RESUMEN

Hydroxyapatite nanoparticles (HANPs) have extensive applications in biomedicine and tissue engineering. However, little information is known about their toxicity. Here, we aim to investigate the possible neurotoxicity of HANPs and the possible protective role of chitosan nanoparticles (CNPs) and curcumin nanoparticles (CUNPs) against this toxicity. In our study, HANPs significantly reduced the levels of neurotransmitters, including acetylcholine (Ach), dopamine (DA), serotonin (SER), epinephrine (EPI), and norepinephrine (NOR). HANPs significantly suppressed cortical expression of the genes controlling mitochondrial biogenesis such as peroxisome proliferator activator receptor gamma coactivator 1α (PGC-1α) and mitochondrial transcription factor A (mTFA). Our findings revealed significant neuroinflammation associated with elevated apoptosis, lipid peroxidation, oxidative DNA damage and nitric oxide levels with significant decline in the antioxidant enzymes activities and glutathione (GSH) levels in HANPs-exposed rats. Meanwhile, co-supplementation of HANP-rats with CNPs and/or CUNPs significantly showed improvement in levels of neurotransmitters, mitochondrial biogenesis, oxidative stress, DNA damage, and neuroinflammation. The co-supplementation with both CNPs and CUNPs was more effective to ameliorate HANPs-induced neurotoxicity than each one alone. So, CNPs and CUNPs could be promising protective agents for prevention of HANPs-induced neurotoxicity.

Asunto(s)

Quitosano , Curcumina , Durapatita , Nanopartículas , Estrés Oxidativo , Animales , Curcumina/farmacología , Quitosano/química , Quitosano/farmacología , Nanopartículas/química , Ratas , Durapatita/química , Estrés Oxidativo/efectos de los fármacos , Masculino , Síndromes de Neurotoxicidad/prevención & control , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/metabolismo , Fármacos Neuroprotectores/farmacología , Neurotransmisores/metabolismo , Apoptosis/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Daño del ADN/efectos de los fármacos

RESUMEN

Malignant tumors of the hematologic system have a high degree of malignancy and high mortality rates. Chimeric antigen receptor T cell (CAR-T) therapy has become an important option for patients with relapsed/refractory tumors, showing astonishing therapeutic effects and thus, it has brought new hope to the treatment of malignant tumors of the hematologic system. Despite the significant therapeutic effects of CAR-T, its toxic reactions, such as Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), cannot be ignored since they can cause damage to multiple systems, including the cardiovascular system. We summarize biomarkers related to prediction, diagnosis, therapeutic efficacy, and prognosis, further exploring potential monitoring indicators for toxicity prevention. This review aims to summarize the effects of CAR-T therapy on the cardiovascular, hematologic, and nervous systems, as well as potential biomarkers, and to explore potential monitoring indicators for preventing toxicity, thereby providing references for clinical regulation and assessment of therapeutic effects.

Asunto(s)

Síndrome de Liberación de Citoquinas , Inmunoterapia Adoptiva , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Síndrome de Liberación de Citoquinas/prevención & control , Síndrome de Liberación de Citoquinas/etiología , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/prevención & control , Biomarcadores , Animales , Receptores Quiméricos de Antígenos/inmunología , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/inmunología , Neoplasias/terapia , Neoplasias/inmunología

RESUMEN

Neurotoxicity is characterized by the accumulation of harmful chemicals such as heavy metals and drugs in neural tissue, resulting in subsequent neuronal death. Among chemicals platinum-based cancer drugs are frequently used due to their antineoplastic effects, but this drug is also known to cause a wide range of toxicities, such as neurotoxicity. The nuclear-factor-erythroid 2-related factor-2 (NRF2) is crucial in combating oxidative stress and maintaining cellular homeostasis. This study thoroughly explores the protective effects of extracellular vesicles derived from NRF2 gene overexpressed neural progenitor cells (NEVs) on cisplatin-induced neurotoxicity. Therefore, extracellular vesicles derived from neural progenitor cells were isolated and characterized. The Cisplatin neurotoxicity dose was 75 µM in mature, post-mitotic neurons. 1.25 µM of tert-butyl hydroquinone that induces NRF2/ARE pathway was used as the positive control. The effects of extracellular vesicles (EVs) were investigated using functional and molecular assays such as PCR and protein-based assays. Here, we observed that NEVs dose-dependently protected post-mitotic neuron cells in response to cisplatin. The study also examined whether the effect was EV-induced by limiting EV biogenesis. The molecular basis of preventive treatment was established. When pre-administered, 1×108 particles/ml of NEVs maintained antioxidant and detoxifying gene and protein expression levels similar to control cell levels. Furthermore, NEVs reduced both cellular and mitochondrial ROS levels and preserved mitochondrial membrane potential. In addition, Catalase and SOD levels were found higher in NEV-treated cells compared to cisplatin control. The findings in NRF2-based protection of cisplatin-induced neurotoxicity may provide further evidence for the relationship between EVs and inhibition of neuronal stress through the NRF2/ARE pathway, increasing the understanding of neuroprotective responses and the development of gene-engineered EV therapy options for peripheral neuropathy or other neurodegenerative diseases. This is the first study in the literature to investigate the neutralizing potency of NRF2 overexpressed neural EVs against cisplatin-induced neurotoxicity.

Asunto(s)

Antineoplásicos , Cisplatino , Vesículas Extracelulares , Factor 2 Relacionado con NF-E2 , Células-Madre Neurales , Transducción de Señal , Cisplatino/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , Vesículas Extracelulares/efectos de los fármacos , Vesículas Extracelulares/metabolismo , Animales , Antineoplásicos/toxicidad , Antineoplásicos/farmacología , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Transducción de Señal/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Síndromes de Neurotoxicidad/prevención & control , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/etiología , Elementos de Respuesta Antioxidante/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Células Cultivadas

RESUMEN

Peripheral neurotoxicity is a dose-limiting adverse reaction of primary frontline chemotherapeutic agents, including vincristine. Neuropathy can be so disabling that patients drop out of potentially curative therapy, negatively impacting cancer prognosis. The hallmark of vincristine neurotoxicity is axonopathy, yet its underpinning mechanisms remain uncertain. We developed a comprehensive drug discovery platform to identify neuroprotective agents against vincristine-induced neurotoxicity. Among the hits identified, SIN-1-an active metabolite of molsidomine-prevents vincristine-induced axonopathy in both motor and sensory neurons without compromising vincristine anticancer efficacy. Mechanistically, we found that SIN-1's neuroprotective effect is mediated by activating soluble guanylyl cyclase. We modeled vincristine-induced peripheral neurotoxicity in rats to determine molsidomine therapeutic potential in vivo. Vincristine administration induced severe nerve damage and mechanical hypersensitivity that were attenuated by concomitant treatment with molsidomine. This study provides evidence of the neuroprotective properties of molsidomine and warrants further investigations of this drug as a therapy for vincristine-induced peripheral neurotoxicity.

Asunto(s)

Molsidomina , Fármacos Neuroprotectores , Guanilil Ciclasa Soluble , Vincristina , Vincristina/efectos adversos , Vincristina/farmacología , Vincristina/toxicidad , Animales , Fármacos Neuroprotectores/farmacología , Ratas , Guanilil Ciclasa Soluble/metabolismo , Molsidomina/farmacología , Molsidomina/análogos & derivados , Humanos , Masculino , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/prevención & control , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Ratas Sprague-Dawley , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/prevención & control , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/etiología

RESUMEN

Sevoflurane, as a commonly used inhaled anesthetic for pediatric patients, has been reported that multiple sevoflurane exposures are associated with a greater risk of developing neurocognitive disorder. N6-Methyladenosine (m6A), as the most common mRNA modification in eukaryotes, has emerged as a crucial regulator of brain function in processes involving synaptic plasticity, learning and memory, and neurodevelopment. Nevertheless, the relevance of m6A RNA methylation in the multiple sevoflurane exposure-induced developmental neurotoxicity remains mostly elusive. Herein, we evaluated the genome-wide m6A RNA modification and gene expression in hippocampus of mice that received with multiple sevoflurane exposures using m6A-sequencing (m6A-seq) and RNA-sequencing (RNA-seq). We discovered 19 genes with differences in the m6A methylated modification and differential expression in the hippocampus. Among these genes, we determined that a total of nine differential expressed genes may be closely associated with the occurrence of developmental neurotoxicity induced by multiple sevoflurane exposures. We further found that the alkB homolog 5 (ALKBH5), but not methyltransferase-like 3 (METTL3) and Wilms tumor 1-associated protein (WTAP), were increased in the hippocampus of mice that received with multiple sevoflurane exposures. And the IOX1, as an inhibitor of ALKBH5, significantly improved the learning and memory defects and reduced neuronal damage in the hippocampus of mice induced by multiple sevoflurane exposures. The current study revealed the role of m6A methylated modification and m6A-related regulators in sevoflurane-induced cognitive impairment, which might provide a novel insight into identifying biomarkers and therapeutic strategies for inhaled anesthetic-induced developmental neurotoxicity.

Asunto(s)

Adenosina , Desmetilasa de ARN, Homólogo 5 de AlkB , Hipocampo , Síndromes de Neurotoxicidad , Sevoflurano , Sevoflurano/toxicidad , Animales , Ratones , Desmetilasa de ARN, Homólogo 5 de AlkB/metabolismo , Desmetilasa de ARN, Homólogo 5 de AlkB/genética , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Masculino , Síndromes de Neurotoxicidad/genética , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/prevención & control , Adenosina/análogos & derivados , Adenosina/metabolismo , Anestésicos por Inhalación/toxicidad , Ratones Endogámicos C57BL , Metilación/efectos de los fármacos , Metiltransferasas/metabolismo , Metiltransferasas/genética

RESUMEN

Silicon dioxide nanoparticles (SiO2-NPs) can be found in many products, such as composites, paints, ceramics, consumer products, and food additives. We recently demonstrated that via breastfeeding, SiO2-NPs transfer to the offspring's brain, interfering negatively with hippocampus development. In this work, we evaluated the protective effect of grape seed extract (GSE) against the adverse effects of SiO2-NPs. After delivery, animals were administered 25 mg/kg SiO2-NPs with/without GSE (300 mg/kg) for 20 days (from 2nd to 21st days post-delivery) by gavage. SiO2-NPs increased malondialdehyde concentration and decreased antioxidant activity in the offspring's hippocampi. The mean number of dark neurons (DNs) was significantly higher in the hippocampi of the SiO2-NPs group, whereas the mean number of DCX + cells was significantly lower than in the control group. The offspring in the SiO2-NPs groups had a weak cognitive performance in adulthood. Interestingly, these adverse effects of SiO2-NPs were alleviated in the GSE-treated groups. Therefore, GSE can attenuate the damaging effects of maternal exposure to SiO2-NPs during lactation.

Asunto(s)

Extracto de Semillas de Uva , Hipocampo , Nanopartículas , Dióxido de Silicio , Animales , Extracto de Semillas de Uva/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Dióxido de Silicio/toxicidad , Femenino , Ratas , Masculino , Embarazo , Ratas Wistar , Efectos Tardíos de la Exposición Prenatal/prevención & control , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Síndromes de Neurotoxicidad/prevención & control , Antioxidantes/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología

RESUMEN

Chemical carcinogen-induced oxidative stress has a key role in cell signaling linked to the development of cancer. Oxidative stress leads to oxidative damage to cellular membranes, proteins, chromosomes and genetic material. It is thought that compounds like hesperidin with high antioxidant and anticancer potential can reduce development of cancer induced by chemical carcinogens via neutralizing their oxidative damages. We investigated protective effect of hesperidin against N-Ethyl-N-Nitrosourea (ENU)-induced neurotoxicity, congenital abnormalities and possible brain cancer after exposure of mice during pregnancy as model of glioma. The mice were divided to four groups; control (normal saline), ENU (40 mg/kg daily for three consecutive days from the 17th to the 19th of pregnancy), hesperidin (pretreated with 25 mg/kg for 30 consecutive days, before mating) + ENU and hesperidin alone. Developmental toxicity parameters (the number of pregnant mice, stillbirths, abortion, live and dead offspring), behavioral tests (novel object recognition, open field and elevated plus maze) were performed. Moreover, the activity of butrylcholinesterase and acetylcholinesterase enzymes, oxidative markers and histopathological abnormalities were detected in brain tissue. Our data showed that conversely, the pretreatment of hesperidin reduces various degrees of developmental toxicity, neurobehavioral dysfunction, neurotoxicity, oxidative stress and histopathological abnormalities induced by ENU as a neurotoxic and carcinogenic agent in the next generation. In conclusion, pre-mating exposure with hesperidin may open new avenues for prevention of primary brain cancer in next generation and could be valuable for enhancing the antioxidant defense and minimizing the developmental and neurotoxicity of DNA alkylating agents.

Asunto(s)

Modelos Animales de Enfermedad , Etilnitrosourea , Glioma , Hesperidina , Estrés Oxidativo , Animales , Hesperidina/farmacología , Glioma/patología , Glioma/tratamiento farmacológico , Glioma/prevención & control , Femenino , Ratones , Embarazo , Etilnitrosourea/toxicidad , Estrés Oxidativo/efectos de los fármacos , Neoplasias Encefálicas/prevención & control , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Masculino , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/metabolismo , Síndromes de Neurotoxicidad/prevención & control , Síndromes de Neurotoxicidad/etiología , Conducta Animal/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Antioxidantes/farmacología

RESUMEN

Monosodium glutamate (MSG) is the sodium compound derived from glutamic acid. Excessive daily ingestion of MSG leads to elevated amounts of glutamic acid in the bloodstream, which can be detrimental to brain structures. Camellia sinensis, often known as green tea (GT), is a rich source of essential hexogen antioxidants that are necessary for the body. Thirty-two adult male albino rats were divided into four groups (n = 8). Group 1 served as a control -ve group. Group 2 was given GT (1.5 ml/rat/day). Group 3 was given MSG (600 mg/kg/day). Group 4 was given MSG (600 mg/kg/day) and GT (1.5 ml/rat/day). All treatments were given orally for 28 days. MSG administration resulted in significant neurotoxicity in rats that was revealed by the significant reduction of serum concentration of glutathione peroxidase (GPx) and nitric oxide (NO), and the significant elevation of total antioxidant capacity (TAC) accompanied by the significant reduction of levels of serum monoamines (dopamine, serotonin, and norepinephrine) and histological changes in the hippocampus area CA1, dentate gyrus, and cerebellar cortex and positive immunohistochemical staining of glial fibrillary acidic proteins (GFAP) and calretinin. Administration of GT with MSG counteracted the MSG-mediated oxidative stress by significantly increasing serum concentrations of GPX and NO and significantly decreasing concentrations of TAC. Furthermore, GT significantly increased levels of serum monoamines (dopamine, serotonin, and norepinephrine). Moreover, it ameliorated the histological changes, GFAP, and calretinin immunostaining in brain tissues. It is envisaged that GT will serve as a viable protective choice for the inclusion of the neurotoxicity treatment procedure.

Asunto(s)

Antioxidantes , Camellia sinensis , Síndromes de Neurotoxicidad , Glutamato de Sodio , Animales , Glutamato de Sodio/toxicidad , Masculino , Camellia sinensis/química , Ratas , Síndromes de Neurotoxicidad/prevención & control , Síndromes de Neurotoxicidad/tratamiento farmacológico , Antioxidantes/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Glutatión Peroxidasa/metabolismo , Óxido Nítrico/metabolismo , Ratas Wistar

RESUMEN

Chronic exposure to lead (Pb) induces neurodegenerative changes in animals and humans. Drugs with strong antioxidant properties are effective against Pb-mediated neurotoxicity. In a prior study, we identified 5,7-dihydroxy-3',4',5'-trimethoxyflavone (TMF) from Ocimum basilicum L. leaves as a potent antioxidant and neuroprotective compound. This research explores TMF's neuroprotective effects against Pb-induced brain toxicity in rats to establish it as a therapeutic agent. Rats received lead acetate (100 mg/kg, orally, once daily) for 30 days to induce brain injury, followed by TMF treatment (5 and 10 mg/kg, oral, once daily) 30 min later. Cognitive and motor functions were assessed using Morris Water Maze and horizontal bar tests. Lead, monoamine oxidase (MAO) A and B enzymes, reduced glutathione (GSH), thiobarbituric acid reactive species (TBARS), Tumor necrosis factor-alpha (TNF-α), and IL-6 levels were measured in the hippocampus and cerebellum. Pb exposure impaired cognitive and motor functions, increased Pb, TBARS, TNF-α, and IL-6 levels, and compromised MAO A & B and GSH levels. TMF reversed Pb-induced memory and motor deficits and normalized biochemical anomalies. TMF's neuroprotective effects against lead involve chelating, antioxidant, anti-inflammatory, and monoaminergic properties, suggesting its potential as a treatment for metal-induced brain injury.

Asunto(s)

Antiinflamatorios , Antioxidantes , Animales , Antioxidantes/farmacología , Masculino , Ratas , Antiinflamatorios/farmacología , Fármacos Neuroprotectores/farmacología , Flavonas/farmacología , Plomo/toxicidad , Quelantes/farmacología , Ratas Wistar , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/prevención & control , Glutatión/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos

RESUMEN

We established experimental models of manganese (Mn) and iron (Fe) exposure in vitro and in vivo, and addressed the effects of manganese and iron combined exposure on the synaptic function of pheochromocytoma derived cell line 12 (PC12) cells and rat cortex, respectively. We investigated the protective effect of sodium para-aminosalicylate (PAS-Na) on manganese and iron combined neurotoxicity, providing a scientific basis for the prevention and treatment of ferromanganese combined neurotoxicity. Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were performed to detect the expression levels of protein and mRNA related to synaptic damage. Y-maze novelty test and balance beam test were used to evaluate the motor and cognitive function of rats. Haematoxylin and eosin (H&E) and Nissl staining were performed to observe the cortical damage of rats. The results showed that the combined exposure of Mn and Fe in rats led to a synergistic effect, attenuating growth and development, and altering learning and memory as well as motor function. The combination of Mn and Fe also caused damage to the synaptic structure of PC12 cells, which is manifested as swelling of dendrites and axon terminals, and even lead to cell death. PAS-Na displayed some antagonistic effects against the Mn- and Fe-induced synaptic structural damage, growth, learning and memory impairment.

Asunto(s)

Ácido Aminosalicílico , Manganeso , Sinapsis , Animales , Ratas , Células PC12 , Sinapsis/efectos de los fármacos , Masculino , Ácido Aminosalicílico/farmacología , Manganeso/toxicidad , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Corteza Cerebral/metabolismo , Ratas Sprague-Dawley , Hierro/metabolismo , Fármacos Neuroprotectores/farmacología , Aprendizaje por Laberinto/efectos de los fármacos , Síndromes de Neurotoxicidad/prevención & control , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/patología , Modelos Animales de Enfermedad

RESUMEN

Although colistin has a crucial antibacterial activity in treating multidrug-resistant gram-negative bacteria strains; it exhibited renal and neuronal toxicities rendering its use a challenge. Previous studies investigated the incretin hormones either glucose-dependent insulinotropic polypeptide (GIP) or glucagonlike peptide-1 (GLP-1) for their neuroprotective and nephroprotective effectiveness. The present study focused on investigating Tirzepatide (Tirze), a dual GLP-1/GIP agonist, as an adjuvant therapy in the colistin treatment protocol for attenuating its renal and neuronal complications. Rats were divided into; The normal control group, the colistin-treated group received colistin (300,000 IU/kg/day for 7 days; i.p.). The Tirze-treated group received Tirze (1.35 mg/kg on the 1,4,7thdays; s.c.) and daily colistin. Tirze effectively enhanced histopathological alterations, renal function parameters, and locomotor activity in rats. Tirze mechanistically acted via modulating various signaling axes evolved under the insult of phosphatidylinositol 3-kinases (PI3K)/phosphorylated protein kinase-B (p-Akt)/ glycogen synthase kinase (GSK)3-ß hub causing mitigation of nuclear factor (NF)-κB (NF-κB) / tumor necrosis factor-α (TNF-α), increment of nuclear factor erythroid 2-related factor 2 (Nrf2)/ glutathione (GSH), downregulation of ER stress-related biomarkers (activation transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP)), antiapoptotic effects coupling with reduction of glial fibrillary acidic protein (GFAP) immunoreactivity and enhancement of phosphorylated c-AMP response element-binding (p-CREB) / brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) neuroprotective pathway. Briefly, Tirze exerts a promising role as adjuvant therapy in the colistin treatment protocol for protection against colistin's nephro- and neurotoxicity according to its anti-inflammatory, antioxidant, and antiapoptotic impacts besides its ability to suppress ER stress-related biomarkers.

Asunto(s)

Factor Neurotrófico Derivado del Encéfalo , Colistina , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Estrés del Retículo Endoplásmico , Glucógeno Sintasa Quinasa 3 beta , Riñón , Estrés Oxidativo , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Animales , Estrés Oxidativo/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Masculino , Transducción de Señal/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Receptor trkB/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , Ratas Wistar , Antibacterianos/uso terapéutico , Antibacterianos/efectos adversos , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/prevención & control , Síndromes de Neurotoxicidad/metabolismo , Enfermedades Renales/inducido químicamente , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/prevención & control , Enfermedades Renales/metabolismo

RESUMEN

Methamphetamine (METH) is a highly abused substance on a global scale and has the capacity to elicit toxicity within the central nervous system. The neurotoxicity induced by METH encompasses neuronal degeneration and cellular demise within the substantia nigra-striatum and hippocampus. Caffeic acid phenethyl ester (CAPE), a constituent of propolis, is a diminutive compound that demonstrates antioxidative and anti-inflammatory characteristics. Numerous investigations have demonstrated the safeguarding effects of CAPE in various neurodegenerative ailments. Our hypothesis posits that CAPE may exert a neuroprotective influence on METH-induced neurotoxicity via specific mechanisms. In order to validate the hypothesis, a series of experimental techniques including behavioral tests, immunofluorescence labeling, RNA sequencing, and western blotting were employed to investigate the neurotoxic effects of METH and the potential protective effects of CAPE. The results of our study demonstrate that CAPE effectively ameliorates cognitive memory deficits and anxiety symptoms induced by METH in mice. Furthermore, CAPE has been observed to attenuate the upregulation of neurotoxicity-associated proteins that are induced by METH exposure and also reduced the loss of hippocampal neurons in mice. Moreover, transcriptomics analysis was conducted to determine alterations in gene expression within the hippocampus of mice. Subsequently, bioinformatics analysis was employed to investigate the divergent outcomes and identify potential key genes. Interferon-stimulated gene 15 (ISG15) was successfully identified and confirmed through RT-qPCR, western blotting, and immunofluorescence techniques. Our research findings unequivocally demonstrated the neuroprotective effect of CAPE against METH-induced neurotoxicity, with ISG15 may have an important role in the underlying protective mechanism. These results offer novel perspectives on the treatment of METH-induced neurotoxicity.

Asunto(s)

Ácidos Cafeicos , Metanfetamina , Fármacos Neuroprotectores , Síndromes de Neurotoxicidad , Alcohol Feniletílico , Animales , Ácidos Cafeicos/farmacología , Alcohol Feniletílico/análogos & derivados , Alcohol Feniletílico/farmacología , Metanfetamina/toxicidad , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Ratones , Masculino , Síndromes de Neurotoxicidad/prevención & control , Síndromes de Neurotoxicidad/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos

RESUMEN

The investigation into the hippocampal function and its response to heavy metal exposure is crucial for understanding the mechanisms underlying neurotoxicity, this can potentially inform strategies for mitigating the adverse effects associated with heavy metal exposure. Melatonin is an essential neuromodulator known for its efficacy as an antioxidant. In this study, we aimed to determine whether melatonin could protect against Nickel (Ni) neurotoxicity. To achieve this, we performed an intracerebral injection of Ni (300 µM NiCl2) into the right hippocampus of male Wistar rats, followed by melatonin treatment. Based on neurobehavioral and neurobiochemical assessments, our results demonstrate that melatonin efficiently enhances Ni-induced behavioral dysfunction and cognitive impairment. Specifically, melatonin treatment positively influences anxious behavior, significantly reduces immobility time in the forced swim test (FST), and improves learning and spatial memory abilities. Moreover, neurobiochemical assays revealed that melatonin treatment modulates the Ni-induced alterations in oxidative stress balance by increasing antioxidant enzyme activities, such as superoxide dismutase (SOD) and catalase (CAT). Additionally, we observed that melatonin significantly attenuated the increased levels of lipid peroxidation (LPO) and nitric oxide (NO). In conclusion, the data from this study suggests that melatonin attenuates oxidative stress, which is the primary mechanism responsible for Ni-induced neurotoxicity. Considering that the hippocampus is the main structure involved in the pathology associated with heavy metal intoxication, such as Ni, these findings underscore the potential therapeutic efficacy of melatonin in mitigating heavy metal-induced brain damage.

Asunto(s)

Melatonina , Síndromes de Neurotoxicidad , Masculino , Ratas , Animales , Antioxidantes/farmacología , Melatonina/farmacología , Melatonina/uso terapéutico , Níquel/toxicidad , Ratas Wistar , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/prevención & control

RESUMEN

BACKGROUND: Excessive manganese exposure can lead to neurotoxicity with detrimental effects on the brain. Neuroinflammatory responses and redox regulation play pivotal roles in this process. Exploring the impact of hyperoside in a Wistar rat model offers insights into potential neuroprotective strategies against manganese-induced neurotoxicity. OBJECTIVE: The study investigated the neuroprotective efficacy of hyperoside isolated from the ethanol leaf extract of Gongronema latifolium (HELEGL), in the brain tissue of Wistar rats following 15 consecutive days of exposure to 30 mg/L of MnCl2. METHODS: Control animals in Group 1 had access to regular drinking water, while animals in groups 2-4 were exposed to MnCl2 in their drinking water. Groups 3 and 4 also received additional HELEGL at doses of 100 mg/kg and 200 mg/kg of body weight, respectively. In Group 5, HELEGL at a dose of 100 mg/kg of body weight was administered alone. Treatment with HELEGL commenced on day 8 via oral administration. RESULTS: HELEGL effectively mitigated MnCl2-induced memory impairment, organ-body weight discrepancies, and fluid intake deficits. Exposure to MnCl2 increased the activities or levels of various markers such as acyl peptide hydrolase, tumour necrosis factor-α, dipeptidyl peptidase IV, nitric oxide, IL-1ß, prolyl oligopeptidase, caspase-3, myeloperoxidase, H2O2, and malondialdehyde, while it decreased the activities or levels of others, including AChE, BChE, DOPA, serotonin, epinephrine, norepinephrine, GST, GPx, CAT, SOD, GSH, and T-SH (p < 0.05). In contrast, HELEGL effectively counteracted the adverse effects of MnCl2 by alleviating oxidative stress, inflammation, apoptosis, mitochondrial dysfunction, cognitive deficits, and bolstering the antioxidant status. Moreover, HELEGL restored the normal histoarchitecture of the brain, which had been distorted by MnCl2. CONCLUSION: In summary, HELEGL reversed the causative factors of neurodegenerative diseases induced by MnCl2 exposure, suggesting its potential for further exploration as a prospective therapeutic agent in the management of Alzheimer's disease and related forms of dementia.

Asunto(s)

Encéfalo , Cloruros , Modelos Animales de Enfermedad , Compuestos de Manganeso , Fármacos Neuroprotectores , Oxidación-Reducción , Estrés Oxidativo , Quercetina , Ratas Wistar , Animales , Quercetina/farmacología , Quercetina/análogos & derivados , Cloruros/toxicidad , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Masculino , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Mediadores de Inflamación/metabolismo , Enfermedades Neuroinflamatorias/inducido químicamente , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Conducta Animal/efectos de los fármacos , Antioxidantes/farmacología , Ratas , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/prevención & control , Síndromes de Neurotoxicidad/patología , Antiinflamatorios/farmacología , Memoria/efectos de los fármacos

RESUMEN

INTRODUCTION: Seizures may occur in up to 30% of non-Hodgkin lymphoma patients who received anti-CD19 CAR T-cell therapy, yet the optimal anti-seizure medication (ASM) prevention strategy has not been thoroughly investigated. METHODS: Consecutive patients affected by refractory non-Hodgkin lymphoma who received anti-CD19 CAR T-cells were included. Patients were selected and assessed using similar internal protocols. ASM was started either as a primary prophylaxis (PP-group) before CAR T-cells infusion or as a pre-emptive therapy (PET-group) only upon the onset of neurotoxicity development. RESULTS: One hundred fifty-six patients were included (PP-group = 88, PET-group = 66). Overall, neurotoxicity and severe neurotoxicity occurred in 45 (29%) and 20 (13%) patients, respectively, equally distributed between the two groups. Five patients experienced epileptic events (PET-group = 3 [4%]; PP-group = 2 [2%]). For all the PET-group patients, seizure/status epilepticus occurred in the absence of overt CAR-T-related neurotoxicity, whereas patients in the PP-group experienced brief seizures only in the context of critical neurotoxicity with progressive severe encephalopathy. ASMs were well-tolerated by all patients, even without titration. No patients developed epilepsy or required long-term ASMs. CONCLUSION: Our data suggest that both primary and pre-emptive anti-seizure prophylaxis are safe and effective in anti-CD19 CAR T-cell recipients. Clinical rationale suggests a possible more favourable profile of primary prophylaxis, yet no definitive conclusion of superiority between the two ASM strategies can be drawn from our study.

Asunto(s)

Anticonvulsivantes , Antígenos CD19 , Inmunoterapia Adoptiva , Linfoma no Hodgkin , Convulsiones , Humanos , Masculino , Femenino , Persona de Mediana Edad , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Convulsiones/prevención & control , Antígenos CD19/inmunología , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/uso terapéutico , Linfoma no Hodgkin/terapia , Linfoma no Hodgkin/inmunología , Adulto , Anciano , Síndromes de Neurotoxicidad/prevención & control , Síndromes de Neurotoxicidad/etiología

RESUMEN

BACKGROUND: Bupivacaine (BUP), a long-acting local anesthetic, has been widely used in analgesia and anesthesia. However, evidence strongly suggests that excessive application of BUP may lead to neurotoxicity in neurons. Sphingosine kinase 2 (SPHK2) has been reported to exert neuroprotective effects. In this study, we intended to investigate the potential role and mechanism of SPHK2 in BUP-induced neurotoxicity in dorsal root ganglion (DRG) neurons. METHODS: DRG neurons were cultured with BUP to simulate BUP-induced neurotoxicity in vitro. CCK-8, LDH, and flow cytometry assays were performed to detect the viability, LDH activity, and apoptosis of DRG neurons. RT-qPCR and western blotting was applied to measure gene and protein expression. Levels. MeRIP-qPCR was applied for quantification of m6A modification. RIP-qPCR was used to analyze the interaction between SPHK2 and YTHDF1. RESULTS: SPHK2 expression significantly declined in DRG neurons upon exposure to BUP. BUP challenge substantially reduced the cell viability and increased the apoptosis rate in DRG neurons, which was partly abolished by SPHK2 upregulation. YTHDF1, an N6-methyladenosine (m6A) reader, promoted SPHK2 expression in BUP-treated DRG neurons in an m6A-dependent manner. YTHDF1 knockdown partly eliminated the increase in SPHK2 protein level and the protection against BUP-triggered neurotoxicity in DRG neurons mediated by SPHK2 overexpression. Moreover, SPHK2 activated the PI3K/AKT signaling to protect against BUP-induced cytotoxic effects on DRG neurons. CONCLUSIONS: In sum, YTHDF1-mediated SPHK2 upregulation ameliorated BUP-induced neurotoxicity in DRG neurons via promoting activation of the PI3K/AKT signaling pathway.

Asunto(s)

Bupivacaína , Síndromes de Neurotoxicidad , Fosfotransferasas (Aceptor de Grupo Alcohol) , Humanos , Bupivacaína/toxicidad , Regulación hacia Arriba , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Síndromes de Neurotoxicidad/prevención & control , Apoptosis , Proteínas de Unión al ARN

RESUMEN

Rutin, a phenolic compound, exhibits a diverse range of biological properties, including antioxidant, anti-inflammatory, and antimicrobial effects. In this study, we aimed to investigate the potential of rutin, a naturally occurring plant bioactive molecule, to mitigate the neurotoxic effects induced by aluminum chloride (AlCl3). Over a period of 6 weeks, rats were intraperitoneally injected with AlCl3 at a weekly dose of 60 mg/kg, while rutin treatment was administered orally via gavage at a daily dose of 30 mg/kg. AlCl3 exposure resulted in a significant increase lipid peroxidation (LPO) by 316.24%, nitrate levels by 504.14%, and tumor necrosis factor-alpha (TNF-α) levels by 93.82% in brain mitochondria. Additionally, AlCl3 exposure led to a reduction in glutathione levels and the activity of antioxidant enzymes, including superoxide dismutase (SOD) by 19.74%, glutathione peroxidase (GPx) by 44.76%, and catalase by 50.50%. There was also a significant decline in the activity of mitochondrial complex enzymes. In contrast, rutin treatment significantly enhanced the activity of antioxidant enzymes while concurrently reducing lipid peroxidation levels in rats. Specifically, rutin administration exerted a modulatory effect on the inflammatory response triggered by aluminum exposure, effectively suppressing the excessive production of nitrate and TNF-α. These findings highlight the potential of rutin as an effective therapeutic strategy in mitigating and combating neuro-inflammation and oxidative stress associated with aluminum-induced toxicity, thereby effectively restoring mitochondrial function.

Asunto(s)

Cloruro de Aluminio , Peroxidación de Lípido , Mitocondrias , Rutina , Animales , Rutina/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ratas , Masculino , Cloruro de Aluminio/toxicidad , Peroxidación de Lípido/efectos de los fármacos , Síndromes de Neurotoxicidad/prevención & control , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamente , Antioxidantes/farmacología , Antioxidantes/metabolismo , Ratas Wistar , Aluminio/toxicidad , Factor de Necrosis Tumoral alfa/metabolismo , Modelos Animales de Enfermedad , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Enfermedades Neurodegenerativas/inducido químicamente , Enfermedades Neurodegenerativas/prevención & control , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico

RESUMEN

Bupivacaine, a common amide local anesthetic, can provide effective analgesia or pain relief but can also cause neurotoxicity, which remains a mounting concern in clinic and animal care. However, the precise underlying mechanisms have not been fully elucidated. A natural compound, notoginsenoside R1 (NG-R1) has been reported to exhibit a neuroprotective role in stress conditions. In this study, we explored the function and mechanism of NG-R1 in alleviating bupivacaine-induced neurotoxicity in mouse hippocampal neuronal (HT-22) and mouse neuroblastoma (Neuro-2a) cell lines. Our results exhibited that NG-R1 treatment can significantly rescue the decline of cell survival induced by bupivacaine. Tunel staining and western blotting showed that NG-R1 could attenuate BPV­induced cell apoptosis. Besides, we focused on Mcl1 as a potential target as it showed opposite expression tendency in response to NG-R1 and bupivacaine exposure. Mcl1 knockdown blocked the inhibitory effect of NG-R1 on cell apoptosis against bupivacaine treatment. Intriguingly, we found that NG-R1 can upregulate Mcl1 transcription by activating Stat3 and promote its nuclear translocation. In addition, NG-R1 can also promote Jak1 phosphorylation and docking analysis provide a predicted model for interaction between NG-R1 and phosphorylated Jak1. Taken together, our results demonstrated that NG-R1 can attenuate bupivacaine induced neurotoxicity by activating Jak1/Stat3/Mcl1 pathway.

Asunto(s)

Ginsenósidos , Síndromes de Neurotoxicidad , Ratones , Animales , Bupivacaína/toxicidad , Ginsenósidos/farmacología , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/prevención & control , Síndromes de Neurotoxicidad/metabolismo , Línea Celular , Apoptosis

RESUMEN

BACKGROUND: The anti-oxidative, anti-inflammatory, and anti-apoptotic effects of erythropoietin may provide neuroprotective effects. Erythropoietin also modulates autophagy signaling that may play a role in anesthesia-induced neurotoxicity (AIN). Herein, we investigated whether AIN can be attenuated by the neuroprotective effect of erythropoietin in the Caenorhabditis elegans (C. elegans). METHODS: Synchronized worms were divided into the control, Iso, EPO, and EPO-Iso groups. The chemotaxis index (CI) was evaluated when they reached the young adult stage. The lgg-1::GFP-positive puncta per seam cell were used to determine the autophagic events. The erythropoietin-mediated pathway of autophagy was determined by measuring the genetic expression level of let-363, bec-1, atg-7, atg-5, and lgg-3. RESULTS: Increased lgg-1::GFP puncta were observed in the Iso, EPO, and EPO-Iso groups. In the Iso group, only the let-363 level decreased significantly as compared to that in the control group (P = 0.009). bec-1 (P < 0.001), atg-5 (P = 0.012), and lgg-3 (P < 0.001) were expressed significantly more in the EPO-Iso group than in the Iso groups. Repeated isoflurane exposure during development decreased the CI. Erythropoietin could restore the decreased CI by isoflurane significantly in the EPO-Iso group. CONCLUSIONS: Erythropoietin showed neuroprotective effects against AIN and modulated the autophagic pathway in C. elegans. This experimental evidence of erythropoietin-related neuroprotection against AIN may be correlated with the induced autophagic degradation process that was sufficient for handling enhanced autophagy induction in erythropoietin-treated worms.

Asunto(s)

Autofagia , Caenorhabditis elegans , Eritropoyetina , Fármacos Neuroprotectores , Animales , Caenorhabditis elegans/efectos de los fármacos , Autofagia/efectos de los fármacos , Autofagia/fisiología , Eritropoyetina/farmacología , Fármacos Neuroprotectores/farmacología , Síndromes de Neurotoxicidad/prevención & control , Anestesia/métodos , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/efectos de los fármacos

RESUMEN

The MTS cell viability test was used to screen a mini library of natural and synthetic 1,4-naphthoquinone derivatives (1,4-NQs) from marine sources. This screening identified two highly effective compounds, U-443 and U-573, which showed potential in protecting Neuro-2a neuroblastoma cells from the toxic effects of rotenone in an in vitro model of neurotoxicity. The selected 1,4-NQs demonstrated the capability to reduce oxidative stress by decreasing the levels of reactive oxygen species (ROS) and nitric oxide (NO) in Neuro-2a neuroblastoma cells and RAW 264.7 macrophage cells and displayed significant antioxidant properties in mouse brain homogenate. Normal mitochondrial function was restored and the mitochondrial membrane potential was also regained by 1,4-NQs after exposure to neurotoxins. Furthermore, at low concentrations, these compounds were found to significantly reduce levels of proinflammatory cytokines TNF and IL-1ß and notably inhibit the activity of cyclooxygenase-2 (COX-2) in RAW 264.7 macrophages. The results of docking studies showed that the 1,4-NQs were bound to the active site of COX-2, analogically to a known inhibitor of this enzyme, SC-558. Both substances significantly improved the behavioral changes in female CD1 mice with rotenone-induced early stage of Parkinson's disease (PD) in vivo. It is proposed that the 1,4-NQs, U-443 and U-573, can protect neurons and microglia through their potent anti-ROS and anti-inflammatory activities.

Asunto(s)

Naftoquinonas , Neuroblastoma , Fármacos Neuroprotectores , Síndromes de Neurotoxicidad , Enfermedad de Parkinson , Femenino , Ratones , Animales , Rotenona/toxicidad , Ciclooxigenasa 2 , Naftoquinonas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/prevención & control , Fármacos Neuroprotectores/farmacología