The IC87201 (a PSD95/nNOS Inhibitor) Attenuates Post- Stroke Injuries.

N-methyl-D-aspartate receptor-dependent excitotoxicity is one of the most important mechanisms underlying stroke injury and the resulting neuronal death. In the present study, in order to reduce post-stroke brain injury and improve behavioral performance, a new molecule named IC87201, which acts as an inhibitor of PSD95/nNOS interaction in the intracellular signaling pathway of NMDA receptors, was administered. Using the middle cerebral artery occlusion (MCAO) technique, 24 adult male rats were subjected to one hour of cerebral ischemia. Animals were randomly divided into sham, MCAO, MCAO + DXM, and MCAO + IC87201 groups, and in the last two groups, intraperitoneal injection of dextromethorphan hydrobromide monohydrate (DXM), as an NMDA antagonist, and IC87201 was performed after ischemia. Neurobehavioral scores were evaluated for seven days, and on the last two days, the rats' memory performance was appraised using the passive avoidance test. On seventh day, the brain tissue was properly prepared for stereological analysis. Stereological studies of the hippocampus CA1 and CA3 regions revealed that changes in the total and infarcted volumes, total number of neurons, non-neurons, and dead neurons are the consequences of cerebral ischemia. Also, following cerebral ischemia, neurobehavioral and memory function impairments which were assessed by modified neurological severity scores (mNSS) and passive avoidance test, were observed. The aforementioned impairments were recovered after administration of IC87201 significantly and more potently than DXM. Based on our findings, IC87201 successfully attenuated post-ischemia damages. Therefore, this molecule can be considered as a new therapeutic approach in future research.

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.

Conditioned Media Therapy in Alzheimer's Disease: Current Findings and Future Challenges.

Alzheimer's disease (AD) is a neurodegenerative disorder accompanied by a reduction in cognition and memory. Till now, there is no definite cure for AD, although, there are treatments available that may improve some symptoms. Currently, in regenerative medicine stem cells are widely used, mainly for treating neurodegenerative diseases. There are numerous forms of stem cells to treat AD aiming at the expansion of the treatment methods for this particular disease. Since 10 years ago, science has gained abundant knowledge to treat AD by understanding the sorts of stem cells, methods, and phasing of injection. Besides, due to the side effects of stem cell therapy like the potentiation for cancer, and as it is hard to follow the cells through the matrix of the brain, researchers have presented a new therapy for AD. They prefer to use conditioned media (CM) that are full of different growth factors, cytokines, chemokines, enzymes, etc. without tumorigenicity or immunogenicity such as stem cells. Another benefit of CM is that CM could be kept in the freezer, easily packaged, and transported, and doesn't need to fit with the donor. Due to the beneficial effects of CM, in this paper, we intend to evaluate the effects of various types of CM of stem cells on AD.

Curcumin mitigates the sleep-deprivation impacts on rat hypothalamic paraventricular nucleus.

Introduction: The paraventricular nucleus of the hypothalamus (PVH) is an important efferent system that relays the circadian rhythm of sleep and stress information to the periphery. Chronic REM sleep deprivation (CSD) is thought to damage this system. We evaluated the effects of CSD after 21 days on the spatial arrangement of PVH in male rats and the anti-apoptotic effects of curcumin on cell loss in sleep-deprived rats. Methods: The rats received 1 mL of 100 mg/kg/day of curcumin in 3 groups: the CSD (through a modified multiple platform apparatus, 18 h/day), grid-floor control, and cage-control along with the same set of matched groups which received 1 mL PBS. In the grid-floor control group, as a control for CSD, animals were placed on stainless-steel-mesh grids positioned upon the CSD apparatus and then allowed to sustain the chance to sleep. After 21 days, their brains were removed for stereological estimations, Voronoi tessellation, and TUNEL assay. In an unbiased stereological approach, Cavalieri's principle and an optical disector were used for estimating the volume and total cell number of the PVH, respectively. The Voronoi tessellation was measured using Image J software. Results: Significant reductions (P < 0.05) in the PVH volume and cell number, along with an increase in dead neurons, were found in CSD animals. The spatial pattern of two types of PVH neurons (parvocellular and magnocellular) showed random distributions after CSD, whereas curcumin not only increased the volume and neuronal number but also retrieved the spatial distribution to a regular one. Conclusions: CSD decreased the volume and altered the spatial arrangement of the neurons in PVH by increasing apoptosis and decreasing the cell number. However, oral use of curcumin could protect PVH from these changes.

The effect of intra-nasal co-treatment with insulin and growth factor-rich serum on behavioral defects, hippocampal oxidative-nitrosative stress, and histological changes induced by icv-STZ in a rat model.

Impaired insulin and growth factor functions are thought to drive many alterations in neurodegenerative diseases like dementia and seem to contribute to oxidative stress and inflammatory responses. Recent studies revealed that nasal growth factor therapy could induce neuronal and oligodendroglia protection in rodent brain damage induction models. Impairment of several growth factors signaling was reported in neurodegenerative diseases. So, in the present study, we examined the effects of intranasal co-treatment of insulin and a pool of growth factor-rich serum (GFRS) which separated from activated platelets on memory, and behavioral defects induced by intracerebroventricular streptozotocin (icv-STZ) rat model also investigated changes in the hippocampal oxidative-nitrosative state and histology. We found that icv-STZ injection (3 mg/kg bilaterally) impairs spatial learning and memory in Morris Water Maze, leads to anxiogenic-like behavior in the open field arena, and induces oxidative-nitrosative stress, neuroinflammation, and neuronal/oligodendroglia death in the hippocampus. GFRS (1µl/kg, each other day, 9 doses) and regular insulin (4 U/40 µl, daily, 18 doses) treatments improved learning, memory, and anxiogenic behaviors. The present study showed that co-treatment (GFRS + insulin with respective dose) has more robust protection against hippocampal oxidative-nitrosative stress, neuroinflammation, and neuronal/oligodendroglia survival in comparison with the single therapy. Memory and behavioral improvements in the co-treatment of insulin and GFRS could be attributed to their effects on neuronal/oligodendroglia survival and reduction of neuroinflammation in the hippocampus.

The antioxidant properties of resveratrol on sperm parameters, testicular tissue, antioxidant capacity, and lipid peroxidation in isoflurane-induced toxicity in mice.

This study explores whether resveratrol effectively protects the reproductive system against isoflurane-induced toxicity in testicular tissue. In this experiment, we randomly divided 60 adult male C57BL/6 mice into six groups (n = 10). Five consecutive days per week, mice were exposed to 1.5% isoflurane for 1 h/day and were given 50 and 100 mg/kg resveratrol. After 35 days (the completion of the mouse spermatogenesis period), the left testis was removed for histomorphometric evaluations, while the right testis was used to determine the Capacity of total antioxidants and lipid peroxidation. To analyze the Parameters of sperm, chromatin maturation, and DNA fragmentation, the left caudal epididymis was used. Based on a one-way analysis of variance (ANOVA), we considered a difference in means of 0.05 to be significant (P0.05). Compared to the control group, the isoflurane group showed a significant decrease in testicular weight, volume, sperm parameters, and tissue histomorphometry. Comparatively, to the control group, malondialdehyde levels increased, and the total antioxidant capacity decreased significantly. Resveratrol improved all of the above parameters in the simultaneous treatment groups compared to the isoflurane group. It did not, however, reach the level of the control group in all cases. It has been demonstrated that resveratrol, with its powerful antioxidant properties, reduces the reproductive toxicity of isoflurane by inhibiting free radicals and increasing the testicular tissue's antioxidant capacity.

Comparison of the efficacy of human umbilical cord mesenchymal stem cells conditioned medium and platelet-rich plasma on the hippocampus of STZ-induced rat model of Alzheimer's disease: A behavioral and stereological study.

Introduction: Alzheimer's disease (AD) is accompanied by progressive cognitive disorders and memory loss. This study aims to determine the combined effects of conditioned medium of human umbilical cord mesenchymal stem cells (CM) and platelet-rich plasma (PRP) on AD model rats. Methods: Forty-eight male Sprague Dawley rats were classified into 6 groups: Control, Sham, AD, and three treatment groups. AD was induced by streptozotocin(STZ; 3 mg/kg, intracerebroventricular (ICV)) and the treatment groups received injections of CM [(200 µl, intraperitoneally (i.p.), and/or PRP (100 µl, intravenously(i.v)] for 8 days. Behavioral tests (Morris water maze and novel objective recognition) were used to assess learning ability and memory. At the end of the behavioral tests, the rats were sacrificed and their brain was entirely removed, sectioned, and stained with cresyl violet. The hippocampus volume and number of neurons were evaluated by stereological techniques. Results: In the AD group, the discrimination ratio, time spent in the target zone, volume of Cornu Ammonis1 (CA1) and Dentate Gyrus (DG), and the number of pyramidal and granular cells decreased significantly compared to the Sham group. The mentioned parameters increased in the CM and CM+PRP groups compared to the AD group (p < 0.01). PRP did not have any noticeable effect on the examined parameters. Conclusions: CM may be beneficial in the treatment of AD as it led to better improvement in STZ-induced learning and memory impairments as well as the structure of the hippocampus.

G-CSF improved the memory and dendritic morphology impairments in the hippocampal CA1 pyramidal neurons after brain ischemia in the male rats.

BACKGROUND: Stroke remains the leading cause of death and disability in the world. A new potential treatment for stroke is the granulocyte colony-stimulating factor (G-CSF), which exerts neuroprotective effects through multiple mechanisms. Memory impairment is the most common cognitive problem after a stroke. The suggested treatment for memory impairments is cognitive rehabilitation, which is often ineffective. The hippocampus plays an important role in memory formation. This project aimed to study the effect of G-CSF on memory and dendritic morphology of hippocampal CA1 pyramidal neurons after middle cerebral artery occlusion (MCAO)in rats. METHODS: Male Sprague-Dawley rats were divided into three groups: the sham, control (MCAO + Vehicle), and treatment (MCAO + G-CSF) groups. G-CSF (50 µg/kg S.C) was administered at 6, 24, and 48 h after brain ischemia induction. The passive avoidance task to evaluate learning and memory was performed on days 6 and 7 post-ischemia. Seven days after MCAO, the brain was removed and the hippocampal slices were stained with Golgi. After that, the neurons were analyzed for dendritic morphology and maturity. OUTCOMES: The data showed that stroke was associated with a significant impairment in the acquisition and retention of passive avoidance tasks, while the G-CSF improved learning and memory loss. The dendritic length, arborization, spine density, and mature spines of the hippocampus CA1 neurons were significantly reduced in the control group, and treatment with G-CSF significantly increased these parameters. CONCLUSION: G-CSF, even with three doses, improved learning and memory deficits, and dendritic morphological changes in the CA1 hippocampal neurons resulted from brain ischemia.

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.

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.

Neuroprotective Effect of Wharton's Jelly-Derived Mesenchymal Stem Cell-Conditioned Medium (WJMSC-CM) on Diabetes-Associated Cognitive Impairment by Improving Oxidative Stress, Neuroinflammation, and Apoptosis.

According to strong evidence, diabetes mellitus increases the risk of cognitive impairment. Mesenchymal stem cells have been shown to be potential therapeutic agents for neurological disorders. In the current study, we aimed to examine the effects of Wharton's jelly-derived mesenchymal stem cell-conditioned medium (WJMSC-CM) on learning and memory, oxidative stress, apoptosis, and histological changes in the hippocampus of diabetic rats. Randomly, 35 male Sprague Dawley rats weighing 260-300 g were allocated into five groups: control, diabetes, and three diabetic groups treated with insulin, WJMSC-CM, and DMEM. The injections of insulin (3 U/day, S.C.) and WJMSC-CM (10 mg/week, I.P.) were done for 60 days. The Morris water maze and open field were used to measure cognition and anxiety-like behaviors. Colorimetric assays were used to determine hippocampus glutathione (GSH), malondialdehyde (MDA) levels, and antioxidant enzyme activity. The histopathological evaluation of the hippocampus was performed by Nissl staining. The expression levels of Bax, Bcl-2, BDNF, and TNF-α were detected by real-time polymerase chain reaction (RT-PCR). According to our findings, WJMSC-CM significantly reduced and increased blood glucose and insulin levels, respectively. Enhanced cognition and improved anxiety-like behavior were also found in WJMSC-CM-treated diabetic rats. In addition, WJMSC-CM treatment reduced oxidative stress by lowering MDA and elevating GSH and antioxidant enzyme activity. Reduced TNF-α and enhanced Bcl-2 gene expression levels and elevated neuronal and nonneuronal (astrocytes and oligodendrocytes) cells were detected in the hippocampus of WJMSC-CM-treated diabetic rats. In conclusion, WJMSC-CM alleviated diabetes-related cognitive impairment by reducing oxidative stress, neuroinflammation, and apoptosis in diabetic rats.

Optimisation of ketamine-xylazine anaesthetic dose and its association with changes in the dendritic spine of CA1 hippocampus in the young and old male and female Wistar rats.

BACKGROUND: A combination of ketamine-xylazine (K-X) is frequently used for anaesthesia in rats. Sex and age affect this cocktail dosage. Ketamine causes a hypnotic effect by blocking NMDA receptors located on the dendritic spine of the CA1 region. OBJECTIVES: The present study aimed to find the optimal dosage of K-X and its association with the changes in dendritic spine number of the CA1 region for aged and young rats of both sexes. METHODS: We injected 150-4 mg/kg of K-X in young and 100-2 mg/kg in aged Wistar rats intraperitoneally and recorded the onset time and duration of anaesthesia and death percentage. Then, animals were sacrificed, brains removed, cut and after Golgi-Cox staining, the total number of dendritic spines on CA1 was estimated. RESULTS: The findings showed that the onset time of anaesthesia lasted longer and its duration lasted shorter, and the number of mature spines decreased with aging, but sex caused no significant effect. The death percentages in young groups comprise 20% and in the aged groups were lower: 5% in males and 0.0% in females. CONCLUSIONS: It seems 100-2 mg/kg of K-X is an optimal dose in aged rats and retains an association with reduction of the mature dendritic spine of CA1.

Exposure to Cadmium Alters the Population of Glial Cell Types and Disrupts the Regulatory Mechanisms of the HPG Axis in Prepubertal Female Rats.

Despite the fact that the brain is susceptible to neurotoxicity induced by cadmium (Cd), the effects of Cd on the neuroanatomical development in the hypothalamus and regulatory mechanisms of the hypothalamic-pituitary-gonadal (HPG) axis are not fully understood. To clarify this issue, we investigated the effects of 25 mg/kg BW/day cadmium chloride (CdCl2) on neuroanatomical alterations in the hypothalamus of prepubertal female rats. Twenty-four Sprague-Dawley rats were randomly assigned to two groups (n = 12), and CdCl2 was administered via gavage from postnatal days (PND) 21 to PND35. The results of the stereological analysis demonstrated that prepubertal exposure to Cd reduced the number of neurons and oligodendrocytes in the arcuate (ARC) and dorsomedial hypothalamus nucleus (DMH) nuclei. In contrast, Cd exposure increased the number of microglial cells in the ARC and DMH nuclei. Cd exposure decreased the mRNA levels of gonadotropin-releasing hormone (GnRH) and increased the mRNA levels of RFamide-related peptide (RFRP-3), but not kisspeptin (Kiss1) in the hypothalamus. Moreover, hormonal assay showed that Cd exposure caused a reduction in the concentration of gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in serum. Immunohistochemical expression of RFRP-3 in neuronal cell bodies demonstrated that the mean number of RFRP-3 expressing neurons in the DMH nucleus of cadmium-treated rats was dramatically higher than the vehicle group. Overall, exposure to Cd during the prepubertal period alters the population of neurons and glial cell types in the hypothalamus. Additionally, Cd exposure disrupts the regulatory mechanisms of the HPG axis.

The medial prefrontal cortex to the medial amygdala connections may affect the anxiety level in aged rats.

BACKGROUND: Aging changes brain function and behavior differently in male and female individuals. Changes in the medial prefrontal cortex (mPFC)-medial amygdala (MeA) connectivity affect anxiety-like behavior. OBJECTIVES: Therefore, this study aimed to investigate the effect of aging and sex on the mPFC-MeA connection and its association with the level of anxiety-like behavior. METHODS: We divided the Wistar rats into the male and female young rats (2-3-month-old) and male and female old rats (18-20 months old). First, the open field test (OFT) was performed, and then 80 nl of Fluoro-Gold (FG) was injected by stereotaxic surgery in the right or left MeA. After 10 days, the animals were perfused, their brain removed, coronal sections cut, and the number of FG-labeled cells in the right and left mPFC of each sample was estimated. RESULTS: Based on our results, old animals revealed less anxiety-like behavior than young ones, and young females were less anxious than young males, too. Interestingly, MeA of old male rats received more fibers from the bilateral mPFC than young ones. Also, this connection was stronger in the young females than young males. Altogether, the present study indicated that old individuals had less anxiety-like behavior and stronger mPFC-MeA connection, and young female rats were less anxious and had a stronger connection of mPFC-amygdala than males of the same age. CONCLUSION: Thus, it seems that there is a negative relationship between anxiety levels based on the rat's performance in the OFT apparatus and the mPFC-MeA connection.

Different paradigms of transcranial electrical stimulation improve motor function impairment and striatum tissue injuries in the collagenase-induced intracerebral hemorrhage rat model.

BACKGROUND: In the horizon of therapeutic restrictions in intracerebral hemorrhage (ICH), recently, non-invasive transcranial electrical stimulation (tES) has achieved considerable prosperities. Translational studies have postulated that transcranial direct current stimulation (tDCS) and the other types of tES remain potentially a novel therapeutic option to reverse or stabilize cognitive and motor impairments. OBJECTIVE: The aim of this study was to comparatively evaluate the effects of the four main paradigms of tES, including tDCS, transcranial alternating (tACS), pulsed (tPCS), and random noise (tRNS) stimulations on collagenase-induced sensorimotor impairments and striatum tissue damage in male rats. METHODS: To induce ICH, 0.5 µl of collagenase was injected into the right striatum of male Sprague Dawley rats. One day after surgery, tES, was applied to the animals for seven consecutive days. Motor functions were appraised by neurological deficit score, rotarod, and wire hanging tests on the day before surgery and postoperative days 3, 7, and 14. After behavioral tests, brain tissue was prepared appropriately to perform the stereological evaluations. RESULTS: The results indicated that the application of the four tES paradigms (tDCS, tACS, tRNS, and tPCS) significantly reversed motor disorders in collagenase-induced ICH groups. Further, the motor function improvement of tACS and tRNS receiving rats in wire-hanging and rotarod tests were higher than the other two tES receiving groups. Structural changes and stereological assessments also confirmed the results of behavioral functions. CONCLUSION: Our findings suggest that in addition to tDCS application in the treatment of ICH, other tES paradigms, especially tACS and tRNS may be considered as add-on therapeutic strategies in stroke.

In Situ Casting of Platelet Rich Plasma/SiO2/Alginate for Bone Tissue Engineering Application in Rabbit Mandible Defect Model.

Statement of the Problem: The administration of both platelet rich plasma (PRP) and silicon dioxide (SiO2) to the bone defects accelerates bone repair and regeneration. Appli-cation of both of them may show synergistic regenerative effects. Purpose: Our objective was to evaluate the possible synergistic osteogenic effects of PRP and SiO2 by injecting them using an ad hoc device. Materials and Method: In this experimental study, PRP/SiO2 scaffolds were fabricated by in situ casting method with the help of CaCl2 as the gelation factor and alginate as the stroma; and then, the biodegradability and spatial arrangement were assessed. The injecta-ble scaffold was introduced into the 40 rabbit mandibular defects by an ad hoc two-channel injecting device. Five defects received PRP/SiO2/alginate as the treatment; the other sets of defects were treated by PRP/alginate, SiO2/alginate, and the last five defects served as the control groups by getting only alginate injections. The osteogenicity of the scaffolds was evaluated by radiological and histological procedures; they were then compared with each other. Analysis of variance and least significant difference tests were used to analyze the data. Results: The SiO2-treated group showed a significant higher bone area compared to PRP/ SiO2-treated groups on day 40 (p= 0.013). The number of osteocytes was higher in SiO2-treated than the control groups on both 20 and 40 days (p= 0.032 and 0.022, respectively). The number of osteoclast was also higher in SiO2-treated than PRP-treated group (p= 0.028). In addition, the cells of this group had just started to create Haversian systems in newly formed bone tissues. Conclusion: Silica demonstrated a superior osteogenic activity over PRP in both short and long term periods. Evidently, they showed no synergistic regenerative effects. Our ad hoc device was efficiently capable of inserting the scaffolds into the injured sites with no diffi-culties or complications.

Effect of dimethyl fumarate on the changes in the medial prefrontal cortex structure and behavior in the poly(I:C)-induced maternal immune activation model of schizophrenia in the male mice.

BACKGROUND: The link between maternal immune activation (MIA) and the risk of developing schizophrenia (SCZ) later in life has been of major focus in recent years. This link could be bridged by activated inflammatory pathways and excessive cytokine release resulting in adverse effects on behavior, histology, and cytoarchitecture. The down-regulatory effects of immunomodulatory agents on the activated glial cells and their therapeutic effects on schizophrenic patients are consistent with this hypothesis. OBJECTIVE: We investigated whether treatment with the anti-inflammatory drug dimethyl fumarate (DMF) could rescue impacts of prenatal exposure to polyinosinic:polycytidylic acid [poly (I:C)]. METHODS: Pregnant dams were administered poly(I:C) at gestational day 9.5. Offspring born from these mothers were treated with DMF for fourteen consecutive days from postnatal day 80 and were assessed behaviorally before and after treatment. The brains were then stained with Cresyl Violet or Golgi-Cox. In addition to the estimation of stereological parameters, cytoarchitectural changes were also evaluated in the medial prefrontal cortex. RESULTS: MIA caused some abnormalities in behavior, as well as changes in the number of neurons and non-neurons. These alterations were also extended to pyramidal layer III neurons with a significant decrease in dendritic complexity and spine density which DMF treatment could prevent these changes. Furthermore, DMF treatment was also effective against abnormal exploratory and depression-related behavior, but not the changes in the number of cells. CONCLUSION: These findings support the idea of using anti-inflammatory agents as adjunctive therapy in patients with SCZ.

Therapeutic Effects of Dimethyl Fumarate on the Rat Model of Brain Ischemia

Abstract Blood-brain barrier (BBB) disruption, inflammation, and cell death are major pathogenic mechanisms in ischemic stroke. Dimethyl fumarate (DMF) has anti-inflammatory and immune-modulatory effects. So, this study aimed to elucidate the effects of DMF on brain ischemia in the middle cerebral artery occlusion (MCAO) model. 69 Sprague-Dawley male rats were allocated into a sham group that was just subjected to surgery stress; vehicle and DMF groups, after MCAO, received vehicle or 30 mg/kg DMF for three days. Neurological scores were evaluated every day. BBB disruption was evaluated by the extravasation of Evans blue. In addition to the measurement of brain water content, the total and infarct volume, numerical density, and the total number of neurons, non-neurons, and dead neurons in the right cortex were estimated by stereological methods. RT-PCR was done to analyze the expression levels of NF-κB and Nrf2. Although brain ischemia treatment with DMF did not have a significant effect on the infarction size, it improved neurobehavioral function, BBB disruption, cerebral edema, increased number of neurons, and expression of Nrf2. It also decreased the number of dead neurons and the expression of NF-κB. DMF beneficial effects on stroke may be mediated through both increase of the Nrf2 and decrease of NF-κB expression

Effect of nicorandil on the spatial arrangement of primary motor cortical neurons in the sub-acute phase of stroke in a rat model.

INTRODUCTION: Ischemic stroke remains a major cause of disability and death worldwide. The density and the spatial distribution of the primary motor (M1) cortical neurons are important in signal transmission and control the movement-related functions. Recently, the neuroprotective effect of nicorandil in cerebral ischemia was described through its anti-apoptosis, antioxidant and anti-inflammatory properties. This study aimed to determine the effects of nicorandil on the neurobehavioral outcome, infarct size, and density, and spatial distribution of M1 cortical neurons after cerebral ischemia. METHODS: Thirty Sprague-Dawley rats were randomly divided into three groups. Sham underwent surgery without middle cerebral artery occlusion (MCAO) and drug. The MCAO and treatment groups after MCAO received saline or nicorandil 2, 24, 48, and 72 h after the induction of brain ischemia. Neurobehavioral tests were performed, brains removed, sectioned, and stained by 2,3,5-triphenyltetrazolium chloride (TTC) to estimate the size of the infarction and Nissl staining to evaluate the numerical density, mean area, and the distribution pattern of M1 cortical neurons, using Voronoi spatial tessellation. RESULTS: Although nicorandil treatment significantly decreased the neurological deficits and density of neuronal neighbors, it could not preserve the normal regular spatial distributions of M1 cortical neurons after MCAO. It also could not significantly improve motor function or reduce ischemic lesion size. CONCLUSIONS: Treatment using the present dose of nicorandil during sub-acute ischemic stroke could not increase neuronal density or preserve the normal regular spatial distributions after MCAO. However, it had beneficial effects on neurobehavioral and motor function and somewhat reduced ischemic lesion size.

Effect of Dimethyl Fumarate on the Motor Function and Spatial Arrangement of Primary Motor Cortical Neurons in the Sub-Acute Phase of Stroke in a Rat Model.

BACKGROUND: The therapeutic effects of dimethyl fumarate (DMF) in patients with multiple sclerosis and animal models of neurologic disease were reported. The density and the distribution pattern of motor neurons are important in transmitting the signal and controlling the movement-related functions. The present study evaluated the effects of DMF treatment on the neurological functions, infarct volume, and spatial distribution of the neurons in the primary motor cortex after cerebral ischemia. METHODS: Thirty-three Sprague-Dawley rats were randomly divided into three groups: The sham group underwent surgery without middle cerebral artery occlusion (MCAO) and drug. The vehicle and treatment groups after MCAO received a vehicle or DMF for three consecutive days. Post-stroke neurological and motor functions were assessed. At the end of the third day, the brains were removed, and the cerebral infarct volume was evaluated. We used cresyl violet staining to analyze the density and the spatial arrangement of motor cortical neurons using Voronoi tessellation. RESULTS: Treatment of the brain ischemia for three days with DMF could not significantly reduce the neurological and motor function deficits and infarct volume. However, it reduced the neuronal area and death and preserved their spatial distribution in the normal regular pattern. CONCLUSION: Cerebral ischemia decreased the neuronal density of the primary motor cortex and changed their distributions to a random pattern. DMF treatment during sub-acute ischemic stroke did not significantly improve the neurological deficit scores. However, it could prevent neuronal swelling and death and preserved the spatial distribution of the cortical neurons in their normal pattern.