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In this study, we delved into the intricate world of autism spectrum disorder (ASD) and its connection to the disturbance in the Wnt signaling pathway and immunological abnormalities. Our aim was to evaluate the impact of silibinin, a remarkable modulator of both the Wnt signaling pathway and the immune system, on the neurobehavioral and molecular patterns observed in a zebrafish model of ASD induced by valproic acid (VPA). Because silibinin is a hydrophobic molecule and highly insoluble in water, it was used in the form of silibinin nanoparticles (nanosilibinin, NS). After assessing survival, hatching rate, and morphology of zebrafish larvae exposed to different concentrations of NS, the appropriate concentrations were chosen. Then, zebrafish embryos were exposed to VPA (1 µM) and NS (100 and 200 µM) at the same time for 120 h. Next, anxiety and inattentive behaviors and the expression of CHD8, CTNNB, GSK3beta, LRP6, TNFalpha, IL1beta, and BDNF genes were assessed 7 days post fertilization. The results indicated that higher concentrations of NS had adverse effects on survival, hatching, and morphological development. The concentrations of 100 and 200 µM of NS could ameliorate the anxiety-like behavior and learning deficit and decrease ASD-related cytokines (IL1beta and TNFalpha) in VPA-treated larvae. In addition, only 100 µM of NS prevented raising the gene expression of Wnt signaling-related factors (CHD8, CTNNB, GSK3beta, and LRP6). In conclusion, NS treatment for the first 120 h showed therapeutic effect on an autism-like phenotype probably via reducing the expression of pro-inflammatory cytokines genes and changing the expression of Wnt signaling components genes.
Subject(s)
Autism Spectrum Disorder , Cytokines , Disease Models, Animal , Valproic Acid , Wnt Signaling Pathway , Zebrafish , Animals , Valproic Acid/pharmacology , Wnt Signaling Pathway/drug effects , Autism Spectrum Disorder/drug therapy , Cytokines/metabolism , Embryo, Nonmammalian/drug effects , Dose-Response Relationship, DrugABSTRACT
GM1 gangliosidosis is one type of hereditary error of metabolism that occurs due to the absence or reduction of ß-galactosidase enzyme content in the lysosome of cells, including neurons. In vitro, the use of neural cell lines could facilitate the study of this disease. By creating a cell model of GM1 gangliosidosis on the SH-SY5Y human nerve cell line, it is possible to understand the main role of this enzyme in breaking down lipid substrate and other pathophysiologic phenomena this disease. To knock-out the human GLB1 gene, guides targeting exons 14 and 16 of the GLB1 gene were designed using the CRISPOR and CHOP-CHOP websites, and high-efficiency guides were selected for cloning in the PX458 vector. After confirming the cloning, the vectors were transformed into DH5α bacteria and then the target vector was extracted and transfected into human nerve cells (SH-SY5Y cell line) by electroporation. After 48 h, GFP+ cells were sorted using the FACS technique and homozygous (compound heterozygous) single cells were isolated using the serial dilution method and sequencing was done to confirm them. Finally, gap PCR tests, X-gal and Periodic acid-Schiff (PAS) staining, and qPCR were used to confirm the knock-out of the human GLB1 gene. Additionally, RNA sequencing data analysis from existing data of the Gene Expression Omnibus (GEO) was used to find the correlation of GLB1 with other genes, and then the top correlated genes were tested for further evaluation of knock-out effects. The nonviral introduction of two guides targeting exons 14 and 16 of the GLB1 gene into SH-SY5Y cells led to the deletion of a large fragment with a size of 4.62 kb. In contrast to the non-transfected cell, X-gal staining resulted in no blue color in GLB1 gene knock-out cells indicating the absence of ß-galactosidase enzyme activity in these cells. Real-time PCR (qPCR) results confirmed the RNA-Seq analysis outcomes on the GEO data set and following the GLB1 gene knock-out, the expression of its downstream genes, NEU1 and CTSA, has been decreased. It has been also shown that the downregulation of GLB1-NEU1-CTSA complex gene was involved in suppressed proliferation and invasion ability of knock-out cells. This study proved that using dual guide RNA can be used as a simple and efficient tool for targeting the GLB1 gene in nerve cells and the knockout SH-SY5Y cells can be used as a model investigation of basic and therapeutic surveys for GM1 gangliosidosis disease.
Subject(s)
CRISPR-Cas Systems , Gangliosidosis, GM1 , Humans , Gangliosidosis, GM1/genetics , Gangliosidosis, GM1/metabolism , beta-Galactosidase/metabolism , beta-Galactosidase/genetics , Neurons/metabolism , Gene Knockout Techniques , Models, BiologicalABSTRACT
The current study aimed to evaluate the effects of action observation on the walking ability and oscillatory brain activity of chronic stroke patients. Fourteen chronic stroke patients were allocated randomly to the action observation (AO) or sham observation (SO) groups. Both groups received 12 sessions of intervention. Each session composed of 12 min of observational training, which depicted exercises for the experimental group but nature pictures for the sham group and 40 min of occupational therapy, which was the same for the both groups. Walking ability was assessed by a motion analysis system and brain activity was monitored using quantitative electroencephalography (QEEG) before and after the intervention. Brain asymmetry at alpha frequency, the percentage of stance phase, and step length showed significant changes in the AO group. Only the change in global alpha power was significantly correlated with the change in velocity after the intervention in AO group. Despite more improvements in walking and brain activity of patients in the AO group, our study failed to show significant correlations between the brain activity changes and functional improvements after the intervention, which might be mainly due to the small sample size in our study. Trial registration: IRCT20181014041333N1.
Subject(s)
Electroencephalography , Stroke Rehabilitation , Stroke , Walking , Humans , Male , Walking/physiology , Female , Electroencephalography/methods , Middle Aged , Stroke Rehabilitation/methods , Stroke/physiopathology , Aged , Recovery of Function/physiology , Chronic Disease , Brain/physiopathology , AdultABSTRACT
Peganum harmala L. and Lavandula angustifolia are two traditional herbs with probable antiseizure effects. This study evaluated the effects of these two herbal extracts on pentylenetetrazol- (PTZ-) induced seizures in mice. We prepared hydroalcoholic extracts using P. harmala seeds and the aerial parts of L. angustifolia and then randomly divided 190 mice into 19 groups. Normal saline (10 mg/kg), diazepam (2 mg/kg), P. harmala (2.5, 5, 10, 15, 30, 45, and 60 mg/kg), and L. angustifolia (200, 400, 600, and 800 mg/kg) were intraperitoneally (IP) administrated 30 min before an IP administration of PTZ (90 mg/kg). Animals were observed for behavioral changes for one hour. In addition, the effects of flumazenil and naloxone on the antiseizure activity of P. harmala and L. angustifolia were assessed. P. harmala showed antiseizure activity at the dose of 10 mg/kg; it prolonged the seizure latency and decreased the seizure duration. The mortality protection rate was 90% for this herbal extract. L. angustifolia (600 mg/kg) prolonged the seizure latency and decreased both seizure duration and mortality. Neither flumazenil nor naloxone significantly reversed the antiseizure activities of P. harmala and L. angustifolia. In mice, the hydroalcoholic extracts of P. harmala and L. angustifolia showed antiseizure activity against PTZ-induced seizures. We could not delineate the exact antiseizure mechanisms of these extracts in the current study.
Subject(s)
Lavandula , Peganum , Mice , Animals , Plant Extracts/pharmacology , Flumazenil/pharmacology , Seizures/chemically induced , Seizures/drug therapy , Naloxone/pharmacologyABSTRACT
Introduction: The present study addressed whether methylprednisolone (MP) as an anti-inflammatory drug used in neurodegenerative diseases and neural stem/progenitor cells (NS/PCs) is safe. Methods: First, embryonic rat NS/PCs were exposed to different concentrations of MP, and then we evaluated their survival by MTT assay, proliferation by analyzing the number and diameter of neurospheres, and the migration of the cells by neurosphere assay. Results: The viability of NS/PCs was reduced following exposure to 10, 15, and 20 µg/mL of MP. In addition, although the number of neurospheres did not change, exposure to different concentrations of MP resulted in the formation of smaller neurospheres. Despite these undesirable effects, the highest concentration of MP (20 µg/mL) increased the migration capacity of the NS/PCs. Conclusion: The combination of MP and NS/PCs is not recommended due to the adverse effects of MP on the survival and proliferation of NS/PCs. Highlights: Methylprednisolone reduced survival of neural stem/progenitor cells.Methylprednisolone decreased proliferation of neural stem/progenitor cells.The highest concentration of MP (20 µg/mL) increased the migration capacity of the neural stem/progenitor cells. Plain Language Summary: In this study, we evaluate the effect of the exposure of neural stem/progenitor cells to methylprednisolone. Based on the results, combination of neural stem/progenitor cells and methylprednisolone not recommended due to reduction of survival and proliferation of the cells.
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Background: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system characterized by infiltration of inflammatory leukocytes to the CNS followed by oligodendrocyte cell death, myelin sheath destruction, and axonal injury. A logical incidence occurring after demyelination is remyelination. G-protein coupled receptors (GPCRs) activate internal signal transduction cascades through binding to different ligands. This family of receptors are targeted by more than 40% of currently marketed drugs. GPCRs can be successfully targeted for induction of remyelination. GPCRs highly enriched in oligodendrocyte progenitor cells compared to oligodendrocytes are proposed to hamper oligodendrocyte differentiation and therefore their inhibition might induce remyelination. This study aimed to investigate the expression of GPCRs in silico and in vitro. Methods: We performed gene expression analysis using DAVID and Panther websites on a RNA-seq dataset (GSE52564 accession number). Primary embryonic neural stem/progenitor cell isolation and culture were performed and subsequently NSPCs were characterized by Immunocytochemistry with Anti-Nestin antibody. Expression of GPR37L1, EDNRB, PDGFRα, CNPase and GFAP were assessed using real-time PCR. All the experiments were conducted at Shiraz University of Medical Sciences (SUMS), Shiraz, Iran, in the year 2018. Results: The 14 most highly expressed GPCRs in oligodendrocyte progenitor cells (OPCs) compared to Oligodendrocytes were presented in our study. Conclusion: The investigation of the most highly expressed GPCRs in OPCs compared to oligodendrocyte in silico and in vitro presents the significant role of GPCRs in remyelination induction. Among the 14 GPCRs mentioned in this study, GPR37L1 is a potential remyelinating drug target and is suggested for further studies.
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Introduction: The present study aimed to evaluate the effects of FTY720 as a neuromodulatory drug on the behaviors of neural stem/progenitor cells (NS/PCs) in two-dimensional (2-D) and three-dimensional (3-D) cultures and in spinal cord injury (SCI). Methods: The NS/PCs isolated from the ganglionic eminence of the 13.5-day old embryos were cultured as free-floating spheres. The single cells obtained from the second passage were cultured in 96-well plates without any scaffold (2-D) or containing PuraMatrix (PM, 3-D) or were used for transplantation in a mouse model of compression SCI. After exposure to 0, 10, 50, and 100 nanomolar of FTY720, the survival, proliferation, and migration of the NS/PCs were evaluated in vitro using MTT assay, neurosphere assay, and migration assay, respectively. Moreover, the functional recovery, survival and migration capacity of transplanted cells exposure to 100 nanomolar FTY720 were investigated in SCI. Results: Cell survival and migration capacity increased after exposure to 50 and 100 nanomolar FTY720. In addition, higher doses of FTY720 led to the formation of more extensive and more neurospheres. Although this phenomenon was similar in both 2-D and 3-D cultures, PM induced better distribution of the cells in a 3-D environment. Furthermore, co-administration of FTY720 and NS/PCs 7 days after SCI enhanced functional recovery and both survival and migration of transplanted cells in the lesion site. Conclusions: Due to the positive effects of FTY720 on the behavior of NS/PCs, using them in combination therapies can be an appealing approach for stem cell therapy in CNS injury.
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According to available evidence, prolonged or chronic exposure to stress is detrimental to various brain structures, including the hippocampus. The current study examined the expression of two critical blood-brain barrier receptors required for amyloid-beta clearance to understand better the mechanism by which chronic stress impairs learning and memory in patients with Alzheimer's disease (AD). Rats were randomly assigned to one of two groups in this study: experiment 1 and experiment 2. Each main group was then divided into four subgroups. Rats were bilaterally injected with streptozotocin (STZ, 3 mg/kg, twice) using the intracerebroventricular (ICV) technique to induce the Alzheimer's model. Additionally, they were subjected to foot shock (1 mA, 1 Hz) for 10 s every 60 s (1 h/day) for ten consecutive days prior to and following STZ injection. The Morris Water Maze (MWM) test was used to assess spatial learning and memory. Real-time PCR was used to determine Low-density lipoprotein receptor-related protein-1 (LRP1) and receptor for advanced glycation end-products (RAGE) mRNA levels in the hippocampus. Moreover, the animals' body weights were determined as physiological parameters in all groups. The results indicated that 10-day chronic electric foot shock stress reduced body weight, impaired spatial learning and memory, decreased hippocampal LRP1 mRNA expression, and increased hippocampal RAGE mRNA expression in a rat AD model. It can be concluded that chronic stress in conjunction with AD alters the expression of LRP1 and RAGE in the hippocampus. The findings pave the way for scientists to develop novel treatment strategies for AD.
Subject(s)
Alzheimer Disease , Rats , Animals , Alzheimer Disease/chemically induced , Alzheimer Disease/metabolism , Streptozocin/pharmacology , Spatial Memory , Receptor for Advanced Glycation End Products/metabolism , Disease Models, Animal , Hippocampus/metabolism , RNA, Messenger/metabolism , Maze LearningABSTRACT
The orexin 2 receptor plays a central role in maintaining sleep and wakefulness. Recently, it has been shown that sleep and wakefulness orchestrate the proliferation and differentiation of oligodendrocytes. Here, we explored the role of a selective orexin 2 receptor antagonist (JNJ-10397049) in proliferation and differentiation of neural progenitor cells (NPCs). We evaluated the proliferation potential of NPCs after exposure to different concentrations of JNJ-10397049 by using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide and neurosphere assays. Moreover, the expression of differentiation markers was assessed by immunocytochemistry and real-time polymerase chain reaction. JNJ-10397049 significantly increased the proliferation of NPCs at lower concentrations. In addition, orexin 2 receptor antagonist facilitated progression of differentiation of NPCs towards oligodendroglial lineage by considerable expression of Olig2 and 2',3'-cyclic-nucleotide 3'-phosphodiesterase as well as decreased expression of nestin marker. The results open a new avenue for future investigations in which the production of more oligodendrocytes from NPCs is needed.
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OBJECTIVE: Stroke is one of the most debilitating neurological disorders that commonly results in both cognitive and motor dysfunctions. Although the recovery of gait is one of the main goals of patients with stroke, only 50-60% of the patients commonly reach this target. This study aimed to evaluate the effects of action observation training, based on mirror neurons, as an add-on therapy to the conventional physical rehabilitation on the gait performance of patients with stroke. METHODS: Fourteen patients with chronic stroke were randomly assigned to the sham or the experimental group. Both groups received a 40-min conventional physical training following a 12-min observation training depicting exercises for the experimental group but nature pictures for the sham group each session. The patients' walking was recorded using a motion analysis system at baseline and after the 12-session intervention. Spatiotemporal parameters of gait and ground reaction forces were measured. RESULTS: Significant improvements were found in most measured spatiotemporal parameters of gait on the unaffected side of the patients in the experimental group, while in the sham group, the recovery was observed only in the percentage of the stance phase. Regarding the affected side, the stride and step length of the patients in the experimental group were parameters with a significant amelioration. CONCLUSION: The results of this study showed that the action observation training had the potential to improve the walking quality of the patients with hemiplegia in the chronic phase of stroke.
Subject(s)
Gait Disorders, Neurologic , Mirror Neurons , Stroke Rehabilitation , Stroke , Exercise Therapy/methods , Gait , Gait Disorders, Neurologic/rehabilitation , Humans , Stroke/complications , Stroke Rehabilitation/methods , Treatment Outcome , Walking/physiologyABSTRACT
Introduction: Spinal Cord Injury (SCI) is a devastating disease with poor clinical outcomes. Animal models provide great opportunities to expand our horizons in identifying SCI pathophysiological mechanisms and introducing effective treatment strategies. The present study introduces a new murine contusion model. Methods: A simple, cheap, and reproducible novel instrument was designed, which consisted of a body part, an immobilization piece, and a bar-shaped weight. The injury was inflicted to the spinal cord using an 8-g weight for 5, 10, or 15 minutes after laminectomy at the T9 level in male C57BL/6 mice. Motor function, cavity formation, cell injury, and macrophage infiltration were evaluated 28 days after injury. Results: The newly designed instrument minimized adverse spinal movement during injury induction. Moreover, no additional devices, such as a stereotaxic apparatus, were required to stabilize the animals during the surgical procedure. Locomotor activity was deteriorated after injury. Furthermore, tissue damage and cell injury were exacerbated by increasing the duration of weight exertion. In addition, macrophage infiltration around the injured tissue was observed 28 days after injury. Conclusion: This novel apparatus could induce a controllable SCI with a clear cavity formation in mice. No accessory elements are needed, which can be used in future SCI studies. Highlights: A simple and precise method has been introduced for creating Spinal Cord Injury (SCI) in mice by a novel device.The device consists of a body part, an immobilization piece, and a bar-shaped weight.Assessment of locomotor activity, tissue damage, and macrophage infiltration confirmed the capability of the new SCI method.Reduction of adverse spinal movements and working without any accessory elements are the key points of this new animal model of SCI. Plain Language Summary: Spinal Cord Injury (SCI) is a medical problem that can cause the permanent motor and sensory dysfunction. Traffic accidents, falls, and violence are the most frequent causes of SCI, often affecting young people. Patients and even their families may encounter other problems, including reducing life quality, psychological burden, and enormous medical costs. Despite scientific and technological advances, no effective treatment has been found for SCI. Therefore, animal models help study damage mechanisms and evaluate novel treatment strategies. All SCI research centers require an economical and reproducible device without using complex surgical procedures by experienced surgeons to minimize variations in damage to the spinal cord. In this study, a simple, cheap, and reproducible novel instrument for SCI induction is introduced. The instrument consists of various parts, including a body part, an immobilization piece, and a bar-shaped weight. An 8-g weight was used for 5, 10, or 15 minutes to inflict injury to the spinal cord. Behavioral and tissue studies indicated that SCI could be induced in rodents in different severity without other elements. This instrument can be used in future investigations for SCI studies, including tissue engineering, stem cell therapy, and drugs delivery to access effective treatment.
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Spinal cord injury (SCI) is a devastating clinical problem that can lead to permanent motor dysfunction. Fingolimod (FTY720) is a sphingosine structural analogue, and recently, its therapeutic benefits in SCI have been reported. The present study aimed to evaluate the therapeutic efficacy of fingolimod-incorporated poly lactic-co-glycolic acid (PLGA) nanoparticles (nanofingolimod) delivered locally together with neural stem/progenitor cells (NS/PCs) transplantation in a mouse model of contusive acute SCI. Fingolimod was encapsulated in PLGA nanoparticles by the emulsion-evaporation method. Mouse NS/PCs were harvested and cultured from embryonic Day 14 (E14) ganglionic eminences. Induction of SCI was followed by the intrathecal delivery of nanofingolimod with and without intralesional transplantation of PuraMatrix-encapsulated NS/PCs. Functional recovery, injury size and the fate of the transplanted cells were evaluated after 28 days. The nanofingolimod particles represented spherical morphology. The entrapment efficiency determined by UV-visible spectroscopy was approximately 90%, and the drug content of fingolimod loaded nanoparticles was 13%. About 68% of encapsulated fingolimod was slowly released within 10 days. Local delivery of nanofingolimod in combination with NS/PCs transplantation led to a stronger improvement in neurological functions and minimized tissue damage. Furthermore, co-administration of nanofingolimod and NS/PCs not only increased the survival of transplanted cells but also promoted their fate towards more oligodendrocytic phenotype. Our data suggest that local release of nanofingolimod in combination with three-dimensional (3D) transplantation of NS/PCs in the acute phase of SCI could be a promising approach to restore the damaged tissues and improve neurological functions.
Subject(s)
Nanoparticles , Neural Stem Cells , Spinal Cord Injuries , Animals , Cell Differentiation , Fingolimod Hydrochloride , Glycols , Mice , Neural Stem Cells/transplantation , Peptides , Recovery of Function , Spinal Cord Injuries/drug therapyABSTRACT
Following acute spinal cord injury (SCI), excessive recruitment of neutrophils can result in inflammation, neural tissue loss and exacerbation of neurological outcomes. Ibrutinib is a bruton's tyrosine kinase inhibitor in innate immune cells such as the neutrophils that diminishes their activation and influx to the site of injury. The present study evaluated the efficacy of ibrutinib administration in the acute phase of SCI on neural tissue preservation and locomotor recovery. Ibrutinib was delivered intravenously at 3.125 mg/kg either immediately, 12 hours after, or both immediately and 12 hours after SCI induction in adult male C57BL/6 mice. Neutrophil influx into the lesion area was evaluated 24 hours following SCI using light microscopy and immunohistochemistry methods. Animals' body weight changes were recorded, and their functional motor recovery was assessed based on the Basso mouse scale during 28 days after treatment. Finally, spinal cord lesion volume was estimated by an unbiased stereological method. While animals' weight in the control group started to increase one week after injury, it stayed unchanged in treatment groups. However, the double injection of ibrutinib led to a significantly lower body weight compared to the control group at 4 weeks post-injury. Mean neutrophil counts per visual field and the lesion volume were significantly decreased in all ibrutinib-treated groups. In addition, ibrutinib significantly improved locomotor functional recovery in all treated groups, especially in immediate and double-injection groups. Neural tissue protection and locomotor functional recovery suggest ibrutinib treatment as a potent immunotherapeutic intervention for traumatic SCI that warrants clinical testing.
ABSTRACT
Maintaining blood-brain barrier (BBB) contributes critically to preserving normal brain functions. According to the available evidence, intense or chronic exposure to stress would potentially affect different brain structures, such as the hippocampus, negatively. The purpose of this study was to define the relationship between the BBB permeability of the hippocampus and the performance of spatial learning and memory under chronically electric foot shock stress. Sixteen rats were divided into the control and stress groups equally. Animals in the stress group were exposed to foot shock (1 mA, 1 Hz) for 10-s duration every 60 s (1 h/day) for 10 consecutive days. The anxiety-related behavior, spatial learning, and memory were assessed by an Open Field (OF) and the Morris Water Maze (MWM) respectively. The hippocampal BBB permeability was determined by Evans blue penetration assay. Our results demonstrated that the stress model not only increased locomotor activities in the OF test but reduced spatial learning and memory in MWM. Moreover, these effects coincided with a significant increase in hippocampal BBB permeability. In sum, the stress model can be used in future studies focusing on the relationship between stress and BBB permeability of the hippocampus.
Subject(s)
Anxiety/physiopathology , Behavior, Animal/physiology , Blood-Brain Barrier/physiopathology , Capillary Permeability/physiology , Hippocampus/physiopathology , Spatial Memory/physiology , Stress, Psychological/physiopathology , Animals , Anxiety/etiology , Disease Models, Animal , Male , Maze Learning/physiology , Rats, Sprague-Dawley , Stress, Psychological/complicationsABSTRACT
Spinal cord injury (SCI) is a disabling neurological disorder that causes neural circuit dysfunction. Although various therapies have been applied to improve the neurological outcomes of SCI, little clinical progress has been achieved. Stem cell-based therapy aimed at restoring the lost cells and supporting micromilieu at the site of the injury has become a conceptually attractive option for tissue repair following SCI. Adult human neural stem/progenitor cells (hNS/PCs) were obtained from the epileptic human brain specimens. Induction of SCI was followed by the application of lentiviral vector-mediated green fluorescent protein-labeled hNS/PCs seeded in PuraMatrix peptide hydrogel (PM). The co-application of hNS/PCs and PM at the SCI injury site significantly enhanced cell survival and differentiation, reduced the lesion volume, and improved neurological functions compared to the control groups. Besides, the transplanted hNS/PCs seeded in PM revealed significantly higher migration abilities into the lesion site and the healthy host tissue as well as a greater differentiation into astrocytes and neurons in the vicinity of the lesion as well as in the host tissue. Our data suggest that the transplantation of hNS/PCs seeded in PM could be a promising approach to restore the damaged tissues and improve neurological functions after SCI.
Subject(s)
Brain Tissue Transplantation , Epilepsy/pathology , Genetic Vectors/metabolism , Lentivirus/metabolism , Neural Stem Cells/metabolism , Peptides/chemistry , Spinal Cord Injuries/pathology , Transduction, Genetic , Animals , Brain/pathology , Cell Survival , Doublecortin Domain Proteins , Glial Fibrillary Acidic Protein/metabolism , Green Fluorescent Proteins/metabolism , Humans , Male , Microtubule-Associated Proteins/metabolism , Neuropeptides/metabolism , Rats, Wistar , Recovery of Function , Tissue Scaffolds/chemistryABSTRACT
PURPOSE: The existing evidence of the potential applications and benefits of stem cell transplantation (SCT) in people with epilepsy and also its adverse effects in humans were systematically reviewed. METHODS: MEDLINE (accessed from PubMed), Google Scholar, and Scopus from inception to August 17, 2020 were systematically reviewed for related published manuscripts. The following key words (in the title) were used: "stem cell" AND "epilepsy" OR "seizure". Articles written in English that were human studies on stem cell transplantation in people with epilepsy were all included. RESULTS: We could identify six related articles. Because of their different methodologies, performing a meta-analysis was not feasible; they included 38 adults and 81 pediatric patients together. Five studies were single-arm human studies; there were no serious adverse events in any of the studies. CONCLUSION: While stem cell transplantation seems like a promising therapeutic option for patients with drug-resistant epilepsy, data on its application is scarce and of low quality. For now, clinical stem cell-based interventions are not justified. Perhaps, in the future, there will be a rigorous and intensely scrutinized clinical trial protocol with informed consent that could provide enough scientific merit and could meet the required ethical standards.
Subject(s)
Drug Resistant Epilepsy/diagnosis , Drug Resistant Epilepsy/therapy , Embryonic Stem Cells/transplantation , Stem Cell Transplantation/methods , Anticonvulsants/therapeutic use , Clinical Trials as Topic/methods , Humans , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cell Transplantation/trends , Mesenchymal Stem Cells , Stem Cell Transplantation/trendsABSTRACT
This study assessed the effect of swimming training on anxiety-like behaviors and corticosterone. Thirty adult male Wistar rats were randomly assigned to five study conditions: swimming training (ST); exposure to chronic mild stress (CS); exposure to chronic mild stress followed by swimming training (CS + ST); exposure to chronic mild stress followed by a recovery period (CS + recovery); control. The exercise training consisted of 60 min of swimming exercise per day, for five days a week, and four consecutive weeks. A chronic mild stress program (CMS) was applied for a period of four weeks. Anxiety-like behaviors were measured by open field test (OFT). The number of excrements and blood corticosterone were used as physiological parameters of anxiety. To assess corticosterone, blood samples were taken 48 h after the last session of experiments. Compared to other study conditions, the lowest anxiety-like behaviors and corticosterone concentrations were observed in the ST condition in unstressed rats. In stressed rats, as in the ST + CS group, swimming training probably reduced some anxiety behaviors, but the results showed increased corticosterone compared to control and CS + Recovery. Anxiety parameters and corticosterone concentrations were greatest in the CS condition. In the ST group, anxiety parameters were less than for the ST + CS group. In the CS + Recovery group, anxiety parameters were less than for the CS group. In summary, self-paced swimming training could attenuate some anxiety parameters in both stressed and non-stressed rats. The effect of swimming training in unstressed rats was more prominent than in stressed rats. In stressed rats, a period of recovery was more effective than swimming training in reducing corticosterone. Mechanisms of anxiety reduction other than cortisol should be investigated in future research.
Subject(s)
Corticosterone , Stress, Psychological , Swimming , Animals , Anxiety , Depression , Male , Rats , Rats, WistarABSTRACT
Although antiepileptic drugs (AEDs) are mainstay of the treatment of epilepsy, they are associated with significant adverse effects. The present study reviews the adverse effects of AEDs on some of the nutrition-related issues, including bone health, body weight, glucose and lipid metabolism, vitamin homeostasis, antioxidant defense system, and pregnancy. This paper also provides some nutritional recommendations for people with epilepsy. Patients with epilepsy should be regularly evaluated with regard to their nutrition status and any possible nutritional problems. Daily intake of adequate amounts of all nutrients from various sources should be encouraged, especially for vulnerable groups such as children, adolescents, elderly, and pregnant women. When necessary, preventative or therapeutic supplementation with appropriate micronutrients could be helpful. Graphical abstract.
Subject(s)
Anticonvulsants , Nutritional Status , Adolescent , Aged , Anticonvulsants/adverse effects , Antioxidants , Body Weight , Child , Female , Glucose , Humans , PregnancyABSTRACT
OBJECTIVES: Neural stem/progenitor cells (NS/PCs) hold a great potential for delivery of therapeutic agents into the injured regions of the brain. Efficient gene delivery using NS/PCs may correct a genetic defect, produce therapeutic proteins or neurotransmitters, and modulate enzyme activation. Here, we investigated the efficiency of a recombinant lentivirus vector expressing green fluorescent protein (GFP) for genetic engineering of human NS/PCs obtained during brain surgery on patients with medically intractable epilepsy. MATERIALS AND METHODS: NS/PCs were isolated from human epileptic neocortical tissues. Three plasmids (pCDH, psPAX2, pMD2.G) were used to make the virus. To produce the recombinant viruses, vectors were transmitted simultaneously into HEk-293T cells. The lentiviral particles were then used to transduce human NS/PCs. RESULTS: Our in vitro study revealed that lentivirus vector expressing GFP efficiently transduced about 80% of human NS/PCs. The expression of GFP was assessed as early as 3 days following exposure and remained persistent for at least 4 weeks. CONCLUSION: Lentiviral vectors can mediate stable, long-term expression of GFP in human NS/PCs obtained from epileptic neocortical tissues. This suggests lentiviral vectors as a potential useful tool in human NS/PCs-based gene therapy for neurological disorders, such as epilepsy.