Benefits of bone marrow mesenchymal stem cells compared to their conditioned medium in valproic acid-induced autism in rats.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behaviors, a limited range of activities, and deficiencies in social communications. Bone marrow mesenchymal stem cells (BM-MSCs), which secrete factors that stimulate surrounding microenvironment, and BM-MSCs conditioned medium (BM-MSCs-CM), which contains cell-secreted products, have been speculated to hold potential as a therapy for ASD. This study aimed to compare the therapeutic effects of BM-MSCs and BM-MSCs-CM on behavioral and microglial changes in an animal model of autism induced by valproic acid (VPA). METHODS AND RESULTS: Pregnant Wistar rats were administered by VPA at a dose of 600 mg/kg at 12.5 days post-conception. After birth, male pups were included in the study. At 6 weeks of age, one group of rats received intranasal administration of BM-MSCs, while another group received BM-MSCs-CM. The rats were allowed to recover for 2 weeks. Behavioral tests, quantitative real-time polymerase chain reaction (qRT-PCR), and immunohistochemistry were performed. Both BM-MSCs and BM-MSCs-CM administration significantly improved some behavioral deficits. Furthermore, these treatments notably reduced Iba-1 marker associated with microgliosis. Additionally, there was a significant reduction in the expression of pro-inflammatory cytokines IL-1ß and IL-6, and an increase in the levels of the anti-inflammatory cytokine IL-10 in rats administered by BM-MSCs and BM-MSCs-CM. CONCLUSIONS: Post-developmental administration of BM-MSCs and BM-MSCs-CM can ameliorate prenatal neurodevelopmental deficits, restore cognitive and social behaviors, and modulate microglial and inflammatory markers. Results indicated that the improvement rate was higher in the BM-MSCs group than BM-MSCs-CM group.

Microglia/macrophage polarization regulates spontaneous remyelination in intermittent cuprizone model of demyelination.

Central nervous system (CNS) lesions can repeatedly be de-and remyelinated during demyelinating diseases such as multiple sclerosis (MS). Here, we designed an intermittent demyelination model by 0.3 % Cuprizone feeding in C57/BL6 mice followed by two weeks recovery. Histochemical staining of luxol fast blue (LFB) was used for study of remyelination, detection of glial and endothelial cells was performed by immunohistochemistry staining for the following antibodies: anti Olig2 for oligodendrocyte progenitor cells, anti APC for mature oligodendrocytes, anti GFAP for astrocytes, and anti Iba-1 for microglia/macrophages, anti iNOS for M1 microglia/macrophage phenotype, anti TREM-2 for M2 microglia/macrophage phenotype and anti CD31 for endothelial cells. Also, real-time polymerase chain reaction was performed for assessment of the expression of the targeted genes. LFB staining results showed enhanced remyelination in the intermittent cuprizone (INTRCPZ) group, which was accompanied by improved motor function, increased mature oligodendrocyte cells, and reduction of astrogliosis and microgliosis. Moreover, switching from M1 to M2 polarity increased in the INTRCPZ group that was in association with downregulation of pro-inflammatory and upregulation of anti-inflammatory genes. Finally, evaluation of microvascular changes revealed a remarkable decrease in the endothelial cells in the cuprizone (CPZ) group which recovered in the INTERCPZ group. The outcomes demonstrate enhanced myelin content during recovery in the intermittent demyelination model which is in association with reshaping macrophage polarity and modification of glial and endothelial cells.

Quercetin as a possible complementary therapy in multiple sclerosis: Anti-oxidative, anti-inflammatory and remyelination potential properties.

Multiple sclerosis (MS) is a complex autoimmune disorder of the central nervous system (CNS) which causes various symptoms such as fatigue, dyscoordination weakness and visual weakness. The intricacy of the immune system and obscure etiology are the main reasons for the lack of a definite treatment for MS. Oxidative stress is one of the most important key factors in MS pathogenesis. It can enhance inflammation, neurodegeneration and autoimmune-mediated processes, which can lead to excessive demyelination and axonal disruption. Recently, promising effects of Quercetin as a non-pharmacological anti-oxidant therapy have been reported in preclinical studies of MS disease. In this review, we provide a compendium of preclinical and clinical studies that have investigated the effects of Quercetin on MS disease to evaluate its potential utility as a complementary therapy in MS. Quercetin treatment in MS disease not only protects the CNS against oxidative stress and neuroinflammation, but it also declines the demyelination process and promotes remyelination potential. The present study clarifies the reported knowledge on the beneficial effects of Quercetin against MS, with future implication as a neuroprotective complementary therapy.

Glial Response to Intranasal Mesenchymal Stem Cells in Intermittent Cuprizone Model of Demyelination.

Intranasal mesenchymal stem cells (MSCs) delivery is a non-invasive method that has received interests for treatment of neurodegenerative diseases, such as multiple sclerosis (MS). The impact of intranasal MSCs on intermittent cuprizone model of demyelination was a focus of this study. C57/BL6 mice were fed with 0.3% cuprizone in an intermittent or single ways. Luxol fast blue (LFB), Rotarod test, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry and western blot (WB) were used for interpretation of outcomes. MSCs effectively homed to the corpus callosum area, were able to improve motor coordination and to promote myelin recovery in the intermittent cuprizone (INTRCPZ/MSCs). Astrogliosis (GFAP+ cells) and microgliosis (Iba-1+ cells) were hampered, and more mature oligodendrocyte cells (APC+ cells) were identified in mice receiving INTRCPZ/MSCs. Such treatment also considerably reduced markers related to the macrophage type 1 (M1) cells, namely iNOS and CD86, but it recovered the M2 markers MRC-1 and TREM-2. In addition, a remarkable decrease in the expressions of pro-inflammatory IL-1ß and TNFα but an increase in the rate of anti-inflammatory TGF-ß and IL-10 were identified in mice that underwent INTRCPZ/MSCs therapy. Finally, microvascular changes were evaluated, and a noticeable increase in the expression of the endothelial cell marker CD31 was found in the INTRCPZ/MSCs-treated mice (p < 0.05 for all). The outcomes are representative of the efficacy of intranasal MSCs delivery in intermittent cuprizone model of MS for reshaping macrophage polarity along with modification of glial, inflammatory, and angiogenic markers in favor of therapy.

Combination effects of mesenchymal stem cells transplantation and anodal transcranial direct current stimulation on a cuprizone-induced mouse model of multiple sclerosis.

Multiple sclerosis (MS) has no absolute treatment, and researchers are still exploring to introduce promising therapy for MS. Transcranial direct current stimulation (tDCS), is a safe, non-invasive procedure for brain stimulating which can enhance working memory, cognitive neurohabitation and motor recovery. Here, we evaluated the effects of tDCS treatment and Mesenchymal stem cells (MSCs) transplantation on remyelination ability of a Cuprizone (CPZ)-induced demyelination mouse model. tDCS significantly increased the motor coordination and balance abilities in CPZ + tDCS and CPZ + tDCS + MSCs mice in comparison to the CPZ mice. Luxol fast blue (LFB) staining showed that tDCS and MSCs transplantation could increase remyelination capacity in CPZ + tDCS and CPZ + MSCs mice compared to the CPZ mice. But, the effect of tDCS with MSCs transplantation on remyelination process was larger than each of treatment alone. Immunofluorescence technique indicated that the numbers of Olig2+ cells were increased by tDCS and MSCs transplantation in CPZ + tDCS and CPZ + MSCs mice compared to the CPZ mice. Interestingly, the combination effect of tDCS and MSCs was larger than each of treatment alone on Oligodendrocytes population. MSCs transplantation significantly decreased the TUNEL+ cells in CPZ + MSCs and CPZ + tDCS + MSCs mice in comparison to the CPZ mice. Also, the combination effects of tDCS and MSCs transplantation was much larger than each of treatment alone on increasing the mRNA expression of BDNF and Sox2, while decreasing P53 as compared to CPZ mice. It can be concluded that the combination usage of tDCS and MSCs transplantation enhance remyelination process in CPZ-treated mice by increasing transplanted stem cell homing, oligodendrocyte generation and decreasing apoptosis.

Protective Features of Calorie Restriction on Cuprizone-induced Demyelination via Modulating Microglial Phenotype.

Multiple sclerosis (MS) is an immune-mediated demyelinating disorder in the central nervous system (CNS) with no definitive treatment, but it can be alleviated by changing life habits. Calorie restriction (CR) is effective in preventing or treating metabolic and autoimmune disorders. CR is one of the helpful approaches to control the progression of MS. In the present study, we investigated the preventive effect of caloric restriction on cuprizone induced-demyelination, a model of multiple sclerosis. To induce acute demyelination in C57/BL6 mice, we added 0.2% Cuprizone (CPZ) to their diet for 6 weeks. To induce calorie restriction, 10% Carboxymethyl cellulose (CMC) was added to the diet as a dietary cellulose fiber for 6 weeks. Remyelination was studied by luxol fast blue (LFB) staining. Microglia activity, M1 and M2 microglial/macrophage phenotypes were assessed by immunohistochemistry of Iba-1, iNOS and Arg-1, respectively. The expression of targeted genes was assessed by the real-time polymerase chain reaction. Luxol fast blue (LFB) staining showed that the CR regimen could decrease the cuprizone-induced demyelination process (p < 0.01). Moreover, the CR application could improve balance and motor performance in cuprizone-intoxicated mice by significantly enhancing protein and gene expression of Sirt1, M2 microglial phenotype marker (Arg-1) and Akt1 gene expression, also decreased M1 microglial phenotype marker (iNOS), Akt2 and P53 gene expressions (p < 0.05). Cumulatively, it can be concluded that caloric restriction was able to counteract MS symptoms through alleviating inflammatory responses.

Calorie restriction promotes remyelination in a Cuprizone-Induced demyelination mouse model of multiple sclerosis.

Over the past few decades several attempts have been made to introduce a potential and promising therapy for Multiple sclerosis (MS). Calorie restriction (CR) is a dietary manipulation to reduce calorie intake which has been shown to improve neuroprotection and attenuate neurodegenerative disorders. Here, we evaluated the effect of 33% CR regimen for 4 weeks on the remyelination capacity of Cuprizone (CPZ) induced demyelination in a mouse model of MS. Results showed that CR induced a significant increase in motor coordination and balance performance in CPZ mice. Also, luxol fast blue (LFB) staining showed that CR regimen significantly improved the remyelination in the corpus callosum of CPZ + CR mice compared to the CPZ group. In addition, CR regimen significantly increased the transcript expression levels of BDNF, Sox2, and Sirt1 in the corpus callosum of CPZ mice, while decreasing the p53 levels. Moreover, CR regimen significantly decreased the apoptosis rate. Furthermore, astrogliosis (GFAP + astrocytes) and microgliosis (Iba-1 + microglia) were significantly decreased by CR regimen while oligodendrogenesis (Olig2+) and Sirt1 + cell expression were significantly increased in the corpus callosum of CPZ + CR mice compared to the CPZ group. In conclusion, CR regimen can promote remyelination potential in a CPZ-demyelinating mouse model of MS by increasing oligodendrocyte generation while decreasing their apoptosis.