a metabolic disorder characterized by elevated homocysteine (Hcy) levels. This study aimed to evaluate the effects of HHcy on eye development of Gallus domesticus. Fertilized eggs were treated with 20 µmol Hcy at embryonic day 2 (E2), with analyses conducted at E6 and E10 using a combination of survival analysis, transmission electron microscopy, flow cytometry for mitochondrial proteins and autophagy markers, and cell viability assay, providing a comprehensive evaluation of HHcy toxicity. A significant 40% reduction in the survival rate relative to control was observed in HHcy-treated embryos. Although eye diameter remained unchanged, ultrastructural analyses revealed mitochondrial damage, including membrane rupture, loss, and disorganization of the cristae, induced by the exposure at both embryonic ages. Analysis of proteins involved in mitochondrial dynamics showed increased Drp1 (fission) and decreased Mfn1 and Mfn2 (fusion) in HHcy-treated embryos. At E10, these changes were accompanied by an increased number of mitochondrial profiles and reduced mitochondrial area. HHcy also induced a reduction in cell viability, highlighting its cytotoxic effects, particularly on mitochondria. Additionally, increased cytoplasmic vesicles and autophagy were observed in HHcy-treated embryos. These findings indicate that mitochondria are key targets of HHcy, with mitochondrial dynamics and ultrastructural integrity significantly impaired by the exposure. These changes highlight the harmful effects of high Hcy levels on embryonic development and eye formation, providing insights into its pathogenic effects.
Neurotox Res
· 2025 Oct · PMID 41108347
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Retinoic Acid (RA) induces differentiation and regulates gene expression through three subtypes (α, β, γ) of the nuclear retinoid receptor heterodimer (RAR/RXR), which also function as transcription factors. Earlier, we...Retinoic Acid (RA) induces differentiation and regulates gene expression through three subtypes (α, β, γ) of the nuclear retinoid receptor heterodimer (RAR/RXR), which also function as transcription factors. Earlier, we reported the long intergenic noncoding RNAs (LINC-RBE and LINC-RSAS) induced by All-Trans Retinoic Acid (ATRA) in cultured primary hippocampal neurons from adult rat brain at transcriptional and post-transcriptional levels, respectively. In this study, we report that ~ 25% of the human neuroblastoma (SH-SY5Y) cells were differentiated by 1 µM ATRA-treatment within 72 h showing extension of neurites from spindle-shaped cells demonstrating neuronal differentiation. Expression of RARβ and interferon regulatory factor-1 (IRF-1) mRNAs was significantly upregulated up to 16xfold at 10 h and 2.6xfold at 8 h by 1 µM ATRA-treatment, respectively. This indicated activation of the RA-signaling pathway in these cells. With a transfection efficiency of ~ 40%, overexpression of LINC-RBE and LINC-RSAS caused ~ 34% and ~ 33% inhibition of cell proliferation, respectively, with an increase in cell death and ~ 10% reduction in number of cells in G1-phase of cell cycle. ATRA-treatment alone caused ~ 40% inhibition of cell proliferation, and induced ~ 66% of cells to G1-phase arrest. Combined effect of LINC-RSAS + ATRA further enhanced inhibition of cell proliferation by additional ~ 32%, whereas LINC-RBE, ATRA and LINC-RBE + ATRA showed similar effects indicating distinct effects and mechanisms of their actions. Moreover, overexpression of these lncRNAs led to fourfold increase in genomicDNA breakage/damage in these cells. Thus it showed an unique relationship between lncRNA and RA during neuronal differentiation, most likely involving regulation of gene expression.
Paudel YN, Blair RE, Hawkins E
… +7 more, Halquist MS, Morgan M, Funderburk J, Calvano D, Koblinski J, Richard H, Deshpande LS
Neurotox Res
· 2025 Oct · PMID 41108329
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Lethal organophosphate (OP) exposure leads to status epilepticus (SE), which, despite standard-of-care (SOC) therapy, is associated with acute mortality and long-term morbidities. Neuronal injury and inflammation are rep...Lethal organophosphate (OP) exposure leads to status epilepticus (SE), which, despite standard-of-care (SOC) therapy, is associated with acute mortality and long-term morbidities. Neuronal injury and inflammation are reported following OP-SE, and drugs targeted at these processes have produced beneficial outcomes. Verapamil (VPM) is a calcium-channel blocker used as an antihypertensive drug and has been shown to exhibit neuroprotective and anti-inflammatory actions in experimental models of CNS injuries. Here, we investigated the feasibility of an adjunctive intramuscular (i.m.) VPM therapy in OP Diisopropyl Fluorophosphate (DFP)-induced SE. We also investigated the safety and toxicity of i.m. VPM and compared its pharmacokinetic (PK) profile to oral (p.o.) administration. Rats were injected with DFP (4 mg/kg, s.c.). One minute later, SOC treatment consisting of atropine (0.5 mg/kg, i.m.) and pralidoxime chloride (2-PAM; 25 mg/kg, i.m.) were administered, and at 1-hour post-SE, midazolam (1.78 mg/kg, i.m.) was given. Rats that met the behavioral SE severity criteria (Racine 4-5) were randomized into two treatment groups: those receiving saline (SAL) or VPM (10 mg/kg, i.m. bid, 3 days). Histological analysis was conducted to assess neuronal injury and injection-site pathology. In a separate group of rats, PK studies were conducted on blood and brain homogenates treated once with saline or VPM (10 mg/kg, p.o. or i.m.). Our data demonstrated that following DFP-SE, i.m. VPM achieved higher blood and brain levels and exhibited a favorable PK profile compared to p.o. route. VPM therapy did not cause significant muscle pathology and produced a robust neuroprotective response. Neuroinflammatory markers and long-term behavioral outcomes were not included in this study. Our studies provide evidence that the i.m. route is an effective method for delivering VPM following SE, producing significant neuroprotective outcomes compared to treatment with the standard-of-care alone in OP-SE.
Liu J, Gu Z, Li H
… +11 more, Yin Q, Yi P, Wang H, Jia H, Li C, Qin J, Xu F, Tian G, Wang L, Mi J, Yang C
Neurotox Res
· 2025 Oct · PMID 41091226
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Novelty-seeking (NS) refers to the tendency of humans and animals to explore novel and unfamiliar stimuli and environments. It is a core feature of Attention Deficit Hyperactivity Disorder (ADHD) and associated with mult...Novelty-seeking (NS) refers to the tendency of humans and animals to explore novel and unfamiliar stimuli and environments. It is a core feature of Attention Deficit Hyperactivity Disorder (ADHD) and associated with multiple psychiatric disorders. Recent researches indicated that NS behavior has an effect on reward-related learning. The hippocampus is a core brain region linked to reward-related learning and memory. However, how the hippocampal proteome modulates NS behavior remain largely elusive. In current study, we identified 165 differentially expressed proteins in the hippocampus between high and low novelty response mice with mass-spectrometry-based proteomics. Among these proteins, the over-expression of Tenascin-R (TNR) in high novelty response mice was verified with Western Blot and Immunofluorescence imaging. Moreover, systematic genetic analysis based on the BXD strains showed the expression of TNR is genetically cis-regulation. Further, gene co-expression analysis revealed that TNR has a negative connection with the expression of dopamine receptor D2 (DRD2) (P = 0.003, r = -0.298). And the knockdown of TNR enhanced the expression of DRD2 in vitro. Finally, we constructed a correlation network to exhibit the links among TNR gene variant, expression of TNR and DRD2, and NS related behaviors. Our study provides a novel hippocampal biomarker with preliminary insights into its association with the dopaminergic synaptic pathway. ROC analysis further confirms TNR's robust discriminatory power for distinguishing novel open field behavior, a key NS - related phenotype, which may be a new strategy for diagnosis of NS-related traits.
Neurotox Res
· 2025 Oct · PMID 41065999
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The coronavirus disease 2019 (COVID-19) pandemic has brought significant challenges to global health, not only due to respiratory symptoms but also due to its impact on psychiatric disorders. Understanding the biological...The coronavirus disease 2019 (COVID-19) pandemic has brought significant challenges to global health, not only due to respiratory symptoms but also due to its impact on psychiatric disorders. Understanding the biological mechanisms underlying psychiatric manifestations in individuals with COVID-19 is crucial. This study aimed to investigate potential alterations in caspase 3 and 8 levels, as well as brain-derived neurotrophic factor (BDNF) levels, in individuals with COVID-19. The association of these markers with mental health was also assessed. A cross-sectional study was conducted, including individuals with COVID-19 and those without the disease. The stress levels were higher in individuals with COVID-19. Caspase 3 and 8 and BDNF levels were increased in individuals with COVID-19 compared to individuals without COVID-19. No significant differences were found in caspase 3 and 8 and BDNF levels between moderate/severe and asymptomatic/mild symptoms of COVID-19. The results indicate that no significant differences were observed between the diagnosis of anxiety disorders and the levels of markers. However, higher caspase 3 levels in individuals without anxiety and COVID-19 were found. No significant associations between the diagnosis of major depressive disorder or psychiatric symptoms and caspase 3, caspase 8, and BDNF levels were found. The results indicate that, although caspase 3, caspase 8, and BDNF levels are increased in individuals with COVID-19, these elevations are not associated with the severity of COVID-19 symptoms or psychiatric conditions and symptoms in post-COVID-19. These findings suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may influence cellular activity and neurotrophic markers, but that other factors likely contribute to psychiatric disorders.
Marcuzzo MB, de Andrade Silveira J, Pinheiro CV
… +9 more, da Rosa JS, Zemniaçak AB, Brondani M, Kist NS, Hoffmann CIH, Schioth HB, Amaral AU, Wajner M, Leipnitz G
Elevated hydrogen sulfide (sulfide) levels are observed in tissues, including the brain, of patients with ethylmalonic encephalopathy. Clinical manifestations of this disorder involve severe neurological symptoms and abn...Elevated hydrogen sulfide (sulfide) levels are observed in tissues, including the brain, of patients with ethylmalonic encephalopathy. Clinical manifestations of this disorder involve severe neurological symptoms and abnormalities such as developmental delay, pyramidal and extrapyramidal signs, cortical atrophy and basal ganglia lesions. To elucidate the pathophysiology of basal ganglia alterations, we investigated the effects of sulfide on bioenergetics, redox status and mitochondrial quality control in the striatum of Wistar rats. After placing the rat in a stereotaxic apparatus, a single intrastriatal administration of sulfide (NaHS; 2 or 4 µmol) or PBS (control) was performed. Thirty minutes after the administration, the rats were euthanized, and the striatum was used for the determination of biochemical parameters. Sulfide administration, at both doses, altered the activities of antioxidant enzymes. At the lowest dose, sulfide showed a strong tendency toward increased activity of citrate synthase. Furthermore, the highest dose of sulfide also reduced respiratory chain complex IV activity and mitochondrial respiration with NADH- and FADH-linked substrates. Levels of Nrf2, the main factor that regulates the expression of antioxidant defenses, were also reduced by 4 µmol of sulfide. The metabolite further increased the content of MFN1, suggesting mitochondrial fusion. Additionally, sulfide elevated Parkin and TBC1D15 and reduced LC3 levels, indicative of mitophagy dysregulation. The content of markers of mitochondrial mass and fission were not changed. Our study shows that high levels of sulfide in the striatum of rats affect bioenergetics, redox status and mitochondrial quality control. We suggest that these pathomechanisms are involved in the pathophysiology of basal ganglia alterations verified in ethylmalonic encephalopathy.
Arsenic (As) contamination of groundwater in some parts of Bangladesh has become a major threat to human health. Chronic exposure to As leads to anxiety development, memory impairment, and muscle weakness in humans and e...Arsenic (As) contamination of groundwater in some parts of Bangladesh has become a major threat to human health. Chronic exposure to As leads to anxiety development, memory impairment, and muscle weakness in humans and experimental animals. Panax ginseng (PG) is an herb utilized for multiple health-related applications. Furthermore, regular exercise (Ex) can reduce the risk of various diseases, and is also effective against heavy metal-associated neurotoxicity. Swiss albino mice were divided into five groups (n = 6) to evaluate the protective effects of Ex and PG (50 mg/kg body weight) supplementation against As-induced (10 mg/kg body weight) muscular weakness and neurobehavioral Changes for 60 days. Mice exposed to As showed weaker muscular strength, impaired memory and increased anxiety-like behavior along with the alteration of biochemical parameters related muscular weakness and neurobehavioral changes compared to control mice. However, As + Ex + PG-exposed mice showed significantly (p < 0.05) better performances in all behavioral tests compared to mice exposed to As alone. Additionally, compared to As-exposed mice, As + Ex + PG-exposed mice showed significantly improved (p < 0.05) activity of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), superoxide dismutase (SOD), and reduced glutathione reductase (rGR) in brain, while serum levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were reduced. Furthermore, levels of nuclear factor erythroid 2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), and interleukin-10 (IL-10) levels were increased, while interleukin-6 (IL-6) levels were decreased in brain tissue of As + Ex + PG-exposed mice compared to As-exposed mice. The results of this study suggest that Ex with PG supplementation can attenuate As-induced muscle weakness, cognitive disorder and anxiety development, possibly through the up-regulation of the Nrf2-HO-1 pathway in the As-exposure mice.
Rotenone, often used to experimentally induce Parkinson's disease in rodents, is a well-known neurotoxic pesticide. One of the most common non-motor symptoms in Parkinson's patients is gastrointestinal dysfunction. There...Rotenone, often used to experimentally induce Parkinson's disease in rodents, is a well-known neurotoxic pesticide. One of the most common non-motor symptoms in Parkinson's patients is gastrointestinal dysfunction. Therefore, protecting the gastrointestinal system plays an important role in the onset and progression of the disease. In this study, both the effects of Rotenone on the stomach and small intestine and the possible protective role of Alpha Pinene against Rotenone toxicity, were investigated. Sixty adult male Sprague-Dawley rats were randomly divided into five groups as Control, Vehicle, Alpha Pinene (50 mg/kg/day), Rotenone (2 mg/kg/day) and Rotenone + Alpha Pinene. At the end of the 28-day experimental period, the stomach and jejunum tissues were examined using histological (haematoxylin-eosin and alcian blue-PAS stainings), biochemical (malondialdehyde, zonulin and Fatty Acid Binding Protein-2 levels) and molecular (Keap1, Nrf2 and HO-1 mRNA levels) techniques. While the data showed the presence of oxidative stress and impaired intestinal permeability in the stomach and jejunum tissues in the Rotenone group, these symptoms were observed to be alleviated in the Rotenone + Alpha Pinene group. This study reveals that Alpha Pinene may be a valuable herbal organic compound for the protection of the stomach and intestine and the reduction of complaints in diseases affecting the gastrointestinal system such as Parkinson's disease.
Gallo-Soljancic P, De Stefano ME, Gonzalez-Cuello AM
… +3 more, Fernandez-Villalba E, Godderis L, Herrero MT
Neurotox Res
· 2025 Jul · PMID 40613933
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This study investigates the effects of an acute 1-metil 4-fenil 1,2,3,6-tetraidro-piridina (MPTP) treatment, a known inducer of parkinsonism, on oxidative stress and epigenetic changes in the mouse ventral midbrain (VM)...This study investigates the effects of an acute 1-metil 4-fenil 1,2,3,6-tetraidro-piridina (MPTP) treatment, a known inducer of parkinsonism, on oxidative stress and epigenetic changes in the mouse ventral midbrain (VM) and striatum. Key markers were analyzed at 4, 8, 24, and 48 h post-injections: the hydroxylated form of the purine guanine (8-hydroxy-2'-deoxyguanosine; 8-OHdG), a marker of oxidative stress; the methylated form of cytosine (5-methylcytosine; 5-mC), associated with gene silencing; the hydroxy methylated form of cytosine (5-hydroxymethylcytosine; 5-hmC), involved in demethylation and gene regulation. The results showed a pronounced decrease in 8-OHdG levels in the VM, suggesting a rapid oxidative stress response, whereas the striatum exhibited a less pronounced response, reflecting regional differences in oxidative stress vulnerability DNA methylation patterns revealed complex and biphasic changes in 5-mC levels in the VM, contrasted with a less pronounced response in the striatum, suggesting disrupted methylation homeostasis and regional epigenetic variability. MPTP treatment also significantly reduced in 5-hmC levels in the VM, pointing to impaired active DNA demethylation and compromised epigenetic flexibility. In contrast, the striatum maintained consistently high 5-hmC levels, reflecting compensatory hydroxymethylation mechanisms specific to this region. These findings highlight pronounced regional differences in oxidative stress vulnerability and epigenetic regulation, with the VM showing heightened sensitivity to oxidative damage and impaired epigenetic flexibility. This underscores the importance of understanding the role of oxidative and epigenetic mechanisms in Parkinson's disease pathophysiology, The changes pave the way for novel therapeutic strategies targeting oxidative DNA damage and epigenetic homeostasis.
Sharma D, Nag TC, Bansal A
… +3 more, Jacob TG, Jain S, Choudhury SD
Neurotox Res
· 2025 Jun · PMID 40512285
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Iron accumulates with aging. This triggers various pathological changes and diseases. We studied the impact of iron administration on mitochondrial iron metabolism in the retina. Control, four-month-old, male Wistar rats...Iron accumulates with aging. This triggers various pathological changes and diseases. We studied the impact of iron administration on mitochondrial iron metabolism in the retina. Control, four-month-old, male Wistar rats (n = 27) received either sterile distilled water (4MC) or ferrous sulphate (500 mg/kg body weight/week) by gavage until 12 months of age (12ME group). Another group of rats, receiving distilled water, was raised until 12 months and served as age-matched control (12MC). We examined the body weight, liver and retinal iron levels, retinal glutathione levels, histology, TEM, immunohistochemistry, and Western blotting of glutathione peroxidase-4 (a marker of ferroptosis), procaspase-3 and mitochondrial ferritin and frataxin, involved in iron regulation. In 12ME rats, there were elevated iron levels in the liver and retina, and decreased retinal glutathione levels, compared to that in 12MC rats. Prussian blue staining and iron estimation indicated iron accumulation in the liver and retina. There was marked degeneration of the retinal pigment epithelium and photoreceptor cells, resulting in gliosis, as seen by GFAP immunolabeling. Western blotting showed decreased levels of mitochondrial ferritin and frataxin, suggesting iron-induced mitochondrial dysfunction, while a decrease in glutathione levels and glutathione peroxidase-4 expression, and lack of expression of active caspase-3 (a marker of apoptosis) indicated an iron-dependent, non-apoptotic mode of retinal cell death (ferroptosis). Despite the smaller sample size in some assays (histopathology), our data show significant pathological changes of the retina due to iron accumulation at 12-month age of rats, and that dysregulation of the mitochondrial iron homeostasis is a step involved in iron-mediated retinal degeneration with aging.
Castelhano FVD, Almeida CAF, Braz GA
… +9 more, Pereira GO, Almeida RYS, Pereira ML, Ribeiro JLF, Simon KA, Ureshino RP, Marcourakis T, Torres LH, Garcia RCT
Neurotox Res
· 2025 Jun · PMID 40481959
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Ketamine is an anesthetic drug that has been illegally used due to its hallucinogenic effects. Its use is often concomitant with drugs such as ethanol, which can cause irreversible damage to the central nervous system. T...Ketamine is an anesthetic drug that has been illegally used due to its hallucinogenic effects. Its use is often concomitant with drugs such as ethanol, which can cause irreversible damage to the central nervous system. This study investigates the neurotoxicity of ketamine-ethanol combination in human neuroblastoma SH-SY5Y cell line, exploring the mechanisms preceding cell death. Cell viability, oxidative stress parameters, and apoptosis pathways were assessed after 3 and 6 h of drug exposure. A concentration-response curve using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay determined the lowest observed adverse effect levels for ketamine (1 mM; K1) and ethanol (100 mM; E100). After 12, 24 and 48 h, MTT assay revealed a decrease in cell viability, with a possible synergistic effect in K1E100 at 48 h, confirmed by annexin-V/7-aminoactinomycin D flow cytometry analysis, which showed a higher proportion of late apoptotic cells. Mechanisms preceding cell death were assessed by measuring reduced glutathione (GSH) levels, glutathione-related enzymes activities, and apoptosis markers (caspase-8, Bax, Bcl-2, and caspase-3). GSH levels decreased after 6 h in E100 and K1E100. Glutathione peroxidase activity increased for all groups after 3 h and in K1 and K1E100 after 6 h. Glutathione reductase and glutathione S-transferase activities increased only for K1E100 after 3 h. K1E100 also showed increased caspase-8 and Bax expression after 3 and 6 h, respectively, indicating activation of both extrinsic and intrinsic apoptotic pathways. These results suggest that ketamine-ethanol combination induces neurotoxicity by triggering oxidative stress and apoptosis in a time-dependent manner prior to cell death, increasing the risk for neuronal damage compared to individual drug exposure. While these findings are promising, they should be interpreted with caution due to certain limitations, such as variability in enzyme activity measurements, reduced sample size for some markers, and the use of an immortalized, proliferative cell line. Further studies using differentiated neuronal cells are needed to validate and expand these observations.
Amenotie AJ, Ben-Azu B, Esuku DT
… +8 more, Chijioke BS, Abo E, Ozah EO, Lawrence EO, Efejene OI, Onyeukwu OB, Alabi BA, Ajayi AM
Neurotox Res
· 2025 Jun · PMID 40474022
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Memory decline is a common hallmark signal of neurodegenerative diseases marked by elevated neuroinflammatory cytokines, oxidative damage and cholinergic insufficiency in cortical regions. Studies indicate that inhibitin...Memory decline is a common hallmark signal of neurodegenerative diseases marked by elevated neuroinflammatory cytokines, oxidative damage and cholinergic insufficiency in cortical regions. Studies indicate that inhibiting these cytokines and associated markers may enhance memory and provide neuroprotection. This study investigates the effects of sabinene, a neuroprotective monoterpene found in essential oils with neuroprotective and antioxidant properties, on lipopolysaccharide (LPS)-induced neuroinflammation, oxidative stress and learning/memory impairment in mice. In this study, mice in groups 1 and 2 received normal saline, while groups 3-5 were pretreated with sabinene (5, 10, and 20 mg/kg). Group 6 received donepezil (1 mg/kg) orally. Groups 2-6 were additionally injected with LPS (0.5 mg/kg, i.p.) 30 min post-treatment for 7 days. Behavioral consequences indicating spatial and non-spatial deficits were assessed through Y-maze and novel-object recognition tests, along with locomotor functions conducted. Biochemical markers of neuroinflammation (TNF-α, IL-6), oxidative stress (glutathione, peroxidase, malondialdehyde, nitrite), cholinergic function, and molybdenum enzymes were analyzed in the prefrontal-cortex (PFC) and hippocampus. Sabinene treatment mitigated LPS-induced memory impairments and reduced motor activity. It also significantly decreased acetylcholinesterase activity and malondialdehyde levels in the hippocampus and PFC while increasing glutathione and glutathione peroxidase levels, respectively. Moreover, sabinene reduced LPS-induced molybdenum enzyme elevation in the PFC. Compared to LPS, sabinene significantly lowered TNF-α and IL-6 levels in the PFC and hippocampus while protecting neuronal cell damage in the PFC. Overall, sabinene enhances memory function in LPS-treated mice by reducing oxidative stress and neuroinflammation while improving cholinergic activity and molybdenum enzymes in the cortical regions of mice brains.
Wongjaikam S, Siengdee P, Somnus A
… +1 more, Govitrapong P
Neurotox Res
· 2025 May · PMID 40442550
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Ferroptosis is an iron-dependent and membrane lipid peroxidation-mediated form of programmed or regulated cell death. A number of recent studies have demonstrated that ferroptosis contributes to Alzheimer's disease (AD)-...Ferroptosis is an iron-dependent and membrane lipid peroxidation-mediated form of programmed or regulated cell death. A number of recent studies have demonstrated that ferroptosis contributes to Alzheimer's disease (AD)-mediated nerve cell death. Melatonin demonstrates strong antioxidant properties and offers protective benefits for the brain in the context of AD. However, it is not fully known whether melatonin protects against ferroptosis and whether ferroptosis affects amyloid precursor protein (APP) processing. In this study, we studied the effects of melatonin on SH-SY5Y cells-induced ferroptosis using erastin, and ferrostatin-1 was used as a ferroptosis inhibitor. To confirm the occurrence of ferroptosis, we conducted measurements of cell cytotoxicity, intracellular iron, reactive oxygen species (ROS), and 4-hydroxynonenal (4-HNE). The protein expressions that were regulated by either ferroptosis or APP processing were measured. Our results revealed that erastin increased intracellular iron levels, ROS, and 4-HNE lipid peroxidation in SH-SY5Y cells, resulting in an increased percentage of cell death. Erastin disrupted the regulation of proteins involved in ferroptosis and increased the production of amyloid beta (Aβ) through APP proteolysis. Following melatonin treatment, intracellular iron, ROS, and 4-HNE levels were significantly reduced. Additionally, the cystine/glutamate antiporter (system xc) and glutathione peroxidase 4 (GPX4) were increased, and acyl-CoA synthetase long chain family member 4 (ACSL4) was diminished. APP, β-site-APP cleaving enzyme 1 (BACE1), presenilin 1 (PS1) and Aβ production were alleviated in erastin-treated SH-SY5Y cells. In conclusion, melatonin effectively inhibits ferroptosis-related cell death and AD-like conditions induced by erastin in SH-SY5Y human neuroblastoma cell lines.