Neurotox Res [JOURNAL]
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200 papers
Monoclonal Antibody Targeting CGRP Relieves Cisplatin-Induced Neuropathic Pain by Attenuating Neuroinflammation.
Xie S, Gao Z, Zhang J … +8 more , Xing C, Dong Y, Wang L, Wang Z, Li Y, Li G, Han G, Gong T
Neurotox Res · 2024 Jan · PMID 38194189 · Publisher ↗
Chemotherapy-induced neuropathic pain (CIPN) is a common side effect of antitumor chemotherapeutic agents. It describes a pathological state of pain related to the cumulative dosage of the drug, significantly limiting th...
Chemotherapy-induced neuropathic pain (CIPN) is a common side effect of antitumor chemotherapeutic agents. It describes a pathological state of pain related to the cumulative dosage of the drug, significantly limiting the efficacy of antitumor treatment. Sofas strategies alleviating CIPN still lack. Calcitonin gene-related peptide (CGRP) is a neuropeptide involved in many pathologic pains. In this study, we explored the effects of CGRP blocking on CIPN and potential mechanisms. Total dose of 20.7 mg/kg cisplatin was used to establish a CIPN mouse model. Mechanical and thermal hypersensitivity was measured using von Frey hairs and tail flick test. Western blot and immunofluorescence were utilized to evaluate the levels of CGRP and activated astrocytes in mouse spinal cord, respectively. In addition, real-time quantitative PCR (RT-qPCR) was used to detect the level of inflammatory cytokines such as IL-6, IL-1β, and NLRP3 in vitro and in vivo. There are markedly increased CGRP expression and astrocyte activation in the spinal cord of mice following cisplatin treatment. Pretreatment with a monoclonal antibody targeting CGRP (ZR8 mAb) effectively reduced cisplatin-induced mechanical hypersensitivity and thermal nociceptive sensitization and attenuated neuroinflammation as marked by downregulated expression of IL-6, IL-1β, and NLRP3 in the mice spinal cord and spleen. Lastly, ZR8 mAb does not interfere with the antitumor effects of cisplatin in tumor-bearing mice. Our findings indicate that neutralizing CGRP with monoclonal antibody could effectively alleviate CIPN by attenuating neuroinflammation. CGRP is a promising therapeutic target for CIPN.
Divergent Pattern of Development in Rats and Humans.
Campos Eusebi W, Iorii T, Presti A … +2 more , Grimson R, Vázquez-Borsetti P
Neurotox Res · 2023 Dec · PMID 38147261 · Publisher ↗
Rattus norvegicus is the second most used laboratory species and the most widely used model in neuroscience. Nonetheless, there is still no agreement regarding the temporal relationship of development between humans and...
Rattus norvegicus is the second most used laboratory species and the most widely used model in neuroscience. Nonetheless, there is still no agreement regarding the temporal relationship of development between humans and rats. We addressed this question by examining the time required to reach a set of homologous developmental milestones in both species. With this purpose, a database was generated with data collected through a bibliographic survey. This database was in turn compared with other databases about the same topic present in the literature. Finally, the databases were combined, covering for the first time the entire development of the rat including the prenatal, perinatal, and postnatal periods. This combined database includes 362 dates of 181 developmental events for each species. The developmental relationship between humans and rats was better fit by a logarithmic function than by a linear function. As development progresses, an increase in the dispersion of the data is observed. Developmental relationships should not be interpreted as a univocal equivalence. In this work is proposed an alternative interpretation where the age of one species is translated into a range of ages in the other.
Modulation of Neuronal Damage in DRG by Asprosin in a High-Glucose Environment and Its Impact on miRNA181-a Expression in Diabetic DRG.
Adam M, Ozcan S, Dalkilic S … +8 more , Tektemur NK, Tekin S, Bilgin B, Hekim MG, Bulut F, Kelestemur MM, Canpolat S, Ozcan M
Neurotox Res · 2023 Dec · PMID 38133838 · Publisher ↗
Asprosin, a hormone secreted from adipose tissue, has been implicated in the modulation of cell viability. Current studies suggest that neurological impairments are increased in individuals with obesity-linked diabetes,...
Asprosin, a hormone secreted from adipose tissue, has been implicated in the modulation of cell viability. Current studies suggest that neurological impairments are increased in individuals with obesity-linked diabetes, likely due to the presence of excess adipose tissue, but the precise molecular mechanism behind this association remains poorly understood. In this study, our hypothesis that asprosin has the potential to mitigate neuronal damage in a high glucose (HG) environment while also regulating the expression of microRNA (miRNA)-181a, which is involved in critical biological processes such as cellular survival, apoptosis, and autophagy. To investigate this, dorsal root ganglion (DRG) neurons were exposed to asprosin in a HG (45 mmol/L) environment for 24 hours, with a focus on the role of the protein kinase A (PKA) pathway. Expression of miRNA-181a was measured by using real-time polymerase chain reaction (RT-PCR) in diabetic DRG. Our findings revealed a decline in cell viability and an upregulation of apoptosis under HG conditions. However, pretreatment with asprosin in sensory neurons effectively improved cell viability and reduced apoptosis by activating the PKA pathway. Furthermore, we observed that asprosin modulated the expression of miRNA-181a in diabetic DRG. Our study demonstrates that asprosin has the potential to protect DRG neurons from HG-induced damage while influencing miRNA-181a expression in diabetic DRG. These findings provide valuable insights for the development of clinical interventions targeting neurotoxicity in diabetes, with asprosin emerging as a promising therapeutic target for managing neurological complications in affected individuals.
Local Administrations of Iron Oxide Nanoparticles in the Prefrontal Cortex and Caudate Putamen of Rats Do Not Compromise Working Memory and Motor Activity.
Irrsack E, Aydin S, Bleckmann K … +3 more , Schuller J, Dringen R, Koch M
Neurotox Res · 2023 Dec · PMID 38133743 · Full text
Iron oxide nanoparticles (IONPs) have come into focus for their use in medical applications although possible health risks for humans, especially in terms of brain functions, have not yet been fully clarified. The presen...
Iron oxide nanoparticles (IONPs) have come into focus for their use in medical applications although possible health risks for humans, especially in terms of brain functions, have not yet been fully clarified. The present study investigates the effects of IONPs on neurobehavioural functions in rats. For this purpose, we infused dimercaptosuccinic acid-coated IONPs into the medial prefrontal cortex (mPFC) and caudate putamen (CPu). Saline (VEH) and ferric ammonium citrate (FAC) were administered as controls. One- and 4-week post-surgery mPFC-infused animals were tested for their working memory performance in the delayed alternation T-maze task and in the open field (OF) for motor activity, and CPu-infused rats were tested for their motor activity in the OF. After completion of the experiments, the brains were examined histologically and immunohistochemically. We did not observe any behavioural or structural abnormalities in the rats after administration of IONPs in the mPFC and the CPu. In contrast, administration of FAC into the CPu resulted in decreased motor activity and increased the number of microglia in the mPFC. Perls' Prussian blue staining revealed that FAC- and IONP-treated rats had more iron-containing ramified cells than VEH-treated rats, indicating iron uptake by microglia. Our results demonstrate that local infusions of IONPs into selected brain regions have no adverse impact on locomotor behaviour and working memory.
Gut-Brain Axis Deregulation and Its Possible Contribution to Neurodegenerative Disorders.
Villavicencio-Tejo F, Olesen MA, Navarro L … +5 more , Calisto N, Iribarren C, García K, Corsini G, Quintanilla RA
Neurotox Res · 2023 Dec · PMID 38103074 · Publisher ↗
The gut-brain axis is an essential communication pathway between the central nervous system (CNS) and the gastrointestinal tract. The human microbiota is composed of a diverse and abundant microbial community that compas...
The gut-brain axis is an essential communication pathway between the central nervous system (CNS) and the gastrointestinal tract. The human microbiota is composed of a diverse and abundant microbial community that compasses more than 100 trillion microorganisms that participate in relevant physiological functions such as host nutrient metabolism, structural integrity, maintenance of the gut mucosal barrier, and immunomodulation. Recent evidence in animal models has been instrumental in demonstrating the possible role of the microbiota in neurodevelopment, neuroinflammation, and behavior. Furthermore, clinical studies suggested that adverse changes in the microbiota can be considered a susceptibility factor for neurological disorders (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). In this review, we will discuss evidence describing the role of gut microbes in health and disease as a relevant risk factor in the pathogenesis of neurodegenerative disorders, including AD, PD, HD, and ALS.
Static Magnetic Field Reduces Intracellular ROS Levels and Protects Cells Against Peroxide-Induced Damage: Suggested Roles for Catalase.
Frachini ECG, Silva JB, Fornaciari B … +3 more , Baptista MS, Ulrich H, Petri DFS
Neurotox Res · 2023 Dec · PMID 38095761 · Publisher ↗
A feature in neurodegenerative disorders is the loss of neurons, caused by several factors including oxidative stress induced by reactive oxygen species (ROS). In this work, static magnetic field (SMF) was applied in vit...
A feature in neurodegenerative disorders is the loss of neurons, caused by several factors including oxidative stress induced by reactive oxygen species (ROS). In this work, static magnetic field (SMF) was applied in vitro to evaluate its effect on the viability, proliferation, and migration of human neuroblastoma SH-SY5Y cells, and on the toxicity induced by hydrogen peroxide (HO), tert-butyl hydroperoxide (tBHP), HO/sodium azide (NaN) and photosensitized oxidations by photodynamic therapy (PDT) photosensitizers. The SMF increased almost twofold the cell expression of the proliferation biomarker Ki-67 compared to control cells after 7 days of exposure. Exposure to SMF accelerated the wound healing of scratched cell monolayers and significantly reduced the HO-induced and the tBHP-induced cell deaths. Interestingly, SMF was able to revert the effects of NaN (a catalase inhibitor), suggesting an increased activity of catalase under the influence of the magnetic field. In agreement with this hypothesis, SMF significantly reduced the oxidation of DCF-H2, indicating a lower level of intracellular ROS. When the redox imbalance was triggered through photosensitized oxidation, no protection was observed. This observation aligns with the proposed role of catalase in cellular proctetion under SMF. Exposition to SMF should be further validated in vitro and in vivo as a potential therapeutic approach for neurodegenerative disorders.
Butyrate Protects and Synergizes with Nicotine against Iron- and Manganese-induced Toxicities in Cell Culture.
Tizabi Y, Getachew B, Aschner M
Neurotox Res · 2023 Dec · PMID 38095760 · Publisher ↗
Toxic exposures to heavy metals, such as iron (Fe) and manganese (Mn), can result in long-range neurological diseases and are therefore of significant environmental and medical concerns. We have previously reported that...
Toxic exposures to heavy metals, such as iron (Fe) and manganese (Mn), can result in long-range neurological diseases and are therefore of significant environmental and medical concerns. We have previously reported that damage to neuroblastoma-derived dopaminergic cells (SH-SY5Y) by both Fe and Mn could be prevented by pre-treatment with nicotine. Moreover, butyrate, a short chain fatty acid (SCFA) provided protection against salsolinol, a selective dopaminergic toxin, in the same cell line. Here, we broadened the investigation to determine whether butyrate might also protect against Fe and/or Mn, and whether, if combined with nicotine, an additive or synergistic effect might be observed. Both butyrate and nicotine concentration-dependently blocked Fe and Mn toxicities. Ineffective concentrations of nicotine and butyrate, when combined, provided full protection against both Fe and Mn. Moreover, the effects of nicotine but not butyrate could be blocked by mecamylamine, a non-selective nicotinic antagonist. On the other hand, the effects of butyrate, but not nicotine, could be blocked by beta-hydroxy butyrate, a fatty acid-3 receptor antagonist. These results not only provide further support for neuroprotective effects of both nicotine and butyrate but also indicate distinct mechanisms of action for each one. Furthermore, potential utility of butyrate and nicotine combination against heavy metal toxicities is suggested.
Mechanistic Implications of GSK and CREB Crosstalk in Ischemia Injury.
Khan H, Bangar A, Grewal AK … +1 more , Singh TG
Neurotox Res · 2023 Dec · PMID 38091155 · Publisher ↗
Ischemia-reperfusion (IR) injury is a damage to an organ when the blood supply is less than the demand required for normal functioning, leading to exacerbation of cellular dysfunction and death. IR injury occurs in diffe...
Ischemia-reperfusion (IR) injury is a damage to an organ when the blood supply is less than the demand required for normal functioning, leading to exacerbation of cellular dysfunction and death. IR injury occurs in different organs like the kidney, liver, heart, brain, etc., and may not only involve the ischemic organ but also cause systemic damage to distant organs. Oxygen-glucose deprivation in cells causes oxidative stress, calcium overloading, inflammation, and apoptosis. CREB is an essential integrator of the body's various physiological systems, and it is widely accepted that dysfunction of CREB signaling is involved in many diseases, including ischemia-reperfusion injury. The activation of CREB can provide life to a cell and increase the cell's survival after ischemia. Hence, GSK/CREB signaling pathway can provide significant protection to cells of different organs after ischemia and emerges as a futuristic strategy for managing ischemia-reperfusion injury. Different signaling pathways such as MAPK/ERK, TLR4/MyD88, RISK, Nrf2, and NF-κB, get altered during IR injury by the modulation of GSK-3 and CREB (cyclic AMP response element (CRE)-binding protein). GSK-3 (protein kinase B) and CREB are the downstream targets for fulfilling the roles of various signaling pathways. Calcium overloading during ischemia increases the expression of calcium-calmodulin-dependent protein kinase (CaMK), which subsequently activates CREB-mediated transcription, thus promoting the survival of cells. Furthermore, this review highlights the crosstalk between GSK-3 and CREB, promoting survival and rendering the cells resistant to subsequent severe ischemia.
(m) RVD-hemopressin (α) Ameliorated Oxidative Stress, Apoptosis and Damage to the BDNF/TrkB/Akt Pathway Induced by Scopolamine in HT22 Cells.
Zhang R, He X, Cheng J … +5 more , Zhang X, Han C, Liu Y, Chen P, Wang Y
Neurotox Res · 2023 Dec · PMID 37971633 · Publisher ↗
Dysfunction in the cholinergic system and oxidative stress are closely related and play roles in Alzheimer's disease (AD). Scopolamine (Scop), which is commonly used to induce cholinergic system damage in cells and anima...
Dysfunction in the cholinergic system and oxidative stress are closely related and play roles in Alzheimer's disease (AD). Scopolamine (Scop), which is commonly used to induce cholinergic system damage in cells and animals, also evokes oxidative stress. Our previous study indicated that the peptide (m) RVD-hemopressin (RVD) reversed the memory-impairing effect of Scop in mice by activating cannabinoid receptor 1 (CBR1), but the mechanism was unclear. In this study, we found that RVD inhibited the oxidative stress, apoptosis, decreased cell viability and downregulation of synapse-associated proteins induced by Scop in HT22 cells. The effect was associated with the BDNF/TrkB/Akt pathway, and the effects of RVD outlined above could be blocked by an antagonist of CBR1. These results suggest that RVD may be a potential drug candidate for disorders associated with damage to the cholinergic system and oxidative stress, such as AD.
Metergoline Shares Properties with Atypical Antipsychotic Drugs Identified by Gene Expression Signature Screen.
Bortolasci CC, Jaehne EJ, Hernández D … +11 more , Spolding B, Connor T, Panizzutti B, Dean OM, Crowley TM, Yung AR, Gray L, Kim JH, van den Buuse M, Berk M, Walder K
Neurotox Res · 2023 Dec · PMID 37922109 · Full text
Novel approaches are required to find new treatments for schizophrenia and other neuropsychiatric disorders. This study utilised a combination of in vitro transcriptomics and in silico analysis with the BROAD Institute's...
Novel approaches are required to find new treatments for schizophrenia and other neuropsychiatric disorders. This study utilised a combination of in vitro transcriptomics and in silico analysis with the BROAD Institute's Connectivity Map to identify drugs that can be repurposed to treat psychiatric disorders. Human neuronal (NT2-N) cells were treated with a combination of atypical antipsychotic drugs commonly used to treat psychiatric disorders (such as schizophrenia, bipolar disorder, and major depressive disorder), and differential gene expression was analysed. Biological pathways with an increased gene expression included circadian rhythm and vascular endothelial growth factor signalling, while the adherens junction and cell cycle pathways were transcriptionally downregulated. The Connectivity Map (CMap) analysis screen highlighted drugs that affect global gene expression in a similar manner to these psychiatric disorder treatments, including several other antipsychotic drugs, confirming the utility of this approach. The CMap screen specifically identified metergoline, an ergot alkaloid currently used to treat seasonal affective disorder, as a drug of interest. In mice, metergoline dose-dependently reduced MK-801- or methamphetamine-induced locomotor hyperactivity confirming the potential of metergoline to treat positive symptoms of schizophrenia in an animal model. Metergoline had no effects on prepulse inhibition deficits induced by MK-801 or methamphetamine. Taken together, metergoline appears a promising drug for further studies to be repurposed as a treatment for schizophrenia and possibly other psychiatric disorders.
Physical Exercise Promotes Beneficial Changes on Neurotrophic Factors in Mesolimbic Brain Areas After AMPH Relapse: Involvement of the Endogenous Opioid System.
H Z R, H J S, R C S B … +3 more , Kr R, R RD, M E B
Neurotox Res · 2023 Dec · PMID 37904065 · Publisher ↗
Addiction is a serious public health problem, and the current pharmacotherapy is unable to prevent drug use reinstatement. Studies have focused on physical exercise as a promising coadjuvant treatment. Our research group...
Addiction is a serious public health problem, and the current pharmacotherapy is unable to prevent drug use reinstatement. Studies have focused on physical exercise as a promising coadjuvant treatment. Our research group recently showed beneficial neuroadaptations in the dopaminergic system related to amphetamine-relapse prevention involving physical exercise-induced endogenous opioid system activation (EXE-OS activation). In this context, additional mechanisms were explored to understand the exercise benefits on drug addiction. Male rats previously exposed to amphetamine (AMPH, 4.0 mg/kg) for 8 days were submitted to physical exercise for 5 weeks. EXE-OS activation was blocked by naloxone administration (0.3 mg/kg) 5 min before each physical exercise session. After the exercise protocol, the rats were re-exposed to AMPH for 3 days, and in sequence, euthanasia was performed and the VTA and NAc were dissected. In the VTA, our findings showed increased immunocontent of proBDNF, BDNF, and GDNF and decreased levels of AMPH-induced TrkB; therefore, EXE-OS activation increased all these markers and naloxone administration prevented this exercise-induced effect. In the NAc, the same molecular markers were also increased by AMPH and decreased by EXE-OS activation. In this study, we propose a close relation between EXE-OS activation beneficial influence and a consequent neuroadaptation on neurotrophins and dopaminergic system levels in the mesolimbic brain area, preventing the observed AMPH-relapse behavior. Our outcomes bring additional knowledge concerning addiction neurobiology understanding and show that EXE-OS activation may be a potential adjuvant tool in drug addiction therapy.
Biological Pathways Associated with Vitamins in Autism Spectrum Disorder.
Gusso D, Prauchner GRK, Rieder AS … +1 more , Wyse ATS
Neurotox Res · 2023 Dec · PMID 37864660 · Publisher ↗
Autism spectrum disorder (ASD) is characterized by early-appearing social communication deficits, with genetic and environmental factors potentially playing a role in its etiology, which remains largely unknown. During p...
Autism spectrum disorder (ASD) is characterized by early-appearing social communication deficits, with genetic and environmental factors potentially playing a role in its etiology, which remains largely unknown. During pregnancy, certain deficiencies in critical nutrients are mainly associated with central nervous system impairment. The vitamin B9 (folate) is primarily related to one-carbon and methionine metabolism, participating in methyl donor generation. In addition, supplementation with folic acid (FA) is recommended by the World Health Organization (WHO) in the first three gestational months to prevent neural tube defects. Vitamin B12 is related to folate regeneration, converting it into an active form. Deficiencies in this vitamin have a negative impact on cognitive function and brain development since it is involved in myelin synthesis. Vitamin D is intimately associated with Ca levels, acting in bone development and calcium-dependent signaling. This vitamin is associated with ASD at several levels since it has a relation with ASD genes and oxidative stress environment. This review carries the recent literature about the role of folate, vitamin B12, and vitamin D in ASD. In addition, we discuss the possible impact of nutrient deficiency or hypersupplementation during fetal development. On the other hand, we explore the biases of vitamin supplementation studies such as the loss of participants in retrospective studies, as well as multiple variants that are not considered in the conclusion, like dietary intake or auto-medication during pregnancy. In this regard, we aim to contribute to the discussion about the role of vitamins in ASD currency, but also in pregnancy and fetal development as well. Furthermore, stress during pregnancy can be an ASD predisposition, with cortisol as a regulator. In this view, we propose that cortisol is the bridge of susceptibility between vitamin disorders and ASD prevalence.
BIN1 in the Pursuit of Ousting the Alzheimer's Reign: Impact on Amyloid and Tau Neuropathology.
Kaur I, Behl T, Sundararajan G … +11 more , Panneerselvam P, Vijayakumar AR, Senthilkumar GP, Venkatachalam T, Jaglan D, Yadav S, Anwer K, Fuloria NK, Sehgal A, Gulati M, Chigurupati S
Neurotox Res · 2023 Dec · PMID 37847429 · Publisher ↗
Alzheimer's disease contributes to 60-70% of all dementia cases in the general population. Belonging to the BIN1/amphiphysin/RVS167 (BAR) superfamily, the bridging integrator (BIN1) has been identified to impact two majo...
Alzheimer's disease contributes to 60-70% of all dementia cases in the general population. Belonging to the BIN1/amphiphysin/RVS167 (BAR) superfamily, the bridging integrator (BIN1) has been identified to impact two major pathological hallmarks in Alzheimer's disease (AD), i.e., amyloid beta (Aβ) and tau accumulation. Aβ accumulation is found to increase by BIN1 knockdown in cortical neurons in late-onset AD, due to BACE1 accumulation at enlarged early endosomes. Two BIN1 mutants, KR and PL, were identified to exhibit Aβ accumulation. Furthermore, BIN1 deficiency by BIN1-related polymorphisms impairs the interaction with tau, thus elevating tau phosphorylation, altering synapse structure and tau function. Even though the precise role of BIN1 in the neuronal tissue needs further investigation, the authors aim to throw light on the potential of BIN1 and unfold its implications on tau and Aβ pathology, to aid AD researchers across the globe to examine BIN1, as an appropriate target gene for disease management.
Pentoxifylline as Add-On Treatment to Donepezil in Copper Sulphate-Induced Alzheimer's Disease-Like Neurodegeneration in Rats.
Elseweidy MM, Mahrous M, Ali SI … +2 more , Shaheen MA, Younis NN
Neurotox Res · 2023 Dec · PMID 37821782 · Full text
Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by behavioral, cognitive, and progressive memory impairments. Extensive neuronal loss, extracellular accumulation of insoluble senile...
Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by behavioral, cognitive, and progressive memory impairments. Extensive neuronal loss, extracellular accumulation of insoluble senile amyloid-β (Aβ) plaques, and intracellular neurofibrillary tangles (NFTs) are the major pathological features. The present study aimed to investigate the therapeutic effect of donepezil (DON) and pentoxifylline (PTX) in combination to combat the neurodegenerative disorders (experimental AD) induced by CuSO intake in experimental rats. Thirty adult male Wistar rats (140-160 g) were used in this study. AD was first induced in rats by CuSO supplement to drinking water (10 mg/L) for 14 weeks. The AD group received no further treatment. Oral treatment with DON (10 mg/kg/day), PTX (100 mg/kg/day), or DON + PTX for the other three groups was started from the 10th week of CuSO intake for 4 weeks. Cortex markers like acetylcholine (ACh), acetylcholinesterase (AChE), total antioxidant capacity (TAC), and malondialdehyde (MDA) and hippocampus markers like β-amyloid precursor protein cleaving enzyme 1 (BACE1), phosphorylated Tau (p-tau), Clusterin (CLU), tumor necrosis factor-α (TNF-α), caspase-9 (CAS-9), Bax, and Bcl-2 were measured. The histopathology studies were done by using hematoxylin and eosin and Congo red stains as well as immunohistochemistry for neurofilament. CuSO induced adverse histological and biochemical changes. The histological injury in the hippocampus was inhibited following the administration of the DON and PTX. The brain tissue levels of AChE, MDA, BACE1, p-tau, CLU, CAS-9, Bax, and TNF-α were significantly increased, while brain tissue levels of ACh, TAC, and Bcl-2 were significantly decreased in CuSO-treated rats as compared with the untreated control group. The effects induced by either DON or PTX on most studied parameters were comparable. Combined treatment of DON and PTX induced remarkable results compared with their individual use. However, more clinical and preclinical studies are still required to further confirm and prove the long-term efficacy of such combination.
Effect of Cannabidiol in LPS-Induced Toxicity in Astrocytes: Possible Role for Cannabinoid Type-1 Receptors.
Ibork H, Idrissi SE, Zulu SS … +5 more , Miller R, Hajji L, Morgan AM, Taghzouti K, Abboussi O
Neurotox Res · 2023 Dec · PMID 37782433 · Publisher ↗
Cerebral metabolic abnormalities are common in neurodegenerative diseases. Previous studies have shown that mitochondrial damage alters ATP production and increases reactive oxygen species (ROS) release which may contrib...
Cerebral metabolic abnormalities are common in neurodegenerative diseases. Previous studies have shown that mitochondrial damage alters ATP production and increases reactive oxygen species (ROS) release which may contribute to neurodegeneration. In the present study, we investigated the neuroprotective effects of cannabidiol (CBD), a non-psychoactive component derived from marijuana (Cannabis sativa L.), on astrocytic bioenergetic balance in a primary cell culture model of lipopolysaccharide (LPS)-induced neurotoxicity. Astrocytic metabolic profiling using an extracellular flux analyzer demonstrated that CBD decreases mitochondrial proton leak, increased spare respiratory capacity and coupling efficiency in LPS-stimulated astrocytes. Simultaneously, CBD increased astrocytic glycolytic capacity and glycolysis reserve in a cannabinoid receptor type 1 (CB1)-dependent manner. CBD-restored metabolic changes were correlated with a significant decrease in the pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) concentration and reduction of ROS production in LPS-stimulated astrocytes. These results suggest that CBD may inhibit LPS-induced metabolic impairments and inflammation by enhancing astrocytic metabolic glycolysis versus oxidative phosphorylation through its action on CB1 receptors. The present findings suggest CBD as a potential anti-inflammatory treatment in metabolic pathologies and highlight a possible role for the cannabinoidergic system in the modulation of mitochondrial oxidative stress. CBD enhances mitochondrial bioenergetic profile, attenuates proinflammatory cytokines release, and ROS overproduction of astrocytes stimulated by LPS. These effects are not mediated directly by CB1 receptors, while these receptors seem to have a key role in the anti-inflammatory response of the endocannabinoid system on astrocytes, as their specific inhibition by SR141716A led to increased pro-inflammatory cytokines release and ROS production. The graphical abstract is created with BioRender.com.
RNA-Binding Proteins: A Role in Neurotoxicity?
Ocharán-Mercado A, Loaeza-Loaeza J, Castro-Coronel Y … +4 more , Acosta-Saavedra LC, Hernández-Kelly LC, Hernández-Sotelo D, Ortega A
Neurotox Res · 2023 Dec · PMID 37776476 · Full text
Despite sustained efforts to treat neurodegenerative diseases, little is known at the molecular level to understand and generate novel therapeutic approaches for these malignancies. Therefore, it is not surprising that n...
Despite sustained efforts to treat neurodegenerative diseases, little is known at the molecular level to understand and generate novel therapeutic approaches for these malignancies. Therefore, it is not surprising that neurogenerative diseases are among the leading causes of death in the aged population. Neurons require sophisticated cellular mechanisms to maintain proper protein homeostasis. These cells are generally sensitive to loss of gene expression control at the post-transcriptional level. Post-translational control responds to signals that can arise from intracellular processes or environmental factors that can be regulated through RNA-binding proteins. These proteins recognize RNA through one or more RNA-binding domains and form ribonucleoproteins that are critically involved in the regulation of post-transcriptional processes from splicing to the regulation of association of the translation machinery allowing a relatively rapid and precise modulation of the transcriptome. Neurotoxicity is the result of the biological, chemical, or physical interaction of agents with an adverse effect on the structure and function of the central nervous system. The disruption of the proper levels or function of RBPs in neurons and glial cells triggers neurotoxic events that are linked to neurodegenerative diseases such as spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), fragile X syndrome (FXS), and frontotemporal dementia (FTD) among many others. The connection between RBPs and neurodegenerative diseases opens a new landscape for potentially novel therapeutic targets for the intervention of these neurodegenerative pathologies. In this contribution, a summary of the recent findings of the molecular mechanisms involved in the plausible role of RBPs in RNA processing in neurodegenerative disease is discussed.
Effects of Multiple High-Dose Methamphetamine Administration on Enteric Dopaminergic Neurons and Intestinal Motility in the Rat Model.
He L, Zheng H, Qiu J … +18 more , Chen H, Li H, Ma Y, Wang Y, Wang Q, Hao Y, Liu Y, Yang Q, Wang X, Li M, Xu H, Peng P, Li Z, Zhou Y, Wu Q, Chen S, Zhang X, Liu T
Neurotox Res · 2023 Dec · PMID 37755670 · Publisher ↗
Several studies have identified the effects of methamphetamine (MA) on central dopaminergic neurons, but its effects on enteric dopaminergic neurons (EDNs) are unclear. The aim of this study was to investigate the effect...
Several studies have identified the effects of methamphetamine (MA) on central dopaminergic neurons, but its effects on enteric dopaminergic neurons (EDNs) are unclear. The aim of this study was to investigate the effects of MA on EDNs and intestinal motility. Male Sprague-Dawley rats were randomly divided into MA group and saline group. The MA group received the multiple high-dose MA treatment paradigm, while the controls received the same saline treatment. After enteric motility was assessed, different intestinal segments (i.e., duodenum, jejunum, ileum, and colon) were taken for histopathological, molecular biological, and immunological analysis. The EDNs were assessed by measuring the expression of two dopaminergic neuronal markers, dopamine transporter (DAT) and tyrosine hydroxylase (TH), at the transcriptional and protein levels. We also used c-Fos protein, a marker of neural activity, to detect the activation of EDNs. MA resulted in a significant reduction in TH and DAT mRNA expression as well as in the number of EDNs in the duodenum and jejunum (p < 0.05). MA caused a dramatic increase in c-Fos expression of EDNs in the ileum (p < 0.001). The positional variability of MA effects on EDNs paralleled the positional variability of its effect on intestinal motility, as evidenced by the marked inhibitory effect of MA on small intestinal motility (p < 0.0001). This study found significant effects of MA on EDNs with locational variability, which might be relevant to locational variability in the potential effects of MA on intestinal functions, such as motility.
Neuroprotective Potential of Tannic Acid Against Neurotoxic Outputs of Monosodium Glutamate in Rat Cerebral Cortex.
Karagac MS, Ceylan H
Neurotox Res · 2023 Dec · PMID 37713032 · Publisher ↗
Glutamate in monosodium glutamate (MSG), which is widely used in the food industry, has an important role in major brain functions such as memory, learning, synapse formation, and stabilization. However, extensive use of...
Glutamate in monosodium glutamate (MSG), which is widely used in the food industry, has an important role in major brain functions such as memory, learning, synapse formation, and stabilization. However, extensive use of MSG has been linked with neurotoxicity. Therefore, in addition to clarifying the underlying mechanisms of MSG-induced neurotoxicity, it is also important to determine safe agents that can diminish the damage caused by MSG. Tannic acid (TA) is a naturally occurring plant polyphenol that exhibits versatile physiological effects such as anti-inflammatory, anti-carcinogenic, antioxidant, and radical scavenging. This study was conducted to assess the neurotoxic and neuroprotective effects of these two dietary components in the rat cerebral cortex. Twenty-four Sprague Dawley rats were divided into 4 equal groups and were treated with MSG (2 g/kg) and TA (50 mg/kg) alone and in combination for 3 weeks. Alterations in oxidative stress indicators (MDA and GSH) were measured in the cortex tissues. In addition, changes in enzymatic activities and gene expression patterns of antioxidant system components (GST, GPx, CAT, and SOD) were investigated. Furthermore, mRNA expressions of FoxO transcription factors (Foxo1 and Foxo3) and apoptotic markers (Casp3 and Casp9) were assessed. Results revealed that dietary TA intake significantly rehabilitated MSG-induced dysregulation in cortical tissue by regulating redox balance, cellular homeostasis, and apoptosis. The present study proposes that MSG-induced detrimental effects on cortical tissue are potentially mitigated by TA via modulation of oxidative stress, cell metabolism, and programmed cell death.
Folic Acid and Folinic Acid Protect Hearts of Aging Triple-transgenic Alzheimer's Disease mice via IGF1R/PI3K/AKT and SIRT1/AMPK Pathways.
Ju DT, Huang RS, Tsai BC … +8 more , Su YC, Chiu PL, Chang YM, Padma VV, Ho TJ, Yao CH, Kuo WW, Huang CY
Neurotox Res · 2023 Dec · PMID 37707697 · Publisher ↗
Patients with Alzheimer's disease have increased risk of developing heart disease, which therefore highlights the need for strategies aiming at reducing Alzheimer's disease-related cardiovascular disease. Folic acid and...
Patients with Alzheimer's disease have increased risk of developing heart disease, which therefore highlights the need for strategies aiming at reducing Alzheimer's disease-related cardiovascular disease. Folic acid and folinic acid are beneficial to the heart. We aimed to investigate the benefits of folic acid and folinic acid in heart of patients with late-stage Alzheimer's disease. Twelve 16-month-old mice of triple-transgenic late-stage Alzheimer's disease were divided into three groups: Alzheimer's disease group, Alzheimer's disease + folic acid group, and Alzheimer's disease + folinic acid group. The mice were administered 12 mg/kg folic acid or folinic acid once daily via oral gavage for 3 months. In the folic acid and folinic acid treatment groups, the intercellular space was reduced, compared with the Alzheimer's disease group. TUNEL assay and western blot images showed that the number of apoptotic cells and the apoptosis-related protein expression were higher in the Alzheimer's disease group than in other two treated groups. Folic acid and folinic acid induced the IGF1R/PI3K/AKT and SIRT1/ AMPK pathways in the hearts of mice with Alzheimer's disease. Our results showed that folic acid and folinic acid treatment increased survival and SIRT1 expression to reduce apoptotic proteins in the heart. The aging mice treated with folinic acid had more IGF1R and SIRT1/AMPK axes to limit myocardial cell apoptosis. In conclusion, folic acid and folinic acid promote cardiac cell survival and prevent apoptosis to inhibit heart damage in aging mice with triple-transgenic late-stage Alzheimer's disease. In particular, folinic acid provides a better curative effect than folic acid.
Correction to: D‑Ribose‑L‑Cysteine Improves Glutathione Levels, Neuronal and Mitochondrial Ultrastructural Damage, Caspase‑3 and GFAP Expressions Following Manganese‑Induced Neurotoxicity.
Akingbade GT, Ijomone OM, Imam A … +2 more , Aschner M, Ajao MS
Neurotox Res · 2023 Dec · PMID 37668878 · Publisher ↗
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