Mechanism of action and therapeutic potential of dimethyl fumarate in ischemic stroke.

Dimethyl fumarate (DMF) is an immunomodulatory drug currently approved for the treatment of multiple sclerosis and psoriasis. Its benefits on ischemic stroke outcomes have recently come to attention. To date, only tissue plasminogen activators (tPAs) and clot retrieval methods have been approved by the FDA for the treatment of ischemic stroke. Ischemic conditions lead to inflammation through diverse mechanisms, and recanalization can worsen the state. DMF and the nuclear factor erythroid-derived 2-related factor 2 (Nrf2) pathway it regulates seem to be important in postischemic inflammation, and animal studies have demonstrated that the drug improves overall stroke outcomes. Although the exact mechanism is still unknown, studies indicate that these beneficial impacts are due to the modulation of immune responses, blood-brain barrier permeability, and hemodynamic adjustments. One major component evaluated before, during, and after tPA therapy in stroke patients is blood pressure (BP). Recent studies have found that DMF may impact BP. Both hypotension and hypertension need correction before treatment, which may delay the appropriate intervention. Since BP management is crucial in managing stroke patients, it is important to consider DMF's role in this matter. That being said, it seems further investigations on DMF may lead to an alternative approach for stroke patients. In this article, we discuss the mechanistic roles of DMF and its potential role in stroke based on previously published literature and laboratory findings.

Chronic exposure to 2.45 GHz microwave radiation improves cognition and synaptic plasticity impairment in vascular dementia model.

Purpose: In this study, we evaluated the effects of 2.45 GHz microwave radiation on cognitive dysfunction induced by vascular dementia (VaD).Methods: The VaD was induced by bilateral-common carotid occlusion (2-VO). The rats were divided into 4 groups including: control (n = 6), sham (n = 6), 2-VO (n = 8), and 2-VO + Wi-Fi (n = 10) groups. Wi-Fi modem centrally located at the distance of 25 cm from the animal's cages and the animals were continuously exposed to Wi-Fi signal while they freely moved in the cage (2 h/day for forty-five days). Therefore, the power density (PD) and specific absorption rate value (SAR) decreased at a distance of 25 to 60 cm (PD = 0.018 to 0.0032 mW/cm2, SAR = 0.0346 to 0.0060 W/Kg). The learning, memory, and hippocampal synaptic-plasticity were evaluated by radial arm maze (RAM), passive avoidance (PA), and field-potential recording respectively. The number of hippocampal CA1 cells was also assessed by giemsa staining.Results: Our results showed that VaD model led to impairment in the spatial learning and memory performance in RAM and PA that were associated with long-term potentiation (LTP) impairment, decrease of basal-synaptic transmission (BST), increase of GABA transmission, and decline of neurotransmitter release-probability as well as hippocampal cell loss. Notably, chronic Wi-Fi exposure significantly recovered the learning-memory performance, LTP induction, and cell loss without any effect on BST.Conclusions: The LTP recovery by Wi-Fi in the 2-VO rats was probably related to significant increases in the hippocampal CA1 neuronal density, partial recovery of neurotransmitter release probability, and reduction of GABA transmissiSon as evident by rescue of paired-pulse ratio 10 ms.

Short-term beneficial effects of human dental pulp stem cells and their secretome in a rat model of mild ischemic stroke.

Although cell therapy has been applied in regenerative medicine for decades, recent years have seen greatly increased attention being given to the use of stem cell-based derivatives such as cell-free secretome. Dental pulp stem cells (DPSCs) are widely available, easily accessible, and have high neuroprotective and angiogenic properties. In addition, DPSC-derived secretome contains a rich mixture of trophic factors. The current investigation evaluated the short-term therapeutic effects of human DPSCs and their secretome in a rat model of mild ischemic stroke. Mild ischemic stroke was induced by 30 min middle cerebral artery occlusion, and hDPSCs or their secretome was administered intra-arterially and intranasally. Neurological function, infarct size, spatial working memory, and relative expression of seven target genes in two categories of neurotrophic and angiogenic factors were assessed three days after stroke. In the short-term, all treatments reduced the severity of neurological and histological deficits caused by ischemic stroke. Moreover, transient middle cerebral artery occlusion led to the striatal and cortical over-expression of BDNF, NT-3, and angiogenin, while NGF and VEGF expression was reduced. Almost all interventions were able to modulate the expression of target genes after stroke. The obtained data revealed that single intra-arterial administration of hDPSCs or their secretome, single intranasal transplantation of hDPSCs, or repeated intranasal administration of hDPSC-derived secretome was able to ameliorate the devastating effects of a mild stroke, at least in the short-term.

Therapeutic potential of hair follicle-derived stem cell intranasal transplantation in a rat model of ischemic stroke.

BACKGROUND: Stem cell-based therapy has received considerable attention as a potential candidate in the treatment of ischemic stroke; however, employing an appropriate type of stem cells and an effective delivery route are still challenging. In the present study, we investigated the therapeutic effect of safe, noninvasive, and brain-targeted intranasal administration of hair follicle-derived stem cells (HFSCs) in a rat model of ischemic stroke. METHODS: Stem cells were obtained from the adult rat hair follicles. In experiment 1, stroke was induced by 30 min middle cerebral artery occlusion (MCAO) and stem cells were intranasally transplanted immediately after ischemia. In experiment 2, stroke was induced by 120 min MCAO and stem cells were administered 24 h after cerebral ischemia. In all experimental groups, neurological performance, short-term spatial working memory and infarct volume were assessed. Moreover, relative expression of major trophic factors in the striatum and cortex was evaluated by the quantitative PCR technique. The end point of experiment 1 was day 3 and the end point of experiment 2 was day 15. RESULTS: In both experiments, intranasal administration of HFSCs improved functional performance and decreased infarct volume compared to the MCAO rats. Furthermore, NeuN and VEGF expression were higher in the transplanted group and stem cell therapy partially prevented BDNF and neurotrophin-3 over-expression induced by cerebral ischemia. CONCLUSIONS: These findings highlight the curative potential of HFSCs following intranasal transplantation in a rat model of ischemic stroke.

The Hospitalization Rate of Cerebral Venous Sinus Thrombosis before and during COVID-19 Pandemic Era: A Single-Center Retrospective Cohort Study.

OBJECTIVES: There are several reports of the association between SARS-CoV-2 infection (COVID-19) and cerebral venous sinus thrombosis (CVST). In this study, we aimed to compare the hospitalization rate of CVST before and during the COVID-19 pandemic (before vaccination program). MATERIALS AND METHODS: In this retrospective cohort study, the hospitalization rate of adult CVST patients in Namazi hospital, a tertiary referral center in the south of Iran, was compared in two periods of time. We defined March 2018 to March 2019 as the pre-COVID-19 period and March 2020 to March 2021 as the COVID-19 period. RESULTS: 50 and 77 adult CVST patients were hospitalized in the pre-COVID-19 and COVID-19 periods, respectively. The crude CVST hospitalization rate increased from 14.33 in the pre-COVID-19 period to 21.7 per million in the COVID-19 era (P = 0.021). However, after age and sex adjustment, the incremental trend in hospitalization rate was not significant (95% CrI: -2.2, 5.14). Patients > 50-year-old were more often hospitalized in the COVID-19 period (P = 0.042). SARS-CoV-2 PCR test was done in 49.3% out of all COVID-19 period patients, which were positive in 6.5%. Modified Rankin Scale (mRS) score ≥3 at three-month follow-up was associated with age (P = 0.015) and malignancy (P = 0.014) in pre-COVID period; and was associated with age (P = 0.025), altered mental status on admission time (P<0.001), malignancy (P = 0.041) and COVID-19 infection (P = 0.008) in COVID-19 period. CONCLUSION: Since there was a more dismal outcome in COVID-19 associated CVST, a high index of suspicion for CVST among COVID-19 positive is recommended.

Long non-coding RNA H19 expression and functional polymorphism rs217727 are linked to increased ischemic stroke risk.

BACKGROUND: Efforts to identify potential biomarkers for the diagnosis of ischemic stroke (IS) are valuable. The H19 gene plays a functional role in increasing the prevalence of IS risk factors. We evaluated the correlation between H19 rs217727 polymorphism and the expression level of H19 lncRNA with susceptibility to IS among the Iranian population. METHODS: Blood samples were collected from IS patients (n = 114) and controls (n = 114). We concentrated on the expression pattern of H19 at different time points (i.e., 0-24, 24-48, and 48-72 h after stroke). The tetra-amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) method was applied for DNA genotyping. We used the quantitative real-time PCR to evaluate H19 expression levels. We used the receiver operating characteristic (ROC) curve to evaluate the diagnosis and prognosis of IS. RESULTS: The rs217727polymorphism of H19 was related with IS susceptibility in the co-dominant (OR = 2.92, 95% CI = 0.91-10.92, P = 0.04) and recessive models (OR = 2.80, 95% CI = 0.96-8.15, P = 0.04). H19 expression was significantly upregulated in IS and remained high for 72 h after stroke. ROC curves showed that H19 expression within the first 24 h from stroke onset might serve as a biomarker for the early diagnosis of IS with 79.49% sensitivity and 80.00% specificity. H19 expression in small vessel occlusion (SVO) and large-artery atherosclerosis (LAA) patients were 3.74 and 3.34 times higher than the undetermined (UD) subtype, respectively [OR = 3.74 95% CL (1.14-12.27) P = 0.030 and OR = 3.34 95% CL (1.13-9.85) P = 0.029]. CONCLUSION: The rs217727 polymorphism of the H19 is correlated with IS susceptibility, and H19 expression levels were higher in SVO and LAA patients. The upregulation of H19 may be considered as a diagnostic biomarker in IS among the Iranian population, but it cannot serve as a useful prognostic marker.

Discovery of Novel Cell Surface Markers for Purification of Embryonic Dopamine Progenitors for Transplantation in Parkinson's Disease Animal Models.

Despite the progress in safety and efficacy of cell replacement therapy with pluripotent stem cells (PSCs), the presence of residual undifferentiated stem cells or proliferating neural progenitor cells with rostral identity remains a major challenge. Here we report the generation of a LIM homeobox transcription factor 1 alpha (LMX1A) knock-in GFP reporter human embryonic stem cell (hESC) line that marks the early dopaminergic progenitors during neural differentiation to find reliable membrane protein markers for isolation of midbrain dopaminergic neurons. Purified GFP positive cells in vitro exhibited expression of mRNA and proteins that characterized and matched the midbrain dopaminergic identity. Further quantitative proteomics analysis of enriched LMX1A+ cells identified several membrane-associated proteins including a polysialylated embryonic form of neural cell adhesion molecule (PSA-NCAM) and contactin 2 (CNTN2), enabling prospective isolation of LMX1A+ progenitor cells. Transplantation of human-PSC-derived purified CNTN2+ progenitors enhanced dopamine release from transplanted cells in the host brain and alleviated Parkinson's disease-related phenotypes in animal models. This study establishes an efficient approach for purification of large numbers of human-PSC-derived dopaminergic progenitors for therapeutic applications.

Hookah Smoking: A Potentially Risk Factor for First-Ever Ischemic Stroke.

OBJECTIVE: Hookah consumption, as a common non-cigarette tobacco product, is wrongly considered as less harmful. Moreover, little is known about hookah consumption and risk of ischemic stroke. The current study aimed to assess the association between hookah consumption and first-ever ischemic stroke (FEIS). METHODS: This case-control study was performed on individuals admitted at a tertiary referral center in Shiraz, Southern Iran between October 1, 2018 and September 20, 2019. We compared FEIS patients with randomly selected stroke-free individuals as a control group. Using a multiple logistic regression analysis, we assessed the association between hookah consumption and FEIS. RESULTS: A total of 208 FEIS patients (mean age 65.2 ± 15.9 years) and 212 age and sex-matched controls (mean age 63.2 ± 14.4) were recruited. The prevalence of vascular risk factors and comorbidities including ischemic heart disease, hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, cigarette smoking, and sleep apnea was higher in patients with FEIS than their control counterparts. After adjusting for a wide range of confounders, including socioeconomic factors, hookah consumption was still an independent risk factor for FEIS (odds ratio: 3.2, 95% CI: 1.7-6.1). CONCLUSION: Hookah consumption is associated strongly with FEIS. Public awareness about risk of hookah consumption should be raised.

2.45 GHz microwave radiation impairs learning, memory, and hippocampal synaptic plasticity in the rat.

Microwave (MW) radiation has a close relationship with neurobehavioral disorders. Due to the widespread usage of MW radiation, especially in our homes, it is essential to investigate the direct effect of MW radiation on the central nervous system. Therefore, this study was carried out to determine the effect of MW radiation on memory and hippocampal synaptic plasticity. The rats were exposed to 2.45 GHz MW radiation (continuous wave with overall average power density of 0.016 mW/cm2 and overall average whole-body specific absorption rate value of 0.017 W/kg) for 2 h/day over a period of 40 days. Spatial learning and memory were tested by radial maze and passive avoidance tests. We evaluated the synaptic plasticity and hippocampal neuronal cells number by field potential recording and Giemsa staining, respectively. Our results showed that MW radiation exposure decreased the learning and memory performance that was associated with decrement of long-term potentiation induction and excitability of CA1 neurons. However, MW radiation did not have any effects on short-term plasticity and paired-pulse ratio as a good indirect index for measurement of glutamate release probability. The evaluation of hippocampal morphology indicated that the neuronal density in the hippocampal CA1 area was significantly decreased by MW.

Mechanism of action and neuroprotective role of nicorandil in ischemic stroke.

Nicorandil is a dual mechanism anti-anginal agent that acts as a nitric oxide (NO) donor and a potassium (K+) channel opener. Recent studies have evaluated the effect of nicorandil on ischemic stroke. Neurons have a low tolerance to hypoxia and therefore the brain tissue is significantly vulnerable to ischemia. Current approved treatments for ischemic stroke are tissue plasminogen activators and clot retrieval methods. The narrow therapeutic time window and lack of efficacy in restoring the dying neurons urge researchers to develop an alternative approach. In the terminal stages of anoxia, K+ channels induce hyperpolarization in various types of neuronal cells, leading to decreased neuronal activity and the preservation of the brain's energy. Nicorandil can open these K+ channels and sustain the hyperpolarization phase, which may have a neuroprotective effect during hypoxia. Additionally, we review how nicorandil can improve overall stroke outcomes through its anti-inflammatory, anti-oxidative, and edema-reducing effects. One of the major components evaluated in stroke patients is blood pressure. Studies have demonstrated that the effect of nicorandil on blood pressure is related to both its K+ channel opening and NO donating mechanisms. Since both hypertension and hypotension need correction before stroke intervention, it's crucial to consider the role of nicorandil and its impact on blood pressure. Previously published studies indicate that the right dosage of nicorandil can improve cerebral blood flow without significant changes in hemodynamic profiles. In this review, we discuss how nicorandil may contribute to better stroke outcomes based on previously published literature and laboratory findings.

Gens PSD-95 and GSK-3ß expression improved by hair follicular stem cells-conditioned medium enhances synaptic transmission and cognitive abilities in the rat model of vascular dementia.

INTRODUCTION: Vascular dementia (VaD) is a common type of dementia. The aim of this study was to investigate the cellular and molecular mechanism of conditioned medium (CM) in VaD. MATERIAL AND METHODS: The rats were divided into four groups of control (n = 9), sham-operation (n = 10), VaD with vehicle (n = 9), and VaD with CM (n = 12) that received CM on days 4, 14, and 24 after 2VO. Before sacrificing the rats, cognitive performance was assessed through the open-field (OP), passive-avoidance, and Morris-water maze. The field-potential recording was used to investigate basal synaptic transmission (BST) and long-term potentiation (LTP). Subsequently, the hippocampus was dissected, and real-time PCR was used to quantify the expression levels of ß1-catenin, insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-ß), glycogen synthase kinase-3ß (GSK-3ß), postsynaptic density protein 95 (PSD-95), and NR2B genes. RESULTS: The results indicated impaired performance in behavioral tests in 2VO rats, coupled with reductions in BST and LTP induction. The expression levels of ß1-catenin, IGF-1, PSD-95, and TGF-ß genes decreased, whereas NR2B and GSK-3ß expression increased. Treatment with CM restores the expression of PSD-95 and GSK-3ß as well as fear-memory, spatial learning, and grooming number without a positive effect on memory retrieval, time spent on the periphery and center of OP. The BST recovered upon administration of CM but, the LTP induction was still impaired. CONCLUSION: The recovery of BST in VaD rats appears to be the most important outcome of this study which is caused by the improvement of gene expression and leads to the restoration of fear memory.

Increased Serum Levels of IL-1ß after Ischemic Stroke are Inversely Associated with Vitamin D.

Background: The initial inflammatory reaction starts following occlusion in ischemic stroke (IS). Interleukin-1ß (IL-1ß) is a pro-inflammatory cytokine with a crucial role in the pathogenesis of neurodegenerative disorders. Objective: To investigate the levels of IL-1ß and vitamin D (VitD) in patients with IS compared with controls and their correlation. Methods: The serum level of 25-OH VitD and IL-1ß was assessed in 102 IS patients (0-24 h after stroke) and 102 controls with an enzyme-linked immunosorbent assay (ELISA) kit. Results: We found a significant increase in IL-1ß (80.14±6.8 vs. 60.32±4.1 pg/ml, p<0.05) and a decrease in VitD level (24.3±1.4 vs. 29.9±1.5 ng/ml, p<0.01) in the IS patients compared with the controls. There was a significantly positive correlation between the National Institutes of Health Stroke Scale (NIHSS) and IL-1ß according to both the Spearman correlation (r=0.35, p=0.0003) and the linear regression (beta=0.255, p=0.014). Also, a significant negative association between VitD and NIHSS was detected by the Spearman correlation (r=-0.41, p<0.0001) and the linear regression (beta=-0.381, p=0.000). Moreover, we found a significant negative correlation (r=-0.26, p=0.006) between the serum levels of VitD and IL-1ß in the patient group. Conclusion: Ischemic stroke correlates positively with IL-1ß and negatively with VitD levels. The speculated role of VitD deficiency in the evolution and severity of stroke may be justified by its role in the modification of inflammation.

Association between Genetic Polymorphism of The lncRNA MIAT rs1894720 with Ischemic Stroke Risk and lncRNA MIAT Expression Levels in The Blood after An Ischemic Stroke: A Case-Control Study.

OBJECTIVE: Genetic aspects can play an essential role in the occurrence and development of ischemic stroke (IS). Rs1894720 polymorphism is one of the eight single nucleotide polymorphisms (SNPs) in the long non-coding RNA (lncRNA) myocardial infarction-associated transcript (MIAT) locus. The aim of study is the lncRNA MIAT rs1894720 polymorphism decreases IS risk by reducing lncRNA MIAT expression. MATERIALS AND METHODS: In this case-control study, we studied 232 Iranian patients and 232 controls. The blood samples were collected from patients admitted at different times after stroke symptoms. We enrolled 80, 78, and 74 patients who arrived at the hospital between 0-24, 24-48, and 48-72 hours after the first appearance of symptoms, respectively. DNA genotyping was done by the tetra-primer ARMS-PCR method. Circulating MIAT levels were evaluated by real-time polymerase chain reaction (PCR). RESULTS: The GT genotype of MIAT rs1894720 showed a significant association with the risk of IS (OR=3.53, 95% CI=2.13-5.84, P<0.001). MIAT expression was higher relative to the control within the first hours after IS. The MIAT levels in IS patients with rs1894720 (GT) were significantly lower relative to patients who had the GG and TT genotypes. Linear regression model indicated a significant correlation between MIAT expression with atherosclerotic risk factors and types of stroke in IS patients. Receiver operating characteristic (ROC) curve analysis showed that the level of lncRNA MIAT after IS could be diagnostic with an area under the curve (AUC) of 0.82. The sensitivity and specificity were 80.17 and 67.24%, respectively (P<0.001). CONCLUSION: Our study demonstrated that the MIAT rs1894720 polymorphism (GT) might increase the risk of IS in the Iranian population. MIAT expression was up-regulated in our IS patients. Hence, it could be a diagnostic biomarker for IS.

Cross-talk between the HPA axis and addiction-related regions in stressful situations.

Addiction is a worldwide problem that has a negative impact on society by imposing significant costs on health care, public security, and the deactivation of the community economic cycle. Stress is an important risk factor in the development of addiction and relapse vulnerability. Here we review studies that have demonstrated the diverse roles of stress in addiction. Term searches were conducted manually in important reference journals as well as in the Google Scholar and PubMed databases, between 2010 and 2022. In each section of this narrative review, an effort has been made to use pertinent sources. First, we will provide an overview of changes in the Hypothalamus-Pituitary-Adrenal (HPA) axis component following stress, which impact reward-related regions including the ventral tegmental area (VTA) and nucleus accumbens (NAc). Then we will focus on internal factors altered by stress and their effects on drug addiction vulnerability. We conclude that alterations in neuro-inflammatory, neurotrophic, and neurotransmitter factors following stress pathways can impact related mechanisms on craving and relapse susceptibility.

Association of Long Non-Coding RNA Malat1 with Serum Levels of Interleukin-1 Beta and Vitamin D in Patients with Ischemic Stroke.

BACKGROUND: Previous studies have demonstrated the strong association of inflammatory cytokines and vitamin D (VitD) deficiency and ischemic stroke (IS) pathogenesis. Due to the negative correlation between long non-coding RNA (lncRNA) Malat1 and pro-inflammatory factors we decided to investigate the associations between Malat1 expression with serum interleukin-1ß (IL-1ß), and VitD levels in IS patients. MATERIALS AND METHODS: In this cross-sectional study, 63 IS patients were included. We used enzyme-linked immunosorbent assays to evaluate the serum levels of VitD and IL-1ß. Malat1 expression was evaluated by the real-time polymerase chain reaction test. The associations between Malat1expression with VitD and IL-1ß were analysed with linear regression (Stepwise model) and Pearson's correlation analysis. RESULTS: The Malat1 expression was inversely correlated with stroke severity (r=-0.25, P=0.043). Stepwise regression analysis showed a significant positive relationship between VitD level and Malat1 expression (Beta=0.28, P=0.02), and also showed a non-significant negative relationship between IL-1ß and stroke severity. VitD level showed a positive Pearson correlation with Malat1 (r=0.28, P=0.023) and a negative correlation with IL-1ß (r=-0.29, P=0.018) while it could not detect a significantly negative correlation with stroke severity. CONCLUSION: For the first time the associations between Malat1 expression with IL-1ß and VitD in IS patients was analyzed. We found a significant positive relationship between VitD and Malat1. This correlation needs to be investigated with a larger sample size to achieve a strong and reliable association between VitD and Malat1.

Combined use of hair follicle stem cells and CEPO (carbamylated erythropoietin)-Fc in a rat model of chronic cerebral hypoperfusion: A behavioral, electrophysiological, and molecular study.

BACKGROUND: In dementia, synaptic dysfunction appears before neuronal loss. Stem cell therapy could potentially provide a promising strategy for the treatment of dementia models. The carbamylated erythropoietin fusion protein (CEPO-Fc) has shown synaptotrophic effects. This study aimed to determine the efficiency of the combined use of hair follicle stem cells (HFSC) and CEPO-Fc in the basal synaptic transmission (BST) and long-term plasticity (LTP) of chronic cerebral hypoperfusion (CCH) rats. METHODS: We divided 64 adult rats into control, sham, CCH+vehicle, CCH+CEPO, CCH+HFSC, and CCH+HFSC+CEPO groups. The CEPO-Fc was injected three times/week for 30 days. HFSC transplantation was done on days 4, 14, and 21 after surgery. The Morris water maze test and passive avoidance were used to assess memory. BST and LTP were assessed by a field-potential recording of the CA1 region. The hippocampal mRNA expression of IGF-1, TGF-ß1, ß1-Catenine, NR2B, PSD-95, and GSk-3ß was evaluated by quantitative RT-PCR. RESULTS: Following combination therapy, spatial memory retention, and BST showed significant improvement relative to HFSC and CEPO-Fc groups. These effects were also confirmed by recovered mRNA expression of ß1-catenin, TGF-ß1, and NR2B. GSK-3ß expression was downregulated in all treatment groups. The upregulated PSD-95 was identified in HFSC and combination groups compared to the vehicle group. CONCLUSIONS: These findings indicate that the combined use of HFSC and CEPO-Fc may be more advantageous for treating memory disruption in the CCH model than CEPO-Fc or HFSC alone. This type of combination therapy may hopefully lead to a new approach to treatment for dementia.

Combination Therapy with Platelet-Rich Plasma and Epidermal Neural Crest Stem Cells Increases Treatment Efficacy in Vascular Dementia.

This study aimed to evaluate the efficacy and treatment mechanism of platelet-rich plasma (PRP) and neural crest-derived epidermal stem cells (ESCs) in their administration alone and combination in vascular dementia (VaD) model by two-vessel occlusion (2VO). Methods. Sixty-six rats were divided into six groups: the control, sham, 2VO + vehicle, 2VO + PRP, 2VO + ESC, and 2VO + ESC + PRP. The treated groups received 1 million cells on days 4, 14, and 21 with or without 500 µl PRP (twice a week) after 2VO. The memory performance and anxiety were evaluated by behavioral tests including open field, passive avoidance, and Morris water maze. The basal-synaptic transmission (BST) and long-term potentiation (LTP) were assessed through field-potential recordings of the CA1. The mRNA expression levels of IGF-1, TGF-ß1, PSD-95, and GSk-3ß were measured in the rat hippocampus by quantitative reverse transcription polymerase chain reaction. Results. The results demonstrated impaired learning, memory, and synaptic plasticity in the 2VO rats, along with a significant decrease in the expression of IGF-1, TGF-ß1, PSD-95, and upregulation of GSK-3ß. Treatment with ESC alone and ESC + PRP showed similar improvements in spatial memory and LTP induction, with associated upregulation of PSD-95 and downregulation of GSK-3ß. However, only the ESC + PRP group showed recovery in BST. Furthermore, combination therapy was more effective than PRP monotherapy for LTP and memory. Conclusions. The transplantation of ESC showed better effects than PRP alone, and combination therapy increased the treatment efficacy with the recovery of BST. This finding may be a clue for the combination therapy of ESC and PRP for VaD.

From Hair to the Brain: The Short-Term Therapeutic Potential of Human Hair Follicle-Derived Stem Cells and Their Conditioned Medium in a Rat Model of Stroke.

The short-term therapeutic impacts of stem cells and their derivatives were frequently reported in preclinical investigations of ischemic stroke (IS); however, several drawbacks including accessibility, abundancy, and ethical concerns limited their clinical application. We describe here for the first time the therapeutic potential of human hair follicle-derived stem cells (hHFSCs) and their conditioned medium (CM) in a rat model of IS. Furthermore, we hypothesized that a combination of cell therapy with repeated CM administration might enhance the restorative efficiency of this approach compared to each treatment alone. Middle cerebral artery occlusion was performed for 30 min to induce IS. Immediately after reperfusion, hHFSCs were transplanted through the intra-arterial route and/or hHFSC-CM administered intranasally. The neurological outcomes, short-term spatial working memory, and infarct size were evaluated. Furthermore, relative expression of seven target genes in three categories of neuronal markers, synaptic markers, and angiogenic markers was assessed. The hHFSCs and hHFSC-CM treatments improved neurological impairments and reduced infarct size in the IS rats. Moreover, molecular data elucidated that IS was accompanied by attenuation in the expression of neuronal and synaptic markers in the evaluated brain regions and the interventions rescued these expression changes. Although there was no considerable difference between hHFSCs and hHFSC-CM treatments in the improvement of neurological function and decrement of infarct size, combination therapy was more effective to reduce infarction and elevation of target gene expression especially in the hippocampus. These findings highlight the curative potential of hHFSCs and their CM in a rat model of IS.

Biliary cirrhosis-induced cardiac abnormality in rats: Interaction between Farnesoid-X-activated receptors and the cardiac uncoupling proteins 2 and 3.

Objectives: This study aimed to evaluate the relationship between Farnesoid-X-activated receptors (FXR) as nuclear regulators of the antioxidant defense system as well as cardiac mitochondrial carrier proteins of UCP2 and UCP3 in cardiac damage induced by cirrhosis. Materials and Methods: Twenty-two male Wistar rats (200-250 g) were randomly divided into 3 experimental groups, including a control group (n=6), a sham-operated group (n=8), and a bile duct ligated (BDL) group (n=8). Four weeks after surgical intervention, biochemical assessment (AST, ALT, GGT, LDH, and ALP), histological observation, and molecular evaluation (FXR, UCP2, UCP3, BNP, Caspase3, and GAPDH) using real-time RT-PCR were performed. Results: Compared with the sham-operation group, the BDL group showed a significant rise in liver enzymes of AST, ALT, GGT, LDH, and ALP. Defined fibrotic and necrotic bundles and thick reticulin fibers were also found in BDL liver tissue. Besides liver morphological alterations, left ventricles of BDL ones were also associated with defined cardiomyocyte hypertrophy, myofiber vacuolization, and clear pigmentation. Findings showed a significant up-regulation of cardiac Brain Natriuretic Peptide (BNP) along with marked down-regulation in hepatic FXR, cardiac FXR, and cardiac UCP2 and UCP3. However, the expression of caspase 3 in the cardiac tissue was not affected by BDL operation during 4 weeks. Conclusion: Expression of FXR as an upstream regulator of cellular redox status, besides the non-enzymatic ROS buffering defense system of cardiac UCPs, has a pivotal role in the pathogenesis of cirrhotic-induced cardiac abnormality in rats.

Neuroprotective effects of sodium valproate on hippocampal cell and volume, and cognitive function in a rat model of focal cerebral ischemia.

Valproate (VPA) as a histone deacetylase (HDAC) inhibitor has shown neuroprotective effects in neurodegenerative diseases. This study evaluated whether VPA treatment ameliorated the synaptic plasticity dysfunction, hippocampal neuronal loss, and spatial memory deficits induced by cerebral ischemia in the middle cerebral artery occlusion (MCAO) model. Thirty-two male Sprague-Dawley rats were randomly divided into 4 groups control, sham, cerebral ischemia+vehicle (MCAO+V), and MCAO+VPA. The right common carotid artery was occluded for 1 hour. VPA (300 mg/kg) or vehicles were injected intraperitoneally on days 0,1,2 and 3 of the reperfusion. After 7 days of reperfusion the Morris water maze, passive avoidance, and open field tests were performed. Hippocampal synaptic plasticity in the CA1 area was recorded by field potential recording. We used the term neuronal Input-Output (I/O) function and paired-pulse ratio (PPR) to refer to basal synaptic transmission and presynaptic neurotransmitter release probability respectively. After that, the brains were removed for assaying stereological parameters of the CA1 neurons. Our results showed the VPA administration significantly reduced the total infarct volume, improved MCAO-induced spatial learning -memory, fear memory, and anxiety compared to the MCAO+V group. In addition, the field potential recording showed that VPA significantly ameliorated the impaired the long- term potentiation (LTP) induced by MCAO, without any effects on basal synaptic transmission and neurotransmitter release probability. Therefore, it seems that a decrease in total infarct volume and induction of long-term potentiation via postsynaptic mechanisms is responsible for improving MCAO-induced cognitive impairment.