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.

Alpha lipoic acid ameliorates THIM-induced prefrontal cell loss and abnormal enzymatically contents in the developing rat.

Thimerosal (THIM) is a common preservative used in many pharmaceutical drugs, vaccines, cosmetics and many other products. Today, it was somewhat clear that Thimerosal (THIM) is a neurotoxicant preservative. We aimed to use of a suitable agent for preventing of THIM side effects on brain. Therefore, in this research, the protective effects of Alpha Lipoic Acid (ALA), against THIM-induced brain cell loss, changes in neuroimmune cell and enzymatically contents were examined. Male Wistar rats (n = 60) were randomly distributed into five groups: 1- THIM group; this group received THIM at dose of 300 µg /kg on 7, 9, 11, 15 days after birth 2- ALA group; received ALA (20 mg/kg) in the same order. 3- THIM & ALA group; this group received ALA in the same dose, 30 min before THIM administration.4& 5; Saline and ALA vehicle groups were also included. At 56th postnatal day, samples of the prefrontal cortex were collected and prepared for stereological, immune-histochemical, and enzymatic evaluations. The result showed that ALA, prevents the adverse effects of THIM on brain cell loss, abnormal changes in neuroimmune cells (p < 0.05), prefrontal cortex volume (p < 0.05), and the glutathione content of prefrontal cortex (p < 0.05). In conclusion, neonatal exposure to THIM can induce abnormal alterations in neuroimmune cells and brain cell density as well as prefrontal cortex volume & glutathione content, and ALA can ameliorate these abnormalities.