Neurotox Res [JOURNAL]
Sun
200 papers
Streptozotocin and L-Buthionine-Sulfoximine Decrease Neuron Membrane Lipid Packing and Alter Insulin Signaling.
Martins YA, Cardinali CAEF, Costa AP … +1 more , Torrão AS
Neurotox Res · 2025 May · PMID 40439741 · Publisher ↗
Membrane composition, permeability and fluidity are essential for proper cellular function. According to the membrane aging hypothesis, aging-related diseases, including neurodegenerative disorders, arise from the aging...
Membrane composition, permeability and fluidity are essential for proper cellular function. According to the membrane aging hypothesis, aging-related diseases, including neurodegenerative disorders, arise from the aging of cell membranes. Membrane proteins, such as the insulin receptor, rely on an optimal membrane environment for proper partitioning and functionality. Our goal was to investigate the effects of streptozotocin (STZ) and L-buthionine-sulfoximine (BSO), two commonly used agents to model aging and neurodegeneration, on membrane composition and permeability, as well as their impact on insulin signaling. Mouse neuroblastoma 2a cell line (neuro-2a) were treated with STZ (6 h) and BSO (24 h). Cell viability was assessed by the MTT assay. Cholesterol and sphingomyelin content were quantified by commercial kits, while membrane polarity was evaluated with the Laurdan probe. Gene expression of Srebf2 and Cyp46a1 was analyzed by qPCR. Proteins from the insulin signaling pathway were examined by immunoblotting. STZ treatment reduced neuronal cholesterol content, downregulated Srebf2 and Cyp46a1 gene expression, and decreased membrane packing. In contrast, BSO-treated cells exhibited increased sphingomyelin content, upregulated Srebf2 and Cyp46a1 gene expression, and decreased membrane packing. Both treatments induced an insulin-resistant state, which we attribute to alterations in the membrane environment.
The Protective Effect of Annexin A1 on Autophagy Via the CAMK2/BECN1 Signaling Pathway in PC12 Cells Stimulated with HO.
Hui S, Long Y, Zhu L … +3 more , Hu J, Zheng Q, Liang L
Neurotox Res · 2025 Apr · PMID 40272685 · Publisher ↗
This study investigates the potential protective role of annexin A1 (ANXA1) in cell models of HO-induced Alzheimer's disease. PC12 cells exposed to varying concentrations of HO exhibited a dose-dependent decrease in cell...
This study investigates the potential protective role of annexin A1 (ANXA1) in cell models of HO-induced Alzheimer's disease. PC12 cells exposed to varying concentrations of HO exhibited a dose-dependent decrease in cell viability. HO exposure led to elevated reactive oxygen species (ROS) levels, reduced superoxide dismutase (SOD) and catalase (CAT) activities, and a decline in ANXA1 protein expression. Under oxidative stress, ANXA1 overexpression increased cell viability, reduced apoptosis rate, enhanced the expression of microtubule-associated protein 3 (LC3) II/I while reducing phosphorylated calcium/calmodulin-dependent protein kinase II (p-CAMK2)/CAMK2 and phosphorylated beclin 1 (p-BECN1)/BECN1. Conversely, ANXA1 knockdown produced contrasting effects. Overexpression of ANXA1, accompanied by administration of KN-93 (a competitive inhibitor of CAMK2), can synergistically diminished p-CAMK2/CAMK2 and p-BECN1/BECN1 levels while significantly increasing LC3 II/I levels, autophagosomes, and autolysosomes. In conclusion, ANXA1 demonstrated a protective role in HO-induced oxidative stress damage model in PC12 cells by inhibiting the CAMK2/BECN1 signaling pathway and enhancing autophagy.
Exploring Retinal Neurodegeneration in Alzheimer's Disease: A Molecular and Cellular Perspective.
Dhapola R, Sharma P, Kumari S … +3 more , Vellingiri B, Medhi B, HariKrishnaReddy D
Neurotox Res · 2025 Apr · PMID 40216597 · Publisher ↗
Increasing evidence of ocular impairments in Alzheimer's disease (AD) has drawn the attention of researchers worldwide towards retinal neurodegeneration in AD. The AD-associated changes observed in the retina include vis...
Increasing evidence of ocular impairments in Alzheimer's disease (AD) has drawn the attention of researchers worldwide towards retinal neurodegeneration in AD. The AD-associated changes observed in the retina include visual discrepancies, pupil size modulations, retinal nerve layer changes, retinal blood flow alterations and histopathological changes. The brain cells that act as pathological triggers for the progression of retinal neurodegeneration associated with AD are microglia, astrocytes and neurons. Various molecular pathways lead to structural and functional abnormalities in the retina, significantly affecting the brain including Aβ accumulation, apoptosis, inflammation and oxidative stress. Therapeutic agents under development that ameliorate disease conditions by targeting retinal anomalies include mesenchymal stem cell-conditioned media, BDNF, glatiramer acetate, salvianolic acid B, Lycium barbarum extract and exosomes. Investigating real-time alterations in the retina in AD may not only affect diagnostic approaches but also help to clarify neuropathological pathways and offer helpful measurements for assessing novel therapeutic approaches for AD.
The Role and Mechanism of TRIM13 Regulation of TRAF6 Ubiquitination in the Synergy of Inflammatory Responses and Neurotoxicity Induced by METH and HIV- 1 Tat Protein in Astrocytes.
Tan Y, Miao L, Wang C … +8 more , Wang H, Li Y, Huang Y, Teng H, Tian Y, Yang G, Zeng X, Li J
Neurotox Res · 2025 Apr · PMID 40192895 · Publisher ↗
Methamphetamine (METH) abuse and HIV infection are major public health concerns worldwide. While both METH and HIV- 1 Tat proteins can induce neurotoxicity and synergistic effects on the nervous system, the mechanisms by...
Methamphetamine (METH) abuse and HIV infection are major public health concerns worldwide. While both METH and HIV- 1 Tat proteins can induce neurotoxicity and synergistic effects on the nervous system, the mechanisms by which they act synergistically remain unclear. Our recent research shows that neuroinflammation plays an important role in neurotoxicity induced by METH and HIV- 1 Tat proteins, but the regulatory mechanism has not been clarified. Tripartite Motif Containing 13 (TRIM13) is a protein known to regulate the inflammatory response through ubiquitination of Tumor Necrosis Factor Receptor Associated Factor 6 (TRAF6). This study investigated the role of TRIM13 and TRAF6 in the inflammatory response of U- 87 MG cells induced by METH and HIV- 1 Tat proteins. U- 87 MG cells were treated with 2 mM METH and/or 100 nM HIV- 1 Tat protein. Western blot (WB), immunofluorescence (IF), and co-immunoprecipitation (Co-IP) experiments were employed to elucidate the role of TRIM13 and TRAF6. The results demonstrated that METH and HIV- 1 Tat protein could synergistically induce an inflammatory response in U- 87 MG cells. Furthermore, the knockdown of TRIM13 significantly enhanced this inflammatory response, while the inhibition of TRAF6 significantly weakened it. Additionally, the study revealed that TRIM13 could degrade TRAF6 via ubiquitination. In conclusion, this study suggests that TRIM13 regulates TRAF6 ubiquitination to dampen the inflammatory response of U- 87 MG cells induced by METH and HIV- 1 Tat proteins. These findings highlight TRIM13 and TRAF6 as potential targets for therapeutic intervention in the context of METH and HIV- 1 Tat protein-induced inflammatory responses and neurotoxic effects.
Associations among Angiotensin-Converting Enzyme, Neuroinflammation, and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease in Non-Dementia Adults.
Wang LY, Hu H, Sheng ZH … +6 more , Hu HY, Ou YN, Guo F, Zhu YK, Tan L, Alzheimer’s Disease Neuroimaging Initiative
Neurotox Res · 2025 Apr · PMID 40186068 · Publisher ↗
Recent studies have identified the angiotensin-converting enzyme (ACE) gene as a potential candidate influencing Alzheimer's disease (AD) risk. It is crucial to investigate the impact of ACE on AD pathology and its under...
Recent studies have identified the angiotensin-converting enzyme (ACE) gene as a potential candidate influencing Alzheimer's disease (AD) risk. It is crucial to investigate the impact of ACE on AD pathology and its underlying mechanisms. A total of 450 non-demented participants from the Alzheimer's disease Neuroimaging Initiative (ADNI) with data on cerebrospinal fluid (CSF) ACE, AD core biomarkers and inflammation-related biomarkers were included. Multiple linear regression was used to assess the associations among CSF ACE, AD core biomarkers and inflammation-related biomarkers. And we used the mediation models to investigate the potential mechanisms through which ACE influenced AD pathology. The results of multiple linear regression were shown that CSF ACE was significantly correlated with CSF Aβ, P-tau, T-tau (all P < 0.001), and inflammation-related biomarkers (soluble triggering receptor expressed on myeloid cells 2 [sTREM2], progranulin [PGRN], glial fibrillary acidic protein [GFAP], transforming growth factor [TGF]-β1, TGF-β2, TGF-β3, tumor necrosis factor [TNF]-R1, TNF-R2, TNF-α, interleukin [IL]-21, IL-6, IL-7, IL-9, IL-10, IL-12p40, vascular cell adhesion molecule-1 [VCAM-1], and intercellular adhesion molecule-1 [ICAM-1]) (all P < 0.05). In addition, the mediation analysis results showed that the association of CSF ACE and inflammation-related biomarkers (sTREM2, PGRN, TGF-β1, TGF-β2, TNFR1, IL-6, IL-7, IL-9, and VCAM-1) mediated the correlation of CSF Aβ with P-tau. Our findings show that CSF ACE and neuroinflammation are correlated and that their correlation mediates the link between Aβ pathology and P-tau. This suggests ACE may play a significant role in the progression from Aβ pathology to tau pathology.
Exploring the potential role of microtubule associated proteins-2 in the pathogenesis of HIV associated neurocognitive disorders.
Becher MK, Avdoshina V, Campbell LA … +1 more , Mocchetti I
Neurotox Res · 2025 Apr · PMID 40175790 · Full text
HIV-associated neurocognitive disorder (HAND) persists in people living with HIV (PLWH) despite antiretroviral therapy. HAND is characterized by synapto-dendritic damage, yet the cause of this pathology is still under in...
HIV-associated neurocognitive disorder (HAND) persists in people living with HIV (PLWH) despite antiretroviral therapy. HAND is characterized by synapto-dendritic damage, yet the cause of this pathology is still under investigation. Various viral proteins, including the envelope protein gp120, have been proposed to be the leading neurotoxic agents underlying HIV-mediated neuronal degeneration. Gp120 has been shown to bind to neuronal microtubules (MTs) and impair their functions. The dynamic properties of MTs are modulated by microtubule-associated proteins (MAP), including MAP2, which is particularly abundant in dendrites. This review article explores how gp120 could be altering the function of the neuronal cytoskeleton by affecting MAP2. These effects may serve as a causal link between viral proteins and HAND pathology.
Kynurenine Pathway in Epilepsy: Unraveling Its Role in Glutamate Excitotoxicity, GABAergic Dysregulation, Neuroinflammation, and Mitochondrial Dysfunction.
Kaur M, Porel P, Patel R … +1 more , Aran KR
Neurotox Res · 2025 Mar · PMID 40153181 · Publisher ↗
Epilepsy is a chronic noncommunicable neurological disorder characterized by recurrent seizures and ranks as the seventh most prevalent neurological disease globally. According to the Global Burden of Disease report, 3.4...
Epilepsy is a chronic noncommunicable neurological disorder characterized by recurrent seizures and ranks as the seventh most prevalent neurological disease globally. According to the Global Burden of Disease report, 3.40 billion people were affected by epilepsy in 2021. The pathophysiology of epilepsy states that a disturbed balance between excitatory and inhibitory signaling at the synaptic level, which can cause seizure activity, is similar across epilepsies and includes mitochondrial dysfunction, neuroinflammation, and kynurenine metabolites such as kynurenic acid and quinolinic acid. The kynurenine pathway (KP) is the major metabolic pathway in which tryptophan (TRP) is the key precursor which is further converted into a variety of neuroactive substances that can have both neurotoxic metabolites (Quinolinic acid) and neuroprotective metabolites such as kynurenic acid, and picolinic acid. KP plays a significant role in the brain such as the metabolism of TRP, the production of metabolites, and its impact on aging. However, higher concentrations of kynurenine and its metabolites, such as quinolinic acid may increase the frequency and intensity of seizures, and dysregulation of the KP has been linked to the pathophysiology of epilepsy. Concurrently, glutamate and GABA signaling is altered by neuroinflammatory processes linked to epilepsy, which results in excitotoxic neuronal damage. This review aims to provide novel therapeutic strategies that might improve the prognosis of individuals with epilepsy and related disorders by elucidating the mechanisms underlying KP dysregulation in these circumstances. To develop targeted therapies for CNS disorders characterized by inflammation and seizures, it is essential to understand how kynurenine metabolites both promote and prevent excitotoxicity.
Mechanistic Analysis of Decabromodiphenyl Ether-Induced Neurotoxicity in Humans Using Network Toxicology and Molecular Docking.
Karakuş F, Kuzu B
Neurotox Res · 2025 Mar · PMID 40123016 · Full text
Commercial decabromodiphenyl ether (c-decaBDE) is a widely used additive flame retardant in textiles and plastics. This formulation predominantly consists of the congener BDE-209, with trace amounts of other brominated d...
Commercial decabromodiphenyl ether (c-decaBDE) is a widely used additive flame retardant in textiles and plastics. This formulation predominantly consists of the congener BDE-209, with trace amounts of other brominated diphenyl ether congeners, such as nonabromodiphenyl ether and octabromodiphenyl ether. Recognized as a persistent organic pollutant due to its potential for long-range environmental transport, c-decaBDE poses significant environmental threats and serious human health risks, including endocrine, reproductive, developmental, and neurotoxic effects. The mechanisms underlying its neurotoxicity remain largely undefined. This study investigates the neurotoxic effects of BDE-209 in humans through network toxicology, multi-level bioinformatics approaches, and molecular docking analyses. Prediction results indicate that BDE-209 can cross the blood-brain barrier, entering the central nervous system and inducing neurotoxic effects. A comprehensive analysis has identified 294 potential targets linked to the neurotoxicity induced by BDE-209. Gene-gene interaction and pathway enrichment analyses revealed significant associations related to cellular responses to chemical stress and synaptic transmission. Further investigation of protein-protein interactions, combined with centrality analysis, identified 14 hub targets, including CaMK-II alpha, PSD-95, GluR-1, and GluN2B, as key proteins in this process. Molecular docking results indicate that BDE-209 exhibits a stronger binding affinity to GluN2B, a subunit of the N-methyl-D-aspartate (NMDA) receptors, compared to other key targets. These findings suggest that BDE-209 may disrupt the function of GluN2B-containing NMDA receptors, potentially leading to their inhibition. Such inhibition could result in reduced excitatory neurotransmission, impairing synaptic potentiation and plasticity, and ultimately contributing to neurotoxicity.
Oxytetracycline and its Non-Antibiotic Derivative DOT Protect Midbrain Dopamine Neurons from Iron-Driven Oxidative Damage.
Alves Fernandes TA, Tourville A, Ciss I … +10 more , Ribeiro Silva R, Andretto de Mattos B, Dos Santos Pereira M, Oblaza M, Brunel JM, Ferrié L, Raisman-Vozari R, Figadère B, Del-Bel E, Michel PP
Neurotox Res · 2025 Mar · PMID 40119187 · Publisher ↗
This study aimed to investigate the neuroprotective potential of the tetracycline (TC) antibiotic oxytetracycline (OT) and its non-antibiotic derivative 4-dedimethylamino 12a-deoxy-oxytetracycline (DOT), in experimental...
This study aimed to investigate the neuroprotective potential of the tetracycline (TC) antibiotic oxytetracycline (OT) and its non-antibiotic derivative 4-dedimethylamino 12a-deoxy-oxytetracycline (DOT), in experimental conditions that mimic the gradual loss of dopamine (DA) neurons in Parkinson's disease (PD). Specifically, we established a model system of mouse midbrain cultures where DA neurons progressively die when exposed to an iron-containing medium. We found that OT (EC = 0.25µM) and DOT (EC = 0.34µM) efficiently protected DA neurons from degeneration, with these effects observable until advanced stages of neurodegeneration. The reference antibiotic TC doxycycline (DOX) also exhibited protective effects in this context. Importantly, DA neurons rescued by OT, DOT, and DOX retained their capacity to accumulate and release DA, indicating full functional integrity. Additionally, molecules with iron-chelating properties (apotransferrin, desferoxamine), as well as inhibitors of lipid peroxidation and ferroptosis (Trolox, Liproxstatin-1), could replicate the rescue of DA neurons provided by OT, DOT, and DOX. Live-cell imaging studies showed that test TCs and other neuroprotective molecules prevented the emission of intracellular reactive oxygen species and the associated disruption of the mitochondrial membrane potential. However, neither OT, DOT, nor DOX could protect DA neurons from selective mitochondrial poisoning by 1-methyl-4-phenylpyridinium. This suggests that test TCs may be protective against iron-mediated damage through a mechanism not directly involving mitochondria. Overall, we demonstrate that OT and DOT possess promising properties that could be useful for combating PD neurodegeneration. However, the absence of antimicrobial activity makes DOT a better candidate drug compared to its parent compound OT.
Protective Effect of myo-Inositol Against Decitabine-Induced Neural Tube Defects in Embryonic Zebrafish.
Rajesh V, Karthi S, Kumudhavalli MV
Neurotox Res · 2025 Mar · PMID 40100479 · Publisher ↗
Neural tube defects (NTDs) are severe congenital anomalies affecting 1-2 infants per 1000 births, and are influenced by genetic and environmental factors, with DNA hypomethylation and methylation cycle suppression being...
Neural tube defects (NTDs) are severe congenital anomalies affecting 1-2 infants per 1000 births, and are influenced by genetic and environmental factors, with DNA hypomethylation and methylation cycle suppression being key causes. In our earlier investigation, decitabine (DCT) caused multiple NTDs in embryonic zebrafish, supporting this hypothesis. Recent research has emphasized the importance of myo-inositol (MI) in embryonic development and its efficacy in reducing the risk of neural tube defects, even in cases resistant to folate. We aimed to examine the effect of MI on DCT-induced NTDs in an embryonic zebrafish model. The embryos were exposed to 1 mM DCT alone, 50 µM MI with 1 mM DCT, 100 µM MI with 1 mM DCT, and a control group for comparison. The development, hatching, mortality rates, neural tube malformations, and neural tube patterning of developing embryos were monitored and recorded. Exposure to MI significantly reduced the incidence of NTDs in developing embryos. At concentrations of 50 µM and 100 µM, MI provided 35% and 30% protection against DCT-induced neural tube malformation, respectively. Multiple NTDs were significantly reduced in the MI groups, with 1 mM DCT causing 95% defects, 50 µM MI with 1 mM DCT causing 50%, and 100 µM MI with 1 mM DCT causing 55% defects. The DCT-induced hatching delay was also reversed by MI treatment. Alizarin red staining and histopathological observations supported these observations. In the context of neural tube development, the protective effects of MI against DCT-induced NTDs could be attributed to its potential role in epigenetic regulation, which may influence genetic expression.
Metformin Protects Human Induced Pluripotent Stem Cell (hiPSC)-Derived Neurons from Oxidative Damage Through Antioxidant Mechanisms.
Gharandouq MH, Ismail MA, Saleh T … +2 more , Zihlif M, Ababneh NA
Neurotox Res · 2025 Mar · PMID 40100475 · Publisher ↗
The antidiabetic drug metformin possesses antioxidant and cell protective effects including in neuronal cells, suggesting its potential use for treating neurodegenerative diseases. This study aimed to assess metformin's...
The antidiabetic drug metformin possesses antioxidant and cell protective effects including in neuronal cells, suggesting its potential use for treating neurodegenerative diseases. This study aimed to assess metformin's effects on viability and antioxidant activity in human-induced pluripotent stem cell (hiPSC)-derived neurons under varying concentrations and stress conditions. Six lines of hiPSC-derived neuronal progenitors derived from healthy human iPSCs were treated with metformin (1-500 µM) on day 18 of differentiation. For mature neurons (day 30), three concentrations (10 µM, 50 µM, and 100 µM) were used to assess cytotoxicity. MG132 proteasomal inhibitor and sodium arsenite (NaArs) were used to investigate oxidative stress, and 50 µM of metformin was tested for its protective effects against oxidative stress in hiPSC-derived neurons. Metformin treatment did not affect cell viability, neuronal differentiation, or trigger reactive oxygen species (ROS) generation in healthy hiPSC-derived motor neurons. Additionally, mitochondrial membrane potential (MMP) loss was not observed at 50 µM metformin. Metformin effectively protected neurons from stress agents and elevated the expression of antioxidant genes when treated with MG132. However, an interplay between MG132 and metformin resulted in lower expression of Nrf2 and NQO1 compared to the MG132 group alone, indicating reduced JC-1 aggregate levels due to MG132 proteasomal inhibition. Metformin upregulated antioxidant genes in hiPSC-derived neurons under stress conditions and protected the cells from oxidative damage.
Multi-Omics Analysis of Hippocampus in Rats Administered Trimethyltin Chloride.
Zakaria D, Yamashita T, Kosugi Y
Neurotox Res · 2025 Mar · PMID 40095120 · Full text
Trimethyltin chloride (TMT) is a neurotoxicant that damages the central nervous system (CNS) and triggers neurodegeneration. This study used multi-omic data, including transcriptomics and proteomics of the rat hippocampu...
Trimethyltin chloride (TMT) is a neurotoxicant that damages the central nervous system (CNS) and triggers neurodegeneration. This study used multi-omic data, including transcriptomics and proteomics of the rat hippocampus, to identify differentially expressed genes and proteins in TMT-induced neurotoxicity over time, related to neuro-axonal damage marked by plasma Neurofilament Light (NfL) levels. Data were collected at 12, 24, 48, 72, and 168 h post-TMT administration. NfL levels surged at 72 and 168 h, confirming neuro-axonal damage. Transcripts of genes in the chemokine signaling pathway (Cxcl10, Cxcl12, Cxcl14, Cxcl16), apoptosis pathway (Caspase-3, PARP1, CTSD), and TNF signaling pathway (TNFR1, MMP9, ICAM-1, TRAF3) showed significant differential expression starting from 48 h, preceding the NfL increase, suggesting their roles in neuro-axonal damage. Additionally, 11 Alzheimer's disease-related proteins, with significant changes from 72 to 168 h, were detected only in the proteomic dataset, indicating post-translational modifications might be crucial in neurotoxicity. Pathway analysis revealed that neurodegeneration and Alzheimer's disease pathways were among the top 15 affected by TMT-induced gene regulation, aligning with the involvement of TNF signaling, apoptosis, and chemokine signaling in neurodegeneration. This research highlighted the value of longitudinal omics studies, combined with pathway enrichment, gene-disease association, and neuro-axonal damage biomarker analyses, to elucidate neurotoxicant-induced neurodegeneration. Findings from this study could enhance the understanding of TMT-induced neurotoxicity, potentially informing future therapeutic strategies and preventive measures.
Evaluation of the Memory Enhancement Effects of Aminopyrimidine Derivatives Using the Scopolamine Model of Dementia in Mice.
Landi B, Khoramjouy M, Lahij AG … +4 more , Fazelkia S, Amidi S, Kobarfard F, Faizi M
Neurotox Res · 2025 Mar · PMID 40088349 · Publisher ↗
Aminopyrimidine compounds have been gaining traction in the field of drug discovery in recent years due to their emergence as multi-targeted molecules. This makes them perfect candidates as agents for cognitive improveme...
Aminopyrimidine compounds have been gaining traction in the field of drug discovery in recent years due to their emergence as multi-targeted molecules. This makes them perfect candidates as agents for cognitive improvement, as cognitive decline is a multifaceted condition. We aim to evaluate their potential for memory enhancement, specifically through their cholinergic properties. This work examines the properties of seven aminopyrimidine derivatives and their effects on memory acquisition and retention. These compounds were administered to NMRI mice after the induction of amnesia by scopolamine, and memory impairment and improvement were assessed using passive avoidance and spontaneous alternation tests with the drug donepezil as the positive control group. These compounds were also analyzed using docking and ADME prediction studies to determine potential affinity to the acetylcholinesterase enzyme, and characterize pharmacokinetic properties, respectively. Additionally, in vitro inhibition of cholinesterase was evaluated. Results showed that three of the seven compounds significantly increased cognition in both behavioral tests. Software analysis suggested allosteric inhibition or modulation of acetylcholinesterase, signifying the potential of these compounds for further optimization and eventual utilization for treatment of cognitive impairment cases.
The Effect of Naringin on Cognitive-Behavioral Functions, CREB/BDNF Signaling, Cholinergic Activity, and Neuronal Density in the Hippocampus of an MSG-Induced Obesity Rat Model.
Alijani B, Edalatmanesh MA, Aghababa H
Neurotox Res · 2025 Feb · PMID 40016546 · Publisher ↗
The global rise in obesity and overweight over the past few decades has led to numerous associated disorders, including cognitive deficits. This study evaluate investigates the effects of Naringin (Nar) on memory and lea...
The global rise in obesity and overweight over the past few decades has led to numerous associated disorders, including cognitive deficits. This study evaluate investigates the effects of Naringin (Nar) on memory and learning, anxiety-like behaviors, brain-derived neurotrophic factor (BDNF), cAMP responsive element binding protein (CREB), acetylcholinesterase (AChE) activity, and neuronal density in the CA₁/CA₃ subfields of the hippocampus in an MSG-induced obese obesity rat model. Forty-eight male Wistar rat pups were randomly divided into four groups: Control, MSG, MSG + Nar50, and MSG + Nar100. MSG (4 g/kg BW) was administered subcutaneously in the cervical region from PND 2 to PND10, while Nar (50 mg/kg BW and 100 mg/kg BW) was administered orally from PND30 to PND42. After the treatment period, cognitive (working memory and passive avoidance) and anxiety-related tests (elevated plus maze and novelty-suppressed feeding test) were performed. Subsequently, hippocampal protein level of BDNF and CREB/BDNF gene expression, AChE activity and neuronal density in the CA₁ and CA₃ regions of the hippocampus were measured. Relative to the MSG group, the Nar-treated rats demonstrated improvements in spatial working memory, reduced anxiety-related behaviors, elevated hippocampal CREB and BDNF genes and BDNF protein levels, and reduced AChE activity. Additionally, Nar treatment increased neuronal density in the CA₁/CA₃ subfields of the hippocampus. These findings suggest that Nar enhances cognitive function and mitigates anxiety in MSG-induced obese rats by modulating CREB/BDNF signaling pathway, inhibiting AChE, and exerting neuroprotective effects in the hippocampus.
Sex-Specific Outcomes in a Rat Model of Early-Life Stress Due to Adverse Caregiving.
Grillo Balboa J, Colapietro AA, Cantarelli VI … +5 more , Ponzio MF, Ceol Retamal MN, Pallarés ME, Antonelli MC, Chertoff M
Neurotox Res · 2025 Feb · PMID 39964605 · Publisher ↗
Early parental care is critical for the development of cortico-limbic circuits regulating stress responses and emotional well-being. Conversely, infant maltreatment can increase susceptibility to mood disorders-such as a...
Early parental care is critical for the development of cortico-limbic circuits regulating stress responses and emotional well-being. Conversely, infant maltreatment can increase susceptibility to mood disorders-such as anxiety and depression-and impair stress-coping abilities. Here, we employed the Scarcity-Adversity Model (SAM) in rats, limiting nesting resources from postnatal days 8-12, to examine its effects on maternal and adult offspring behavior. SAM-exposed mothers exhibited fragmented care and increased violence towards pups. By postpartum day (PPD) 13, maternal fecal corticosterone metabolites (FCM) were elevated, indicating heightened stress. At weaning, SAM dams also showed increased anxiety-like behavior in the Elevated Plus Maze (EPM), suggesting significant emotional alterations. In adulthood, SAM-exposed offspring underwent anxiogenic tests. Both male and female SAM offspring showed increased latency to enter open arms and reduced risk-assessment in the EPM, though females displayed anxiolytic-like behavior in the Light-Dark Box. Male SAM rats had reduced locomotion in the Open Field, earlier onset and increased immobility in the Forced Swim, and increased latency to groom in the Sucrose Splash. When exposed to acute stress, male SAM rats had lower FCM levels, consistent with their passive stress reactivity. These findings confirm SAM induces long-lasting, sex-specific changes in risk-taking, novelty responsiveness, and stress reactions, underscoring the importance of early nurturing in promoting well-being and reducing psychopathological risk.
Restoration of MPTP-induced Dopamine and Tyrosine Hydroxylase Depletion in the Mouse Brain Through Ethanol and Nicotine.
Jamal M, Takei S, Tsukamoto I … +4 more , Miki T, Ohta KI, Hossain MZ, Kinoshita H
Neurotox Res · 2025 Feb · PMID 39937382 · Publisher ↗
Dopamine (DA) has long been considered a major factor in the development of Parkinson's disease (PD). Ethanol (EtOH) and nicotine (Nic), either alone or in combination, have been shown to affect nigrostriatal dopaminergi...
Dopamine (DA) has long been considered a major factor in the development of Parkinson's disease (PD). Ethanol (EtOH) and nicotine (Nic), either alone or in combination, have been shown to affect nigrostriatal dopaminergic neuronal activity. Here, we investigate whether EtOH and Nic alone or in co-exposure can restore the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced depletion of dopamine (DA), DA metabolites, and tyrosine hydroxylase (TH) in the striatum and hippocampus of C57BL/6N mice. MPTP-treated mice were treated intraperitoneally with saline (control), EtOH (1.0-3.0 g/kg), Nic (0.5-2.0 mg/kg), or a combination of EtOH and Nic. Brain samples were collected 1 h after treatment. DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovanillic acid (HVA) were measured by HPLC-ECD, while TH protein content and TH phosphorylation at Ser31 (pSer31 TH) were quantified by Western blot. EtOH (2.0 and 3.0 g/kg) alone reversed the effects of MPTP treatment in both studied brain regions, as evidenced by an increase in DA, DOPAC, and HVA contents, TH protein, and pSer31 TH compared to the MPTP group, indicating restorative effects on DA neurons in the MPTP model. Likewise, Nic (1.0 and 2.0 mg/kg) alone reversed MPTP treatment effects, with treated mice showing increased DA, DOPAC, and HVA contents, TH protein, and pSer31 TH compared to MPTP mice. Co-administration of EtOH (2.0 g/kg) and Nic (1.0 mg/kg) further increased DA, DOPAC and HVA tissue contents, TH protein, and pSer31 TH, indicating an additive effect. These results show that moderate to high doses of EtOH and Nic induce similar increases in brain DA and TH via TH phosphorylation activation in MPTP model mice. EtOH and Nic showed an additive effect in combination, suggesting that their co-application could be a potent therapeutic strategy for treating PD.
Cannabidiol-Induced Autophagy Ameliorates Tau Protein Clearance.
Vrechi TAM, Guarache GC, Oliveira RB … +11 more , Guedes EDC, Erustes AG, Leão AHFF, Abílio VC, Zuardi AW, Hallak JEC, Crippa JA, Bincoletto C, Ureshino RP, Smaili SS, Pereira GJS
Neurotox Res · 2025 Feb · PMID 39900844 · Full text
Tau is a neuronal protein that confers stability to microtubules; however, its hyperphosphorylation and accumulation can lead to an impairment of protein degradation pathways, such as autophagy. Autophagy is a lysosomal...
Tau is a neuronal protein that confers stability to microtubules; however, its hyperphosphorylation and accumulation can lead to an impairment of protein degradation pathways, such as autophagy. Autophagy is a lysosomal catabolic process responsible for degrading cytosolic components, being essential for cellular homeostasis and survival. In this context, autophagy modulation has been postulated as a possible therapeutic target for the treatment of neurodegenerative diseases. Studies point to the modulatory and neuroprotective role of the cannabinoid system in neurodegenerative models and here it was investigated the effects of cannabidiol (CBD) on autophagy in a human neuroblastoma strain (SH-SY5Y) that overexpresses the EGFP-Tau WT (Wild Type) protein in an inducible Tet-On system way. The results demonstrated that CBD (100 nM and 10 µM) decreased the expression of AT8 and total tau proteins, activating autophagy, evidenced by increased expression of light chain 3-II (LC3-II) protein and formation of autophagosomes. Furthermore, the cannabinoid compounds CBD, ACEA (CB1 agonist) and GW-405,833 (CB2 agonist) decreased the fluorescence intensity of EGFP-Tau WT; and when chloroquine, an autophagic blocker, was used, there was a reversal in the fluorescence intensity of EGFP-Tau WT with CBD (1 and 10 µM) and GW-405,833 (2 µM), demonstrating the possible participation of autophagy in these groups. Thus, it was possible to conclude that CBD induced autophagy in EGFP-Tau WT cells which increased tau degradation, showing its possible neuroprotective role. Hence, this study may contribute to a better understanding of how cannabinoids can modulate autophagy and present a potential therapeutic target in a neurodegeneration model.
Glioprotective Effects of Resveratrol Against Glutamate-Induced Cellular Dysfunction: The Role of Heme Oxygenase 1 Pathway.
Quincozes-Santos A, Bobermin LD, Tramontina AC … +10 more , Wartchow KM, Da Silva VF, Gayger-Dias V, Thomaz NK, de Moraes ADM, Schauren D, Nardin P, Gottfried C, Souza DO, Gonçalves CA
Neurotox Res · 2025 Jan · PMID 39869271 · Publisher ↗
Resveratrol, a natural polyphenol, has shown promising neuroprotective effects in several in vivo and in vitro experimental models. However, the mechanisms by which resveratrol mediates these effects are not fully unders...
Resveratrol, a natural polyphenol, has shown promising neuroprotective effects in several in vivo and in vitro experimental models. However, the mechanisms by which resveratrol mediates these effects are not fully understood. Glutamate is the major excitatory neurotransmitter in the brain; however, excessive extracellular glutamate levels can affect neural activity in several neurological diseases. Astrocytes are the glial cells that maintain brain homeostasis and can attenuate excitotoxicity by actively participating in glutamate neurotransmission. This study aimed to investigate the glioprotective effects of resveratrol against glutamate-induced cellular dysfunction in hippocampal slices and primary astrocyte cultures, with a focus on the role of heme-oxygenase 1 (HO-1). Glutamate impaired glutamate uptake activity through a glutamate receptor-dependent mechanism, in addition to altering other important astroglial parameters, including glutamine synthetase activity, glutathione levels and cystine uptake, which were normalized by resveratrol. Resveratrol also prevented glutamate-induced disruption in antioxidant defenses, as well as in trophic and inflammatory functions, including the nuclear factor κB (NFκB) transcriptional activity. Most of the effects of resveratrol, mainly in astrocytes, were dependent on the HO-1 signaling pathway, as they were abrogated when HO-1 was pharmacologically inhibited. Resveratrol also increased HO-1 mRNA expression and its transcriptional regulator, nuclear factor erythroid-derived 2-like 2 (Nrf2). Finally, resveratrol prevented glutamate-induced p21 senescence marker, indicating an anti-aging effect. Therefore, we demonstrated that the activation of the Nrf2/HO-1 system in astrocytes by resveratrol represents an astrocyte-targeted neuroprotective mechanism in neurodegeneration, with glutamate excitotoxicity, oxidative stress, and neuroinflammation as common neurochemical alterations.
Correction to: Dexmedetomidine Promoted HSPB8 Expression via Inhibiting the lncRNA SNHG14/UPF1 Axis to Inhibit Apoptosis of Nerve Cells in AD : The Role of Dexmedetomidine in AD.
Tan Q, Liu L, Wang S … +2 more , Wang Q, Sun Y
Neurotox Res · 2025 Jan · PMID 39856348 · Publisher ↗
Abstract loading — click title to view on PubMed.
Exploring the Different Impacts of Ketamine on Neurotrophic Factors and Inflammatory Parameters in a Cecal Ligation and Puncture-Induced Sepsis Model.
Aguiar-Geraldo JM, Canever L, Marino DP … +7 more , Coan C, Possamai-Della T, Pescador B, Quevedo J, Dal-Pizzol F, Valvassori SS, Zugno AI
Neurotox Res · 2025 Jan · PMID 39833594 · Publisher ↗
Given ketamine's conflicting impacts on the central nervous system, investigating its effects within an inflammatory context becomes crucial. This study aimed to assess the impact of varying ketamine doses on neurotrophi...
Given ketamine's conflicting impacts on the central nervous system, investigating its effects within an inflammatory context becomes crucial. This study aimed to assess the impact of varying ketamine doses on neurotrophin and inflammatory cytokine levels within the brains of rats submitted to the sepsis model. Wistar rats were submitted to the cecal ligation and puncture (CLP) model of sepsis. Intraperitoneal ketamine injections (5, 15, or 25 mg/kg) or saline were administered daily for seven days, thirty days post-CLP. Rats were euthanized thirty minutes following the last injection for analysis of IL-1β, IL-6, IL-10, TNF-α, BDNF, NGF, NT-3, and GDNF levels in the frontal cortex, hippocampus, and striatum. CLP-induced elevated IL-1𝛽, IL-6, IL-10, and TNF-α levels in the frontal cortex and hippocampus of rats, with reduced BDNF levels across all structures examined. Furthermore, reduced NGF and GDNF levels were observed solely in the hippocampus. Ketamine at 5 mg/kg normalized CLP-induced alterations and, in Sham animals, increased BDNF and NGF levels in the frontal cortex and/or hippocampus. At 15 mg/kg, ketamine elevated BDNF and NGF levels in Sham animals, while at 25 mg/kg, it exacerbated the inflammatory response initiated by CLP. These findings suggest variable effects of ketamine within a context of systemic inflammation, emphasizing the importance of considering individual inflammatory backgrounds when utilizing ketamine.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe