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.

Effects of Calorie Restriction on Multiple Sclerosis: A Review of the Preclinical and Clinical Studies.

It has been indicated that calorie restriction (CR) leads to several neuroprotective effects against physiological aging and different neurodegenerative disorders. Unfortunately, the definite therapeutic strategy is not introduced for Multiple sclerosis (MS) as an autoimmune disease of central nervous system (CNS) and researchers are striving to find the best treatment procedures and then optimize them. More recently, several preclinical studies have reported beneficial effects of CR on MS. It was stated that CR can decline demyelination, improve remyelination and decrease neuroinflammation in animal model of MS, as well as reduce body weight and enhance emotional wellbeing in MS patients. In this context we designed this review to examine studies exploring the effects of CR on MS disease based on the clinical and animal models to highlight involved mechanistic implications and future prospective.

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 Therapy of Mesenchymal Stem Cell Transplantation and Astrocyte Ablation Improve Remyelination in a Cuprizone-Induced Demyelination Mouse Model.

Astrocytes display an active, dual, and controversial role in multiple sclerosis (MS), a chronic inflammatory demyelination disorder. However, mesenchymal stem cells (MSCs) can affect myelination in demyelinating disorders. This study aimed to investigate the effect of single and combination therapies of astrocyte ablation and MSC transplantation on remyelination in the cuprizone (CPZ) model of MS. C57BL/6 mice were fed 0.2% CPZ diet for 12 weeks. Astrocytes were ablated twice by L-a-aminoadipate (L-AAA) at the beginning of weeks 13 and 14 whereas MSCs were injected in the corpus callosum at the beginning of week 13. Motor coordination and balance were assessed through rotarod test whereas myelin content was evaluated by Luxol-fast blue (LFB) staining and transmission electron microscopy (TEM). Glial cells were assessed by immunofluorescence staining while mRNA expression was evaluated by quantitative real-time PCR. Combination treatment of ablation of astrocytes and MSC transplantation (CPZ + MSC + L-AAA) significantly decreased motor coordination deficits better than single treatments (CPZ + MSCs or CPZ + L-AAA), in comparison to CPZ mice. In addition, L-AAA and MSCs treatment significantly enhanced remyelination compared to CPZ group. Moreover, combination therapy caused a significant decrease in the number of GFAP+ and Iba-1+ cells, whereas oligodendrocytes were significantly increased in comparison to CPZ mice. Finally, MSC administration resulted in a significant upregulation of BDNF and NGF mRNA expression levels. Our data indicate that transient ablation of astrocytes along with MSCs treatment improve remyelination through enhancing oligodendrocytes and attenuating gliosis in a chronic demyelinating mouse model of MS.

Metformin Therapy Attenuates Pro-inflammatory Microglia by Inhibiting NF-κB in Cuprizone Demyelinating Mouse Model of Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic disorder characterized by reactive gliosis, inflammation, and demyelination. Microglia plays a crucial role in the pathogenesis of MS and has the dynamic plasticity to polarize between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. Metformin, a glucose-lowering drug, attenuates inflammatory responses by activating adenosine monophosphate protein kinase (AMPK) which suppresses nuclear factor kappa B (NF-κB). In this study, we indirectly investigated whether metformin therapy would regulate microglia activity in the cuprizone (CPZ)-induced demyelination mouse model of MS via measuring the markers associated with pro- and anti-inflammatory microglia. Evaluation of myelin by luxol fast blue staining revealed that metformin treatment (CPZ + Met) diminished demyelination, in comparison to CPZ mice. In addition, metformin therapy significantly alleviated reactive microgliosis and astrogliosis in the corpus callosum, as measured by Iba-1 and GFAP staining. Moreover, metformin treatment significantly downregulated the expression of pro-inflammatory associated genes (iNOS, H2-Aa, and TNF-α) in the corpus callosum, whereas expression of anti-inflammatory markers (Arg1, Mrc1, and IL10) was not promoted, compared to CPZ mice. Furthermore, protein levels of iNOS (pro-inflammatory marker) were significantly decreased in the metformin group, while those of Trem2 (anti-inflammatory marker) were increased. In addition, metformin significantly increased AMPK activation in CPZ mice. Finally, metformin administration significantly reduced the activation level of NF-κB in CPZ mice. In summary, our data revealed that metformin attenuated pro-inflammatory microglia markers through suppressing NF-κB activity. The positive effects of metformin on microglia and remyelination suggest that it could be used as a promising candidate to lessen the incidence of inflammatory neurodegenerative diseases such as MS.

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.

17ß-Estradiol Reduces Demyelination in Cuprizone-fed Mice by Promoting M2 Microglia Polarity and Regulating NLRP3 Inflammasome.

Estrogen produces a beneficial role in animal models of multiple sclerosis (MS). The effect of 17ß-estradiol therapy on microglia polarization and neuroinflammation in the corpus callosum of the cuprizone-induced demyelination model has not been elucidated. In this study, mice were given 0.2% cuprizone (CPZ) for 5 weeks to induce demyelination during which they received 50 ng of 17ß-estradiol (EST), injected subcutaneously in the neck region, twice weekly. Data revealed that treatment with 17ß-estradiol therapy (CPZ+EST) improved neurological behavioral deficits, displayed by a significant reduction in escape latencies, in comparison to untreated CPZ mice. Also, administration of 17ß-estradiol caused a decrease in demyelination levels and axonal injury, as demonstrated by staining with Luxol fast blue, immunofluorescence to myelin basic protein, and transmission electron microscopy analysis. In addition, at the transcriptional level in the brain, mice treated with 17ß-estradiol (CPZ+EST) showed a decrease in the levels of M1-assosicted microglia markers (CD86, iNOS and MHC-II) whereas M2-associated genes (Arg-1, CD206 and Trem-2) were increased, compared to CPZ mice. Moreover, administration of 17ß-estradiol resulted in a significant reduction (∼3-fold) in transcript levels of NLRP3 inflammasome and its downstream product IL-18, compared to controls. In summary, this study demonstrated for the first time that exogenous 17ß-estradiol therapy robustly leads to the reduction of M1 phenotype, stimulation of polarized M2 microglia, and repression of NLRP3 inflammasome in the corpus callosum of CPZ demyelination model of MS. The positive effects of 17ß-estradiol on microglia and inflammasome seems to facilitate and accelerate the remyelination process.

The effect of microglial ablation and mesenchymal stem cell transplantation on a cuprizone-induced demyelination model.

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system with symptoms such as neuroinflammation, astrocytosis, microgliosis, and axonal degeneration. Mesenchymal stem cells (MSCs) with their immunomodulation, differentiation, and neuroprotection abilities can influence the remyelination process. The goal of this study is to investigate the impact of microglial ablation and MSCs transplantation on remyelination processes in the corpus callosum (CC) of the cuprizone demyelination model. For the induction of a chronic demyelination model, C57BL6 mice were fed with chow containing 0.2% cuprizone (wt/wt) for 12 weeks. For the depletion of microglia, PLX3397 was used as a colony-stimulating factor 1 receptor inhibitor for 21 days. MSCs were injected to the right lateral ventricle and after 2 weeks, the mice were killed. We assessed glial cells using specific markers such as APC, Iba-1, and GFAP using the immunohistochemistry method. Remyelination was evaluated by Luxol fast blue (LFB) staining and transmission electron microscope (TEM). The specific genes of microglia and MSCs were evaluated by a quantitative real-time polymerase chain reaction. According to the results of the study, 21 days of PLX3397 treatment significantly reduced microglial cells, and MSCs transplantation decreased the number of astrocytes, whereas the oligodendrocytes population increased significantly in PLX + MSC group in comparison with the cuprizone mice. Furthermore, PLX and MSC treatment elevated levels of remyelination compared with the cuprizone group, as confirmed by LFB staining and TEM analysis. The molecular results showed that MSC transplantation significantly decreased the number of microglia through the CX3CL1/CX3CR1 axis. These results revealed that PLX3397 treatment and MSCs injection reduced microgliosis and astrocytosis. It also increased the oligodendrocytes population by enhancing remyelination in the CC of the cuprizone model of MS.

Mesenchymal Stem Cells Ameliorate Cuprizone-Induced Demyelination by Targeting Oxidative Stress and Mitochondrial Dysfunction.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. The main causes of MS disease progression, demyelination, and tissue damage are oxidative stress and mitochondrial dysfunction. Hence, the latter are considered as important therapeutic targets. Recent studies have demonstrated that mesenchymal stem cells (MSCs) possess antioxidative properties and are able to target mitochondrial dysfunction. Therefore, we investigated the effect of transplanting Wharton's jelly-derived MSCs in a demyelination mouse model of MS in which mice were fed cuprizone (CPZ) for 12 weeks. CPZ is a copper chelator that impairs the activity of cytochrome oxidase, decreases oxidative phosphorylation, and produces degenerative changes in oligodendrocytes, leading to toxic demyelination similar to those found in MS patients. Results showed that MSCs caused a significant increase in the percentage of myelinated areas and in the number of myelinated fibers in the corpus callosum of the CPZ + MSC group, compared to the CPZ group, as assessed by Luxol fast blue staining and transmission electron microscopy. In addition, transplantation of MSCs significantly increased the number of oligodendrocytes while decreasing astrogliosis and microgliosis in the corpus callosum of the CPZ + MSC group, evaluated by immunofluorescence. Moreover, the mechanism by which MSCs exert these physiological effects was found to be through abolishing the effect of CPZ on oxidative stress markers and mitochondrial dysfunction. Indeed, malondialdehyde significantly decreased while glutathione and superoxide dismutase significantly increased in CPZ + MSC mice group, in comparison witth the CPZ group alone. Furthermore, cell therapy with MSC transplantation increased the expression levels of mitochondrial biogenesis transcripts PGC1α, NRF1, MFN2, and TFAM. In summary, these results demonstrate that MSCs may attenuate MS by promoting an antioxidant response, reducing oxidative stress, and improving mitochondrial homeostasis.

Effects of Exogenous Melatonin on MAM Induced Lung Injury and Lung Development in Mice Offspring.

BACKGROUND: Melatonin as an antioxidant agent can have an effective role in lung development. In this study, the effect of melatonin administration on lung injury in the neonate mice was assessed. MATERIALS AND METHODS: Lung injury was induced by two injections of 15 mg/kg methylazoxymethanol (MAM) on gestational day 15 (E15). Pregnant BALB/c mice were randomly divided into five groups: Control (CO), Melatonin (MEL), Luzindole (Luz), MAM, and MAM+MEL. Melatonin and luzindole were intra-peritoneally injected at a dose of 10 mg/kg (from E15 until delivery). Histopathological changes including: hemorrhage, neutrophils infiltration and fibrosis in the neonate lung were studied by hematoxylin and eosin (H&E) and Masson's Trichrome staining. Alveolarization and alveolar wall thickness were measured. RESULTS: In histological examination, hemorrhage, neutrophils infiltration and fibrosis were seen in the MAM and Luz groups; however, these injuries were attenuated in the MAM plus melatonin group. Significant reduction of alveolarization was recorded in the MAM and Luz groups compared to the control group, while the alveolar wall thickness was significantly increased in these groups compared to control group. CONCLUSION: Administration of exogenous melatonin in pregnant mice could have a protective effect on the pulmonary development of neonates and could decrease lung injury in neonate mice.

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.

The Effect of Melatonin on Mitochondrial Function and Autophagy in In Vitro Matured Oocytes of Aged Mice.

OBJECTIVE: This study examined the in vitro effect of melatonin on the protein synthesis of mitochondria, as well as autophagy in matured oocytes of aged mice. MATERIALS AND METHODS: In this experimental study, germinal vesicles (GV) oocytes were collected from aged (with the age of six-months-old) and young mice (with age range of 6-8 weeks old) and then cultured in the in vitro culture medium (IVM) for 24 hours to each metaphase II (MII) oocytes and then supplemented with melatonin at a concentration of 10 µM. The culture medium of MII oocytes was devoid of melatonin. Afterward, the expression of the SIRT-1 and LC3 was assessed by immunocytochemistry. ATP-dependent luciferin-luciferase bioluminescence assay was employed for the measurement of the ATP contents. Intracellular reactive oxygen specious (ROS) was detected by DCFH-DA, and the total antioxidant capacity (TAC) level was determined by TAC assay. RESULTS: The expression of SIRT-1 and LC3, as well as the measurement of the ATP content, was significantly increased in oocytes treated with melatonin compared with the oocytes receiving no treatment. Moreover, TAC was considerably higher in melatonin-treated oocytes than oocytes receiving no treatment. On the other hand, the level of ROS was significantly decreased in oocytes treated with melatonin in comparison with the untreated oocytes. The results indicated that melatonin considerably improved the development of oocytes as well. CONCLUSION: According to the data, melatonin increased mitochondrial function and autophagy via an increase in the expression of SIRT1 and LC3, as well as the ATP contents while it decreased the levels of ROS and increased TAC in oocytes derived from aged mice.

The Role of Thyroid Diseases and their Medications in Cardiovascular Disorders: A Review of the Literature.

The association between thyroid disease and cardiovascular manifestations is significant and undeniable. Previous studies have explained several aspects of the effects of thyroid hormone on the heart and cardiovascular system. Accordingly, both hyper and hypothyroidism can cause important alterations in cardiac rhythm, output and contractility as well as vascular resistance and blood pressure. Since treating the thyroid abnormality, especially in its initial stages, could lead to a significant improvement in most of its resultant cardiovascular disturbances, early suspicion and recognition of thyroid dysfunction, is necessary in patients with cardiovascular manifestations. In this in-depth review, we discuss the physiological roles as well as the effects of abnormal levels of thyroid hormones on the cardiovascular system. We also review the effects of the medications used for the treatment of hyper and hypothyroidism on cardiac function. In the end, we discuss the association between thyroid function and amiodarone, an effective and frequently-used antiarrhythmic drug, because of its well-known effects on the thyroid.

Intranasal delivery of SDF-1α-preconditioned bone marrow mesenchymal cells improves remyelination in the cuprizone-induced mouse model of multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS) that leads to disability in middle-aged individuals. High rates of apoptosis and inappropriate homing are limitations for the application of stem cells in cell therapy. Preconditioning of bone marrow mesenchymal stem cells (BMSCs) with stromal cell-derived factor 1α (SDF-1α), also called C-X-C motif chemokine 12 (CXCL12), is an approach for improving the functional features of the cells. The aim of this study was to investigate the therapeutic efficacy of intranasal delivery of SDF-1α preconditioned BMSCs in the cuprizone-induced chronically demyelinated mice model. BMSCs were isolated, cultured, and preconditioned with SDF-1α. Then, intranasal delivery of the preconditioned cells was performed in the C57BL/6 mice receiving cuprizone for 12 weeks. Animals were killed at 30 days after cell delivery. SDF-1α preconditioning increased C-X-C chemokine receptor type 4 (CXCR4) expression on the surface of BMSCs, improved survival of the cells, and decreased their apoptosis in vitro. SDF-1α preconditioning also improved CXCL12 level within the brain, and enhanced spatial learning and memory (assessed by Morris water maze [MWM]), and myelination (assessed by Luxol fast blue [LFB] and transmission electron microscopy [TEM]). In addition, preconditioning of BMSCs with SDF-1α reduced the protein expressions of glial fibrillary acidic protein and ionized calcium-binding adapter molecule (Iba-1) and increased the expressions of oligodendrocyte lineage transcription factor-2 (Olig-2) and adenomatous polyposis coli (APC), evaluated by immunofluorescence. The results showed the efficacy of intranasal delivery of SDF-1α-preconditioned BMSCs for improving remyelination in the cuprizone model of MS.

Oligoprotective effect of metformin through the AMPK-dependent on restoration of mitochondrial hemostasis in the cuprizone-induced multiple sclerosis model.

Oxidative stress with mitochondrial defects has a central role in the development and deterioration of Multiple sclerosis (MS). According to new findings of the effects of metformin on mitochondrial function, has attracted a lot of attention. Furthermore, it is suggested that metformin exerts its beneficial influence through AMP-activated protein kinase (AMPK) pathway. In the current study, we investigated the possible protective effects of metformin on oxidative stress and mitochondrial function by activating the AMPK pathway in the cuprizone-induced demyelination. Mice were fed with cuprizone for 6 weeks. Animals simultaneously received metformin. After sacrificing animals, myelinations, and gliosis, changes in transcription factor and biochemical analysis were assessed. Transmission electron microscopy and luxol fast blue staining revealed that the myelinated axons within corpus callosum of cuprizone-induced demyelination animals increased after administration of metformin. Metformin also upregulated the expression of mitochondrial biogenesis genes. Furthermore, the biochemical analysis demonstrated that metformin ameliorated the oxidative stress induced by cuprizone. Immunohistochemistry analysis showed that astrogliosis and microgliosis were decreased after metformin administration while it enhanced the number of oligodendrocytes. Our data implicated that metformin exerts its therapeutic effects on MS by AMPK signaling improved mitochondrial homeostasis and protected oligodendrocytes.

Preconditioning with SDF-1 Improves Therapeutic Outcomes of Bone marrow-derived Mesenchymal Stromal Cells in a Mouse Model of STZ-induced Diabetes.

BACKGROUND: Nowadays, transplantation of Bone marrow-derived Mesenchymal Stromal Cells (BMSCs) is currently an important alternative therapy for patient's type 1 diabetes mellitus. But a number of critical obstacles lie ahead of this new strategy including reducing stem cell homing to the damaged tissue due to oxidative stress. The purpose of the present study was to investigate whether preconditioning of BMSCs with SDF-1 could enhance their homing to the pancreas and promote regeneration of the pancreatic ß cells after being intravenously injected. METHODS: Mice BMSCs were isolated and expanded. Cell proliferation was assayed by MTT Assay. Preconditioning was performed with 10 ng/ml SDF-1α for 24 hr. Male NMRI mice were injected with high-dose STZ (150 mg/kg). The preconditioned or un-preconditioned BMSCs at a dose of 1×106 cells were infused via the tail vein. Blood and pancreatic tissue samples were taken from all mice for flow cytometry, biochemical and histological studies. RESULTS: Proliferation and homing of BMSCs to the pancreas were significantly increased in the BMSCs with SDF-1α preconditioning. Differentiation of transplanted BMSCs, were significantly increased in preconditioning group. Although BMSCs without SDF-1 preconditioning exhibited remarkable recovery of pancreatic islets structure but this recovery were significantly increased in the BMSCs with SDF-1α preconditioning. CONCLUSION: Our results showed the effectiveness of SDF-1α preconditioning in BMSCs transplantation of STZ induced diabetes mice which might be achieved through improvement of BMSCs homing into the injured pancreas.