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.

Effect of berberine on the hippocampal structure, biochemical factors, memory, and blood-brain barrier in rat model of transient global cerebral ischemia.

Global cerebral ischemia (GCI) results in damage to the neurons and leads to cognitive impairments. Berberine (BBR) is known for its neuroprotective qualities. This study aimed to investigate the effects of BBR on memory, Blood-brain barrier (BBB) permeability, biochemical factors, and neuronal structure. Sixty-three adult male Wistar rats were divided randomly into Sham (21), GCI (21), and GCI + BBR (21) groups. The GCI + BBR group received 50 mg/kg of BBR for 7 days before and 6 h after 20 min of GCI induction. After 24 h, assessments included hippocampal neuronal structure, catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GPX) levels, memory performance, and BBB permeability. The GCI + BBR group reduced volume loss in the CA1 and its sublayers (oriens, pyramidal, and radiatum) compared to the GCI group (p < 0.0001, p < 0.001, p < 0.01 and p < 0.001, respectively). Additionally, the GCI + BBR group showed higher pyramidal neuron density (p < 0.0001) and number (p < 0.0001) compared to the GCI group. BBR also decreased MDA levels (p < 0.0001) and increased CAT activity (p < 0.0001) in the GCI + BBR group compared to the GCI group, with GPX and SOD activity approaching Sham levels (p < 0.0001, both). BBR demonstrated significant improvements in short and long-term memory compared to the GCI group (p < 0.01, p < 0.0001, respectively). Furthermore, BBB permeability in the GCI + BBR group was significantly reduced compared to the GCI group (p < 0.0001). These findings demonstrated BBR's potential to protect the neurons in the CA1 and BBB structures, enhance antioxidant activity, and alleviate GCI-induced memory impairments.

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.

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.

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.

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.

Curcumin prevents neuronal loss and structural changes in the superior cervical (sympathetic) ganglion induced by chronic sleep deprivation, in the rat model.

BACKGROUND: In modern societies, sleep deprivation is a serious health problem. This problem could be induced by a variety of reasons, including lifestyle habits or neurological disorders. Chronic sleep deprivation (CSD) could have complex biological consequences, such as changes in neural autonomic control, increased oxidative stress, and inflammatory responses. The superior cervical ganglion (SCG) is an important sympathetic component of the autonomic nervous system. CSD can lead to a wide range of neurological consequences in SCG, which mainly supply innervations to circadian system and other structures. As the active component of Curcuma longa, curcumin possesses many therapeutic properties; including neuroprotective. This study aimed to evaluate the effect of CSD on the SCG histomorphometrical changes and the protective effect of curcumin in preventing these changes. METHODS: Thirty-six male rats were randomly assigned to the control, curcumin, CSD, CSD + curcumin, grid floor control, and grid floor + curcumin groups. The CSD was induced by a modified multiple platform apparatus for 21 days and animals were sacrificed at the end of CSD or treatment, and their SCGs removed for stereological and TUNEL evaluations and also spatial arrangement of neurons in this structure. RESULTS: Concerning stereological findings, CSD significantly reduced the volume of SCG and its total number of neurons and satellite glial cells in comparison with the control animals (P < 0.05). Treatment of CSD with curcumin prevented these decreases. Furthermore, TUNEL evaluation showed significant apoptosis in the SCG cells in the CSD group, and treatment with curcumin significantly decreased this apoptosis (P < 0.01). This decrease in apoptosis was observed in all control groups that received curcumin. CSD also changed the spatial arrangement of ganglionic neurons into a random pattern, whereas treatment with curcumin preserved its regular pattern. CONCLUSIONS: CSD could potentially induce neuronal loss and structural changes including random spatial distribution in the SCG neurons. Deleterious effects of sleep deprivation could be prevented by the oral administration of curcumin. Furthermore, the consumption of curcumin in a healthy person might lead to a reduction of cell death.

Insulin-Like Growth Factor 2 (IGF-2) Regulates Neuronal Density and IGF-2 Distribution Following Hippocampal Intracerebral Hemorrhage.

BACKGROUND: The insulin-like growth factor 2 (IGF-2) is a growth factor and anti-inflammatory cytokine that plays a crucial role in memory consolidation. However, the precise role of this factor in acute brain damage is still unclear. The present study aimed to evaluate the variations in hippocampal IGF-2 distribution on different days and investigate the effect of recombinant IGF-2 on memory cell density, and IGF-2 distribution following acute hippocampal damage resulting from intracerebral hemorrhage (ICH). METHODS: ICH was induced by injection of 100 µL of autologous blood into the left hippocampus of 72 male Sprague-Dawley rats. Recombinant IGF-2 was injected into the damaged hippocampus 30 min post-induction of ICH in the ICH-IGF-2 group. Then, on postoperative days 1, 3, 7, and 14, samples of brain tissue were collected to perform histopathological and immunohistochemical examinations. RESULTS: The stereological study indicated that the volume of the hippocampus and the number of neurons had a significant reduction, and the infarct volume had a significant increase following ICH. Following the injection of IGF-2, a significant improvement was observed in stereological studies. Immunohistochemical data showed that IGF-2 distribution increased in the hippocampus on different days after ICH, and IGF-2 injection led to a dramatic reduction in this distribution. CONCLUSIONS: In summary, the gradual increase of endogenous IGF-2 as growth and anti-inflammatory factor following hemorrhagic stroke reveals a critical role of this factor in brain recovery after injury. Moreover, the injection of IGF-2 can prevent cell death and alleviate the damage caused by the hemorrhagic stroke.

Evaluation of the Possible Synergic Regenerative Effects of Platelet-Rich Plasma and Hydroxyapatite/Zirconia in the Rabbit Mandible Defect Model.

BACKGROUND: Platelet-rich plasma (PRP) and bioceramics such as hydroxyapatite (HA) and zirconium oxide (ZrO2) are used to reconstruct mandibular defects. We sought to determine the synergistic effects of HA/ZrO2 and PRP and compare their osteogenic activity. METHODS: ZrO2 scaffolds were constructed by the slurry method and were then coated with HA and impregnated by PRP/heparan sulfate (HS). Bilateral mandibular defects were created in 26 male rabbits. In 20 rabbits, the left defects were treated with HA/ZrO2/PRP (Group 1) and the corresponding right defects were filled with HA/ZrO2 (Group 2). The 6 remaining models were treated with PRP gels at both sides (Group 3). The osteoconductivity of HA/ZrO2/PRP was compared with that of HA/ZrO2 or PRP by radiological and histological methods after the follow-up period, at weeks 2, 6 and 8. The statistical analyses were performed by ANOVA and LSD using SPSS, version 16.0, for Windows (P<0.05). RESULTS: After 2 weeks, the percentage of the surface occupied by bone was significantly higher in the HA/ZrO2/PRP-treated defects than in the PRP-treated defects (P=0.007). Osteoblast and osteocyte counts were higher significantly in the PRP-treated group (P=0.032); however, the cells had not started matrix formation on a large scale and just small islands of osteoid with trapped osteocytes were observed. In the long term, the regenerative potential of all the scaffolds was the same. CONCLUSION: HA/ZrO2 showed a superior osteoconductive capacity over PRP in the short term; however, they showed no long-term synergic effects.

Effects of Platelet-Rich Plasma on Kidney Regeneration in Gentamicin-Induced Nephrotoxicity.

Platelet-rich plasma (PRP) as a source of growth factors may induce tissue repairing and improve fibrosis. This study aimed to assess the effects of PRP on kidney regeneration and fibrosis in gentamicin (GM)-induced nephrotoxicity rat model by stereological study. Thirty-two male rats were selected. Nephrotoxicity was induced in animals by administration of GM (80 mg/kg/daily, intraperitoneally [IP], 8 day) and animals were treated by PRP (100 µL, intra-cortical injection using surgical microscopy, single dose). Blood samples were collected for determine blood urea nitrogen (BUN) and creatinine (Cr) before and after PRP therapy. At the end of experiment, right kidneys were sectioned by Isotropic Uniform Random (IUR) method and stained with H & E and Masson's Trichrome. The stereological methods were used for estimating the changes in different structures of kidney. PRP increased the number of epithelial cells in convoluted tubules, and decreased the volume of connective tissue, renal corpuscles and glomeruli in GM-treated animals (P < 0.05). Our findings indicate that PRP had beneficial effects on proliferation of epithelial cells in convoluted tubules and ameliorated GM-induced fibrosis.

Kisspeptin expression features in the arcuate and anteroventral periventricular nuclei of hypothalamus of letrozole-induced polycystic ovarian syndrome in rats.

PURPOSE: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of the reproductive system characterized by polycystic ovaries and androgen excess. Letrozole is a nonsteroidal aromatase inhibitor that is used in experimental research to induce PCOS. Kisspeptin is an essential protein in regulation of cyclicity. Kisspeptin receptor is expressed in the hypothalamus and pituitary glands, and kisspeptin containing neurons are affected from sex steroid hormones. We aimed to investigate the number of kisspeptin-positive cells in the arcuate (Arc) and anteroventral periventricular nuclei (AVPV) of hypothalamus in the letrozole-induced PCOS. METHODS: 40 female Wistar rats were divided into the proestrus control, diestrus control, proestrus vehicle, diestrus vehicle and letrozole. Animals were sacrificed after 3 weeks, and sera, ovary and brain samples were harvested for further evaluations. RESULTS: Letrozole group had high weight gain, high numbers of ovarian follicular cysts, high levels of luteinizing hormone and testosterone and increase number of kisspeptin-positive cells in the Arc nucleus, as compared with the control groups (P ≤ 0.05 vs. proestrus control and proestrus vehicle). Letrozole group showed a decrease in the number of kisspeptin-positive cells in the AVPV nucleus (P ≤ 0.05 vs. proestrus control and proestrus vehicle). CONCLUSION: Our findings show that the number of kisspeptin-positive cells may be affected from letrozole, and that the changes in the number of these cells may be in favor of the appearance of PCOS features in this group.

The Effects of Acoustic White Noise on the Rat Central Auditory System During the Fetal and Critical Neonatal Periods: A Stereological Study.

AIM: To evaluate the effects of long-term, moderate level noise exposure during crucial periods of rat infants on stereological parameters of medial geniculate body (MGB) and auditory cortex. MATERIALS AND METHODS: Twenty-four male offspring of 12 pregnant rats were divided into four groups: fetal-to-critical period group, which were exposed to noise from the last 10 days of fetal life till postnatal day (PND) 29; fetal period group that exposed to noise during the last 10 days of fetal life; critical period group, exposed to noise from PND 15 till PND 29, and control group. White noise at 90 dB for 2 h per day was used. STATISTICAL ANALYSIS USED: Variance for variables was performed using Proc GLM followed by mean comparison by Duncan's multiple range test. RESULTS: Numerical density of neurons in MGB of fetal-to-critical period group was lower than control group. Similar results were seen in numerical density of neurons in layers IV and VI of auditory cortex. Furthermore, no significant difference was observed in the volume of auditory cortex among groups, and only MGB volume in fetal-to-critical period group was higher than other groups. Estimated total number of neurons in MGB was not significantly different among groups. CONCLUSION: It seems necessary to prevent long-term moderate level noise exposure during fetal-to-critical neonatal period.

Foramen Tympanicum or Foramen of Huschke: A Bioarchaeological Study on Human Skeletons from an Iron Age Cemetery at Tabriz Kabud Mosque Zone.

The foramen tympanicum is an anatomical variation that is created in the tympanic plate of temporal bone during the first year of life. The tympanic plate grows and foramen tympanicum is gradually closed by about the fifth postnatal year. However, due to a defect in normal ossification, foramen tympanicum sporadically remains throughout life. The construction of a shopping center in Tabriz, northwest of Iran, led to the discovery of an Iron Age cemetery (1500-500 BC). Several tombs have been uncovered below one meter of sterile soil so far and a thick level of architectural debris from the medieval city has been discovered. Up to now, no bioarchaeological data has been gathered about the burials in this area. Thus, the present study aimed to evaluate the prevalence of foramen tympanicum in this area. In this study, 45 skeletons were studied and the prevalence of this foramen was about 4.4% bilaterally. We also reported on two babies with fused and un-fused squamotympanic fissure. The persistence of this foramen is a possible risk factor for otologic complications after arthroscopy of the temporomandibular joint and salivary gland fistula through this foramen. The closure of this foramen could be also used for age estimation in sub-adult individuals. The incidence of this trait in this study was similar to other available studies on modern skeletons.

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.

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.

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.

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.

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.

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.