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1.
Nanotechnology ; 36(2)2024 Oct 21.
Article in English | MEDLINE | ID: mdl-39389086

ABSTRACT

Reduced graphene oxide (rGO) has unique physicochemical properties that make it suitable for therapeutic applications in neurodegenerative scenarios. This study investigates the therapeutic potential of rGO in a cuprizone-induced demyelination model in mice through histomorphological techniques and analysis of biochemical parameters. We demonstrate that daily intraperitoneal administration of rGO (1 mg ml-1) for 21 days tends to reduce demyelination in theCorpus callosumby decreasing glial cell recruitment during the repair mechanism. Additionally, rGO interferes with oxidative stress markers in the brain and liver indicating potential neuroprotective effects in the central nervous system. No significant damage to vital organs was observed, suggesting that multiple doses could be used safely. However, further long-term investigations are needed to understand rGO distribution, metabolism, routes of action and associated challenges in central neurodegenerative therapies. Overall, these findings contribute to the comprehension of rGO effectsin vivo, paving the way for possible future clinical research.


Subject(s)
Cuprizone , Demyelinating Diseases , Graphite , Oxidative Stress , Animals , Graphite/chemistry , Demyelinating Diseases/chemically induced , Demyelinating Diseases/drug therapy , Demyelinating Diseases/pathology , Mice , Oxidative Stress/drug effects , Male , Neuroprotective Agents/pharmacology , Neuroprotective Agents/chemistry , Brain/pathology , Brain/drug effects , Brain/metabolism , Disease Models, Animal , Mice, Inbred C57BL , Liver/drug effects , Liver/pathology , Liver/metabolism , Corpus Callosum/drug effects , Corpus Callosum/pathology , Corpus Callosum/metabolism
2.
Cells ; 13(19)2024 Oct 03.
Article in English | MEDLINE | ID: mdl-39404410

ABSTRACT

Though the mechanisms are not fully understood, tryptophan (Trp) and physical exercise seem to regulate mechanical hypersensitivity in fibromyalgia. Here, we tested the impact of Trp supplementation and continuous low-intensity aerobic exercise on the modulation of mechanical hypersensitivity in a fibromyalgia-like model induced by acid saline in female rats. Twelve-month-old female Wistar rats were randomly divided into groups: [control (n = 6); acid saline (n = 6); acid saline + exercise (n = 6); acid saline + Trp (n = 6); and acid saline + exercise + Trp (n = 6)]. Hypersensitivity was caused using two intramuscular jabs of acid saline (20 µL; pH 4.0; right gastrocnemius), 3 days apart. The tryptophan-supplemented diet contained 7.6 g/hg of Trp. The three-week exercise consisted of progressive (30-45 min) treadmill running at 50 to 60% intensity, five times (Monday to Friday) per week. We found that acid saline induced contralateral mechanical hypersensitivity without changing the levels of Trp, serotonin (5-HT), and kynurenine (KYN) in the brain. Hypersensitivity was reduced by exercise (~150%), Trp (~67%), and its combination (~160%). The Trp supplementation increased the levels of Trp and KYN in the brain, and the activity of indoleamine 2,3-dioxygenase (IDO), and decreased the ratio 5-HT:KYN. Exercise did not impact the assessed metabolites. Combining the treatments reduced neither hypersensitivity nor the levels of serotonin and Trp in the brain. In conclusion, mechanical hypersensitivity induced by acid saline in a fibromyalgia-like model in female rats is modulated by Trp supplementation, which increases IDO activity and leads to improved Trp metabolism via the KYN pathway. In contrast, physical exercise does not affect mechanical hypersensitivity through brain Trp metabolism via either the KYN or serotonin pathways. Because this is a short study, generalizing its findings warrants caution.


Subject(s)
Disease Models, Animal , Fibromyalgia , Physical Conditioning, Animal , Rats, Wistar , Serotonin , Tryptophan , Animals , Tryptophan/metabolism , Tryptophan/pharmacology , Fibromyalgia/metabolism , Female , Rats , Serotonin/metabolism , Kynurenine/metabolism , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Hyperalgesia/metabolism , Brain/metabolism , Brain/drug effects , Brain/pathology , Dietary Supplements
3.
Neuroscience ; 560: 20-35, 2024 Nov 12.
Article in English | MEDLINE | ID: mdl-39293731

ABSTRACT

Binge eating disorder is the most prevalent eating disorder, affecting both sexes but more commonly found in women. Given the frequent co-occurrence of psychiatric disorders, this study aimed to establish a standardized experimental intermittent protocol to investigate overeating associated with depression. A 10-day protocol induced uncontrolled eating behavior in C57BL/6J female mice. The first experiment included the following groups: naive group (chow ad libitum), control group (chow and sucrose solution ad libitum), and fasting groups (16 and 20 h) exposed to an intermittent sucrose solution (10 %) and chow regimen. Subsequently, the feeding test, open field test, elevated plus maze test, tail suspension test, and light/dark conflict test were conducted. Furthermore, monoamine oxidase (MAO) A and B activities in brain structures and plasma corticosterone levels were assessed. Food overconsumption and depressive-like behavior were observed in both sucrose fasting groups, while risk-taking behaviors were specifically observed in the 20-hour fasting sucrose group. While both fasting sucrose groups caused reduced hippocampal MAO-A activity, only the F20 sucrose group inhibited MAO-B in the cortex and hypothalamus. Moreover, both fasting sucrose groups exhibited elevated corticosterone levels. In a separate design (Experiment 2), groups with 16 and 20 h of fasting alone (without sucrose) did not show the same behavioral results as the intermittent fasting sucrose groups, thus avoiding fasting bias. Based on these results, the 20-hour sucrose fasting group was chosen as the ideal protocol for mimicking overeating behavior associated with depression to investigate future therapeutic approaches for this comorbidity.


Subject(s)
Depression , Fasting , Hyperphagia , Mice, Inbred C57BL , Animals , Female , Fasting/physiology , Depression/etiology , Depression/metabolism , Mice , Corticosterone/blood , Monoamine Oxidase/metabolism , Brain/metabolism , Feeding Behavior/physiology , Sucrose/administration & dosage , Behavior, Animal/physiology , Behavior, Animal/drug effects
4.
Neurochem Res ; 49(12): 3383-3395, 2024 Dec.
Article in English | MEDLINE | ID: mdl-39302597

ABSTRACT

Population aging is a global reality driven by increased life expectancy. This demographic phenomenon is intrinsically linked to the epidemic of cognitive disorders such as dementia and Alzheimer's disease, posing challenges for elderly and their families. In this context, the search for new therapeutic strategies to prevent or minimize cognitive impairments becomes urgent, as these deficits are primarily associated with oxidative damage and increased neuroinflammation. Ferulic acid (FA), a natural and potent antioxidant compound, is proposed to be nanoencapsulated to target the central nervous system effectively with lower doses and an extended duration of action. Here, we evaluated the effects of the nanoencapsulated FA on d-galactose (d-Gal)- induced memory impairments. Male Wistar adult rats were treated with ferulic acid-loaded nanocapsules (FA-Nc) or non-encapsulated ferulic acid (D-FA) for 8 weeks concurrently with d-Gal (150 mg/kg s.c.) injection. As expected, our findings showed that d-Gal injection impaired memory processes and increased anxiety behavior, whereas FA-Nc treatment ameliorated these behavioral impairments associated with the aging process induced by d-Gal. At the molecular level, nanoencapsulated ferulic acid (FA-Nc) ameliorated the decrease in ACh and glutamate induced by d-galactose (d-Gal), and also increased GABA levels in the dorsal hippocampus, indicating its therapeutic superiority. Additional studies are needed to elucidate the mechanisms underlying our current promising outcomes. Nanoscience applied to pharmacology can reduce drug dosage, thereby minimizing adverse effects while enhancing therapeutic response, particularly in neurodegenerative diseases associated with aging. Therefore, the strategy of brain-targeted drug delivery through nanoencapsulation can be effective in mitigating aging-related factors that may lead to cognitive deficits.


Subject(s)
Aging , Anxiety , Coumaric Acids , Galactose , Glutamic Acid , Memory Disorders , Rats, Wistar , gamma-Aminobutyric Acid , Animals , Coumaric Acids/pharmacology , Coumaric Acids/therapeutic use , Male , Aging/drug effects , Aging/metabolism , Memory Disorders/drug therapy , Memory Disorders/metabolism , gamma-Aminobutyric Acid/metabolism , Anxiety/drug therapy , Anxiety/metabolism , Glutamic Acid/metabolism , Rats , Brain/metabolism , Brain/drug effects , Nanostructures , Nanocapsules
5.
Chem Rec ; 24(10): e202400013, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39318079

ABSTRACT

Over three decades ago, two independent groups of investigators identified free D-aspartic and later D-serine in specific brain nuclei and endocrine glands. This finding revealed a novel, non-proteinogenic role of these molecules. Moreover, the finding that aged proteins from the human eye crystallin, teeth, bone, blood vessels or the brain incorporate D-aspartic acids to specific primary protein sequences fostered the hypothesis that aging might be related to D-amino acid isomerization of body proteins. The experimental confirmation that schizophrenia and neurodegenerative diseases modify plasma free D-amino acids or tissue levelsnurtured the opportunity of using D-amino acids as therapeutic agents for several disease treatments, a strategy that prompted the successful current application of D-amino acids to human medicine.


Subject(s)
Amino Acids , Humans , Amino Acids/chemistry , Amino Acids/metabolism , Schizophrenia/drug therapy , Schizophrenia/metabolism , Serine/chemistry , Serine/metabolism , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/metabolism , Aging/metabolism , Stereoisomerism , Animals , D-Aspartic Acid/metabolism , D-Aspartic Acid/chemistry , Brain/metabolism , Clinical Relevance
6.
Sci Rep ; 14(1): 20416, 2024 09 02.
Article in English | MEDLINE | ID: mdl-39223259

ABSTRACT

Autism spectrum disorders (ASD) are complex neurodevelopmental conditions characterized by impairments in social communication, repetitive behaviors, and restricted interests. Epigenetic modifications serve as critical regulators of gene expression playing a crucial role in controlling brain function and behavior. Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, has emerged as one of the highest ASD risk genes, but the precise effects of KDM6B mutations on neuronal activity and behavioral function remain elusive. Here we show the impact of KDM6B mosaic brain knockout on the manifestation of different autistic-like phenotypes including repetitive behaviors, social interaction, and significant cognitive deficits. Moreover, KDM6B mosaic knockout display abnormalities in hippocampal excitatory synaptic transmission decreasing NMDA receptor mediated synaptic transmission and plasticity. Understanding the intricate interplay between epigenetic modifications and neuronal function may provide novel insights into the pathophysiology of ASD and potentially inform the development of targeted therapeutic interventions.


Subject(s)
Autism Spectrum Disorder , Jumonji Domain-Containing Histone Demethylases , Mice, Knockout , Synaptic Transmission , Animals , Jumonji Domain-Containing Histone Demethylases/genetics , Jumonji Domain-Containing Histone Demethylases/metabolism , Synaptic Transmission/genetics , Autism Spectrum Disorder/genetics , Mice , Brain/metabolism , Neuronal Plasticity/genetics , Behavior, Animal , Hippocampus/metabolism , Epigenesis, Genetic , Male , Synapses/metabolism
7.
Alzheimers Dement ; 20(10): 6709-6721, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39140361

ABSTRACT

INTRODUCTION: Brain glucose hypometabolism, indexed by the fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) imaging, is a metabolic signature of Alzheimer's disease (AD). However, the underlying biological pathways involved in these metabolic changes remain elusive. METHODS: Here, we integrated [18F]FDG-PET images with blood and hippocampal transcriptomic data from cognitively unimpaired (CU, n = 445) and cognitively impaired (CI, n = 749) individuals using modular dimension reduction techniques and voxel-wise linear regression analysis. RESULTS: Our results showed that multiple transcriptomic modules are associated with brain [18F]FDG-PET metabolism, with the top hits being a protein serine/threonine kinase activity gene cluster (peak-t(223) = 4.86, P value < 0.001) and zinc-finger-related regulatory units (peak-t(223) = 3.90, P value < 0.001). DISCUSSION: By integrating transcriptomics with PET imaging data, we identified that serine/threonine kinase activity-associated genes and zinc-finger-related regulatory units are highly associated with brain metabolic changes in AD. HIGHLIGHTS: We conducted an integrated analysis of system-based transcriptomics and fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) at the voxel level in Alzheimer's disease (AD). The biological process of serine/threonine kinase activity was the most associated with [18F]FDG-PET in the AD brain. Serine/threonine kinase activity alterations are associated with brain vulnerable regions in AD [18F]FDG-PET. Zinc-finger transcription factor targets were associated with AD brain [18F]FDG-PET metabolism.


Subject(s)
Alzheimer Disease , Brain , Fluorodeoxyglucose F18 , Positron-Emission Tomography , Alzheimer Disease/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/diagnostic imaging , Humans , Fluorodeoxyglucose F18/metabolism , Male , Female , Brain/metabolism , Brain/diagnostic imaging , Aged , Transcriptome , Hippocampus/metabolism , Hippocampus/diagnostic imaging , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/genetics , Cognitive Dysfunction/diagnostic imaging , Aged, 80 and over
8.
Metab Brain Dis ; 39(8): 1495-1503, 2024 Dec.
Article in English | MEDLINE | ID: mdl-39120852

ABSTRACT

Obesity is a significant health concern that is correlated with various adverse health outcomes. Diet-induced obesity (DIO) is associated with impaired cognitive function. Pharmacological treatments for obesity are limited and may have serious adverse effects. Zingiber officinale (ZO) has anti-inflammatory and antioxidant effects, in addition to metabolic effects. This study aimed to assess the effects of Zingiber officinale supplementation on cognitive function, anxiety levels, neurotrophin levels, and the inflammatory and oxidative status in the cortex following DIO in mice. Two-month-old male Swiss mice were fed DIO or standard chow for 4 months and subsequently subdivided into the following groups (n = 10 mice/group): (i) control - vehicle (CNT + vehicle); (ii) CNT supplemented with ZO (CNT + ZO); (iii) obese mice (DIO + vehicle); and (iv) obese mice supplemented with ZO (DIO + ZO) (n = 10). Zingiber officinale extract (400 mg/kg/day) was administered for 35 days via oral gavage. The DIO + vehicle group exhibited impaired recognition memory. The CNT + ZO group presented a greater number of crossings in the open field. No difference between the groups was observed in the plus maze test. DIO + vehicle increased the DCFH and carbonylation levels in the cortex. The DIO + vehicle group presented a reduction in catalase activity. The expression of inflammatory or neurotrophin markers in the cerebral cortex was not different. In conclusion, our findings indicate that supplementation with ZO reverses the cognitive impairment in DIO mice and enhances the antioxidant status of the cerebral cortex.


Subject(s)
Brain , Cognitive Dysfunction , Diet, High-Fat , Dietary Supplements , Oxidative Stress , Zingiber officinale , Animals , Oxidative Stress/drug effects , Male , Mice , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/etiology , Diet, High-Fat/adverse effects , Brain/metabolism , Brain/drug effects , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Obesity/metabolism , Obesity/drug therapy , Antioxidants/pharmacology , Antioxidants/therapeutic use
9.
Metab Brain Dis ; 39(8): 1679-1687, 2024 Dec.
Article in English | MEDLINE | ID: mdl-39145861

ABSTRACT

Exercise increases peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) expression, which in turn causes the fibronectin type III domain containing 5 (FNDC5) protein to be produced. This protein is then cleaved, primarily in skeletal muscle fibers, to produce irisin. When the mature FNDC5 is cleaved by proteases, Irisin - which is the fibronectin III domain without the signal sequence - is released. Resistance, aerobic, and high-intensity interval training (HIIT) are recognized as forms of physical exercise that raise irisin levels, and insulin receptor phosphorylation in tyrosine residues, favoring an increase in the activity of the insulin-dependent pathway (PI3K pathway) and assisting in the fight against insulin resistance, inflammation, and cognitive decline. Irisin may represent a promising option for the therapeutic targeting in several brain-related pathological conditions, like Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, type 2 diabetes, and obesity. Exercise protocols are healthy and inexpensive interventions that can help find cellular and molecular changes in several brain-related pathological conditions. Here, it was reviewed what is known about exercise-produced irisin studies involving AD, PD, epilepsy, type 2 diabetes, and obesity.


Subject(s)
Exercise , Fibronectins , Humans , Fibronectins/metabolism , Exercise/physiology , Animals , Alzheimer Disease/metabolism , Diabetes Mellitus, Type 2/metabolism , Parkinson Disease/metabolism , Parkinson Disease/therapy , Obesity/metabolism , Epilepsy/metabolism , Brain/metabolism
10.
Chemosphere ; 364: 143012, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39103101

ABSTRACT

Due to its extensive use as a painkiller, anti-inflammatory, and immune modulatory agent, as well as its effectiveness in treating severe COVID-19, dexamethasone, a synthetic glucocorticoid, has gained attention not only for its impact on public health but also for its environmental implications. Various studies have reported its presence in aquatic environments, including urban waters, surface samples, sediments, drinking water, and wastewater effluents. However, limited information is available regarding its toxic effects on nontarget aquatic organisms. Therefore, this study aimed to investigate the mechanism of toxicity underlying dexamethasone-induced brain damage in the bioindicator Danio rerio following long-term exposure. Adult zebrafish were treated with environmentally relevant concentrations of dexamethasone (20, 40, and 60 ng L-1) for 28 days. To elucidate the possible mechanisms involved in the toxicity of the pharmaceutical compound, we conducted a behavioral test battery (Novel Tank and Light and Dark tests), oxidative stress biomarkers, acetylcholinesterase enzyme activity quantification, histopathological analysis, and gene expression analysis using qRT-PCR (p53, bcl-2, bax, caspase-3, nrf1, and nrf2).The results revealed that the pharmaceutical compound could produce anxiety-like symptoms, increase the oxidative-induced stress response, decrease the activity of acetylcholinesterase enzyme, and cause histopathological alterations, including perineuronal vacuolization, granular and molecular layers deterioration, cell swallowing and intracellular spaces. The expression of genes involved in the apoptotic process (p53, bax, and casp-3) and antioxidant defense (nrf1 and nrf2) was upregulated in response to oxidative damage, while the expression of the anti-apoptotic gene bcl-2 was down-regulated indicating that the environmental presence of dexamethasone may pose a threat to wildlife and human health.


Subject(s)
Apoptosis , Dexamethasone , Oxidative Stress , Water Pollutants, Chemical , Zebrafish , Animals , Oxidative Stress/drug effects , Apoptosis/drug effects , Dexamethasone/toxicity , Water Pollutants, Chemical/toxicity , Glucocorticoids/toxicity , Brain/drug effects , Brain/metabolism , Brain/pathology , Brain Injuries/chemically induced
11.
Biomolecules ; 14(8)2024 Aug 01.
Article in English | MEDLINE | ID: mdl-39199321

ABSTRACT

Epidemiological studies and meta-analyses have shown a strong association between high seroprevalence of Toxoplasma gondii (T. gondii) and schizophrenia. Schizophrenic patients showed higher levels of anti-Toxoplasma immunoglobulins M and G (IgM and IgG) when compared to healthy controls. Previously, in a rat model, we demonstrated that the progeny of mothers immunized with T. gondii lysates before gestation had behavioral and social impairments during adulthood. Therefore, we suggested that T. gondii infection can trigger autoreactivity by molecularly mimicking host brain proteins. Here, we aimed to identify the occurrence of antigenic mimicry between T. gondii epitopes and host brain proteins. Using a bioinformatic approach, we predicted T. gondii RH-88 B cell epitopes and compared them to human cell-surface proteins involved in brain development and differentiation (BrainS). Five different algorithms for B-cell-epitope prediction were used and compared, resulting in 8584 T. gondii epitopes. We then compared T. gondii predicted epitopes to BrainS proteins by local sequence alignments using BLASTP. T. gondii immunogenic epitopes significantly overlapped with 42 BrainS proteins. Among these overlapping proteins essential for brain development and differentiation, we identified HSP90 and NOTCH receptors as the proteins most likely to be targeted by the maternally generated pathogenic antibodies due to their topological overlap at the extracellular region of their sequence. This analysis highlights the relevance of pregestational clinical surveillance and screening for potential pathogenic anti-T. gondii antibodies. It also identifies potential targets for the design of vaccines that could prevent behavioral and cognitive impairments associated with pre-gestational T. gondii exposure.


Subject(s)
Brain , Epitopes, B-Lymphocyte , Molecular Mimicry , Toxoplasma , Toxoplasma/immunology , Molecular Mimicry/immunology , Humans , Epitopes, B-Lymphocyte/immunology , Brain/parasitology , Brain/immunology , Brain/metabolism , Computational Biology/methods , Toxoplasmosis/immunology , Animals , Antibodies, Protozoan/immunology , Rats
12.
Int J Mol Sci ; 25(15)2024 Aug 03.
Article in English | MEDLINE | ID: mdl-39126055

ABSTRACT

Rasmussen's encephalitis (RE) stands as a rare neurological disorder marked by progressive cerebral hemiatrophy and epilepsy resistant to medical treatment. Despite extensive study, the primary cause of RE remains elusive, while its histopathological features encompass cortical inflammation, neuronal degeneration, and gliosis. The underlying molecular mechanisms driving disease progression remain largely unexplored. In this case study, we present a patient with RE who underwent hemispherotomy and has remained seizure-free for over six months, experiencing gradual motor improvement. Furthermore, we conducted molecular analysis on the excised brain tissue, unveiling a decrease in the expression of cell-cycle-associated genes coupled with elevated levels of BDNF and TNF-α proteins. These findings suggest the potential involvement of cell cycle regulators in the progression of RE.


Subject(s)
Encephalitis , Humans , Encephalitis/genetics , Encephalitis/pathology , Encephalitis/metabolism , Male , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Brain/pathology , Brain/metabolism , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Cerebral Cortex/pathology , Cerebral Cortex/metabolism , Female , Tumor Necrosis Factor-alpha/metabolism , Tumor Necrosis Factor-alpha/genetics , Cell Cycle/genetics
13.
Adv Neurobiol ; 39: 269-284, 2024.
Article in English | MEDLINE | ID: mdl-39190079

ABSTRACT

Autism spectrum disorder (ASD) comprises a complex neurodevelopmental condition characterized by an impairment in social interaction, involving communication deficits and specific patterns of behaviors, like repetitive behaviors. ASD is clinically diagnosed and usually takes time, typically occurring not before four years of age. Genetic mutations affecting synaptic transmission, such as neuroligin and neurexin, are associated with ASD and contribute to behavioral and cognitive deficits. Recent research highlights the role of astrocytes, the brain's most abundant glial cells, in ASD pathology. Aberrant Ca2+ signaling in astrocytes is linked to behavioral deficits and neuroinflammation. Notably, the cytokine IL-6 overexpression by astrocytes impacts synaptogenesis. Altered neurotransmitter levels, disruptions in the blood-brain barrier, and cytokine dysregulation further contribute to ASD complexity. Understanding these astrocyte-related mechanisms holds promise for identifying ASD subtypes and developing targeted therapies.


Subject(s)
Astrocytes , Autism Spectrum Disorder , Neurons , Autism Spectrum Disorder/metabolism , Autism Spectrum Disorder/genetics , Humans , Astrocytes/metabolism , Neurons/metabolism , Animals , Synaptic Transmission , Blood-Brain Barrier/metabolism , Brain/metabolism
14.
PLoS One ; 19(8): e0308976, 2024.
Article in English | MEDLINE | ID: mdl-39146369

ABSTRACT

Chronic stress can trigger several pathologies including mood disorders for which no clear diagnostic molecular markers have been established yet. Attractive biomarker sources are extracellular vesicles (EVs). Evs are released by cells in health and disease and contain genetic material, proteins and lipids characteristic of the cell state. Here we show that Evs recovered from the blood of animals exposed to a repeated interrupted stress protocol (RIS) have a different protein profile compared to those obtained from control animals. Proteomic analysis indicated that proteins differentially present in bulk serum Evs from stressed animals were implicated in metabolic and inflammatory pathways and several of them were previously related to psychiatric disorders. Interestingly, these serum Evs carry brain-enriched proteins including the stress-responsive neuronal protein M6a. Then, we used an in-utero electroporation strategy to selectively overexpress M6a-GFP in brain neurons and found that M6a-GFP could also be detected in bulk serum Evs suggesting a neuronal origin. Finally, to determine if these Evs could have functional consequences, we administered Evs from control and RIS animals intranasally to naïve mice. Animals receiving stress EVs showed changes in behavior and brain M6a levels similar to those observed in physically stressed animals. Such changes could therefore be attributed, or at least in part, to EV protein transfer. Altogether these findings show that EVs may participate in stress signaling and propose proteins carried by EVs as a valuable source of biomarkers for stress-induced diseases.


Subject(s)
Extracellular Vesicles , Proteome , Stress, Psychological , Animals , Extracellular Vesicles/metabolism , Proteome/metabolism , Mice , Stress, Psychological/blood , Stress, Psychological/metabolism , Male , Behavior, Animal , Brain/metabolism , Proteomics/methods , Neurons/metabolism , Mice, Inbred C57BL
15.
BMC Neurosci ; 25(1): 42, 2024 Aug 29.
Article in English | MEDLINE | ID: mdl-39210265

ABSTRACT

Genetic and environmental factors have been linked with neurodegeneration, especially in the elderly. Yet, efforts to impede neurodegenerative processes have at best addressed symptoms instead of underlying pathologies. The gap in the understanding of neuro-behavioral plasticity is consistent from insects to mammals, and cockroaches have been proven to be effective models for studying the toxicity mechanisms of various chemicals. We therefore used head injection of 74 and 740 nmol STZ in Nauphoeta cinerea to elucidate the mechanisms of chemical-induced neurotoxicity, as STZ is known to cross the blood-brain barrier. Neurolocomotor assessment was carried out in a new environment, while head homogenate was used to estimate metabolic, neurotransmitter and redox activities, followed by RT-qPCR validation of relevant cellular signaling. STZ treatment reduced the distance and maximum speed travelled by cockroaches, and increased glucose levels while reducing triglyceride levels in neural tissues. The activity of neurotransmitter regulators - AChE and MAO was exacerbated, with concurrent upregulation of glucose sensing and signaling, and increased mRNA levels of redox regulators and inflammation-related genes. Consequently, STZ neurotoxicity is conserved in insects, with possible implications for using N. cinerea to target the multi-faceted mechanisms of neurodegeneration and test potential anti-neurodegenerative agents.


Subject(s)
Acetylcholinesterase , Monoamine Oxidase , Oxidation-Reduction , Streptozocin , Animals , Monoamine Oxidase/metabolism , Oxidation-Reduction/drug effects , Acetylcholinesterase/metabolism , Cockroaches , Brain/metabolism , Brain/drug effects , Behavior, Animal/drug effects
16.
Methods Mol Biol ; 2831: 351-375, 2024.
Article in English | MEDLINE | ID: mdl-39134862

ABSTRACT

Fluorescent and non-fluorescent neural tract tracers enable the investigation of neural pathways in both peripheral and central nervous systems in laboratory animals demonstrating images with high resolution and great anatomic precision. Anterograde and retrograde viral tracers are important cutting-edge tools for neuroanatomical mapping. The optogenetic consists of an advanced alternative for in vivo neural tract tracing procedures, fundamentally considering the possibility to dissect and modulate pathways either exciting or inhibiting neural circuits in laboratory animals. The neurotractography by diffusion tensor imaging in vivo procedures enables the study of neural pathways in humans with reasonable accuracy. Here we describe the procedure of classical anatomic neural tract tracing and modern optogenetic technique performed in anima vili in addition to different diffusion tensor neurotractography performed in anima nobili.


Subject(s)
Diffusion Tensor Imaging , Optogenetics , Optogenetics/methods , Animals , Diffusion Tensor Imaging/methods , Neuroanatomical Tract-Tracing Techniques/methods , Neural Pathways , Brain/diagnostic imaging , Brain/physiology , Brain/metabolism , Neuronal Tract-Tracers , Humans , Mice
17.
Commun Biol ; 7(1): 811, 2024 Jul 04.
Article in English | MEDLINE | ID: mdl-38965360

ABSTRACT

Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease affecting the central nervous system (CNS) in animals that parallels several clinical and molecular traits of multiple sclerosis in humans. Herpes simplex virus type 1 (HSV-1) infection mainly causes cold sores and eye diseases, yet eventually, it can also reach the CNS, leading to acute encephalitis. Notably, a significant proportion of healthy individuals are likely to have asymptomatic HSV-1 brain infection with chronic brain inflammation due to persistent latent infection in neurons. Because cellular senescence is suggested as a potential factor contributing to the development of various neurodegenerative disorders, including multiple sclerosis, and viral infections may induce a premature senescence state in the CNS, potentially increasing susceptibility to such disorders, here we examine the presence of senescence-related markers in the brains and spinal cords of mice with asymptomatic HSV-1 brain infection, EAE, and both conditions. Across all scenarios, we find a significant increases of senescence biomarkers in the CNS with some differences depending on the analyzed group. Notably, some senescence biomarkers are exclusively observed in mice with the combined conditions. These results indicate that asymptomatic HSV-1 brain infection and EAE associate with a significant expression of senescence biomarkers in the CNS.


Subject(s)
Brain , Cellular Senescence , Herpes Simplex , Herpesvirus 1, Human , Multiple Sclerosis , Animals , Mice , Brain/virology , Brain/pathology , Brain/metabolism , Multiple Sclerosis/virology , Multiple Sclerosis/pathology , Multiple Sclerosis/metabolism , Herpesvirus 1, Human/physiology , Herpesvirus 1, Human/pathogenicity , Herpes Simplex/virology , Herpes Simplex/pathology , Female , Mice, Inbred C57BL , Encephalomyelitis, Autoimmune, Experimental/virology , Encephalomyelitis, Autoimmune, Experimental/pathology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Phenotype , Central Nervous System/virology , Central Nervous System/metabolism , Central Nervous System/pathology , Spinal Cord/virology , Spinal Cord/metabolism , Spinal Cord/pathology , Biomarkers/metabolism , Encephalitis, Herpes Simplex/virology , Encephalitis, Herpes Simplex/pathology , Encephalitis, Herpes Simplex/metabolism
18.
Biol Res ; 57(1): 49, 2024 Jul 27.
Article in English | MEDLINE | ID: mdl-39068496

ABSTRACT

BACKGROUND: The significant role of embryonic cerebrospinal fluid (eCSF) in the initial stages of brain development has been thoroughly studied. This fluid contains crucial molecules for proper brain development such as members of the Wnt and FGF families, apolipoproteins, and retinol binding protein. Nevertheless, the source of these molecules remains uncertain since they are present before the formation of the choroid plexus, which is conventionally known as the primary producer of cerebrospinal fluid. The subcommissural organ (SCO) is a highly conserved gland located in the diencephalon and is one of the earliest differentiating brain structures. The SCO secretes molecules into the eCSF, prior to the differentiation of the choroid plexus, playing a pivotal role in the homeostasis and dynamics of this fluid. One of the key molecules secreted by the SCO is SCO-spondin, a protein involved in maintenance of the normal ventricle size, straight spinal axis, neurogenesis, and axonal guidance. Furthermore, SCO secretes transthyretin and basic fibroblast growth factor 2, while other identified molecules in the eCSF could potentially be secreted by the SCO. Additionally, various transcription factors have been identified in the SCO. However, the precise mechanisms involved in the early SCO development are not fully understood. RESULTS: To uncover key molecular players and signaling pathways involved in the role of the SCO during brain development, we conducted a transcriptomic analysis comparing the embryonic chick SCO at HH23 and HH30 stages (4 and 7 days respectively). Additionally, a public transcriptomic data from HH30 entire chick brain was used to compare expression levels between SCO and whole brain transcriptome. These analyses revealed that, at both stages, the SCO differentially expresses several members of bone morphogenic proteins, Wnt and fibroblast growth factors families, diverse proteins involved in axonal guidance, neurogenic and differentiative molecules, cell receptors and transcription factors. The secretory pathway is particularly upregulated at stage HH30 while the proliferative pathway is increased at stage HH23. CONCLUSION: The results suggest that the SCO has the capacity to secrete several morphogenic molecules to the eCSF prior to the development of other structures, such as the choroid plexus.


Subject(s)
Brain , Gene Expression Profiling , Subcommissural Organ , Animals , Brain/metabolism , Brain/embryology , Brain/growth & development , Subcommissural Organ/metabolism , Subcommissural Organ/embryology , Chick Embryo , Gene Expression Regulation, Developmental
19.
Commun Biol ; 7(1): 904, 2024 Jul 26.
Article in English | MEDLINE | ID: mdl-39060467

ABSTRACT

The difficulty of obtaining samples from certain human tissues has led to efforts to find accessible sources to analyze molecular markers derived from DNA. In this study, we look for DNA methylation patterns in blood samples and its association with the brain methylation pattern in neurodegenerative disorders. Using data from methylation databases, we selected 18,293 CpGs presenting correlated methylation levels between blood and brain (bb-CpGs) and compare their methylation level between blood samples from patients with neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, and X Fragile Syndrome) and healthy controls. Sixty-four bb-CpGs presented significant distinct methylation levels in patients, being: nine for Alzheimer's disease, nine for Parkinson's disease, 28 for Multiple Sclerosis, and 18 for Fragile X Syndrome. Similar differences in methylation pattern for the nine Alzheimer's bb-CpGs was also observed when comparing brain tissue from patients vs. controls. The genomic regions of some of these 64 bb-CpGs are placed close to or inside genes previously associated with the respective condition. Our findings support the rationale of using blood DNA as a surrogate of brain tissue to analyze changes in CpG methylation level in patients with neurodegenerative diseases, opening the possibility for characterizing new biomarkers.


Subject(s)
Biomarkers , Brain , CpG Islands , DNA Methylation , Neurodegenerative Diseases , Humans , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/blood , Brain/metabolism , Biomarkers/blood , Alzheimer Disease/genetics , Alzheimer Disease/blood , Male , Female , Case-Control Studies
20.
Curr Neurol Neurosci Rep ; 24(8): 323-340, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38980658

ABSTRACT

PURPOSE OF REVIEW: Self-awareness can be defined as the capacity of becoming the object of one's own awareness and, increasingly, it has been the target of scientific inquiry. Self-awareness has important clinical implications, and a better understanding of the neurochemical basis of self-awareness may help clarifying causes and developing interventions for different psychopathological conditions. The current article explores the relationship between neurochemistry and self-awareness, with special attention to the effects of psychedelics. RECENT FINDINGS: The functioning of self-related networks, such as the default-mode network and the salience network, and how these are influenced by different neurotransmitters is discussed. The impact of psychedelics on self-awareness is reviewed in relation to specific processes, such as interoception, body ownership, agency, metacognition, emotional regulation and autobiographical memory, within a framework based on predictive coding. Improved outcomes in emotional regulation and autobiographical memory have been observed in association with the use of psychedelics, suggesting higher-order self-awareness changes, which can be modulated by relaxation of priors and improved coping mechanisms linked to cognitive flexibility. Alterations in bodily self-awareness are less consistent, being potentially impacted by doses employed, differences in acute/long-term effects and the presence of clinical conditions. Future studies investigating the effects of different molecules in rebalancing connectivity between resting-state networks may lead to novel therapeutic approaches and the refinement of existing treatments.


Subject(s)
Awareness , Brain , Hallucinogens , Neurotransmitter Agents , Humans , Hallucinogens/pharmacology , Neurotransmitter Agents/metabolism , Brain/drug effects , Brain/metabolism , Awareness/physiology , Awareness/drug effects , Nerve Net/drug effects , Nerve Net/metabolism
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