---

Introduction: Investigations have shown that ovarian steroids are involved in reduction of movement disorders during neurodegenerative diseases especially Parkinson's disease. These steroids have many side effects, thus, other estrogenic agents with fewer side effects are needed to develop alternative treatment strategies. The main objection of this study was to evaluate the effects of soy meal on movement disorders in ovariectomized animal model of Parkinson's disease. Materials & Methods: Animals were divided into 3 groups: intact, treated by normal diet and treated by soy meal diet. Female Wistar rats with the exception of intact group were ovariectomized at the first line of study. Then Stride length test was done and animals received special diet for 4 weeks post substantia nigra pars compacta (SNc) electrical lesion. At the end, Stride length and Morpurgo's test was performed. Results: Soy meal diet in ovariectomized rats with SNc Lesion improved muscle stiffness without any effect on stride length. Conclusion: Our results suggest that soy meal is a potential alternative to estrogen in the treatment of Parkinson’s disease.

---

Introduction: Brain damage is often irreversible due to poor brain's self-repairing ability. New treatment strategies focused on stem cell therapy and 3-dimension matrix for brain tissue injury. The extracellular matrix (ECM) of animal tissues is a complex mixture of macromolecules that play an essential instructional role in the development of tissues and organs. Therefore, tissue engineering approaches rely on the need to present the correct cues to cells and to guide them to maintain tissue-specific functions. Recent research efforts on ECM have showed various sequences and motifs, which play key roles in improvement of the brain function after injury. Conclusion: Small motif from ECM molecules can mimic some of the biological functions of their large molecules. Peptides sequences and motifs laminin can be linked to various biomaterials scaffolds and provide the cells with mechanical support. This may ensure appropriate cell growth that aids the formation of the correct tissue structure.

---

Introduction: Spinal cord injury (SCI) is a serious disabling condition associated with paralysis. Owing to suitable effects of hydrogels compared to preformed scaffolds, in this study a hydrogel based biomaterial, Matrigel, was applied. Matrigel is a termogel that forms nanofibers and hydrogel above 20°C. It contains laminin, nidogen and some growth factors that induce neural differentiation. Materials and Methods: A moderate spinal cord contusion was performed in adult rats and 10 days after injury, matrigel was implanted. Then, they follow up via Basso, Beattie, Bresnahan test for 42 days. Cresyl violet staining was performed as a histopatological analysis. Results: Our data indicated less inflammation and dark cells in Matrigel group compared to control group. Locomotor test showed significant improvement of motor recovery in Matrigel group. Conclusion: Our results suggest that Matrigel via some growth factors and adhesive molecules may have beneficial effects on functional recovery in SCI.

---

Introduction: Brain development requires a complex interplay of genetic and environmental factors. Disruption of these elements can affect neuronal structure, function, or connectivity and can alter developmental trajectory. Neurotransmitters and neuromodulators, such as dopamine, participate in a wide range of behavioral and cognitive functions in the adult brain. Dopamine-mediated signaling plays a fundamental neurodevelopmental role in forebrain differentiation and circuit formation. In addition, D1 and D2 dopaminergic receptors activation influences neuronal proliferation, migration and differentiation. Conclusion: As dopamine receptors affect the developing brain and play an essential role in adult brain, better understanding of the role of these receptors in different regions of the developing brain can be helpful for treatment of brain developmental disorders.

---

Brain derived neurotrophic factor (BDNF) is a neurotrophin acting at several levels in the brain. Additionally, BDNF was shown to be responsible for the survival, maintenance and growth of neurons. Also, BDNF plays an important role in synaptic plasticity and memory processes. In activity-dependent synaptic plasticity, BDNF enhances long-term potentiation (LTP) in the hippocampus but blocks the induction of long-term depression (LTD) in the visual cortex. A relation between BDNF expression and anxiety was shown in the elevated plus maze where BDNF overexpression in mouse hippocampal astrocytes promotes local neurogenesis and elicits anxiolytic like activities. Moreover, BDNF is implicated in the pathophysiology of depression. Postmortem studies have shown that hippocampal BDNF levels are decreased in depressed patients and increased in patients receiving antidepressant treatment. On the other hand, it has been suggested that infections and inflammatory processes may act as causative factors in emotional disorders, including anxiety and depression. Lipopolysaccharide (LPS) is a component of the cell wall of gram negative bacteria and is known to induce a profound inflammatory and immunostimulatory response. Substantial evidence exists to suggest that the negative effects of LPS on synaptic function are due to the neurodegenerative effects. It elicits through its activation of proinflammatory cytokines such as interleukin-1β (IL-1β). However, it has been proposed that LPS can affect expression of neurotrophins and their receptors in the CNS and that this action may contribute to the functional impairments observed upon LPS injection injection of LPS has been reported to significantly decrease BDNF expression in the hippocampus and several cortical regions may create to anxiety and depression.

---

Adenosine acts as neuromodulator in the brain, which its involvement in a wide range of brain processes and diseases has been studied, such as epilepsy, sleep, anxiety, panic disorder, Alzheimer’s disease, Parkinson’s disease and schizophrenia. Adenosine receptors have been detected: A1R, A2AR (A2AR), A2BR, and A3R. A1R and A2R inhibit cAMP production, while A2AR and A2BR stimulate cAMP production. These receptors are distributed in various areas of the central nervous system. A2AR is highly expressed in the olfactory bulb, caudate putamen, nucleus accumbens, and tuberculum olfactorium. The function of several receptors such as dopamine D2 receptor (D2R) is influenced by activation of adenosine A2A receptor. Three distinct dopamine projection pathways are formed from the substantia nigra–ventral tegmental area complex. Mesocortical pathway and mesolimbic pathway are known as first and second pathways. Axons project to the striatum, described nigrostriatal pathway known as third pathway. This pathway completes the neural circuits of the basal ganglia responsible for motor control, although recent document also points to a very important role in the motor changes associated with severe depression. Adenosine A2A receptor and D2R are co-localized in the dorsal and ventral striatum and are mutual inhibitors. On one hand, A2AR–D2R heteromers are formed and, when the A2AR is activated, conformational changes are transferred to the D2R. This ultimate to a reduction in D2R recognition and signaling on the other hand, D2R activation inhibits cAMP mediated-effects of A2AR by inhibiting adenylyl-cyclase. Finally, recant study showed that A2AR overexpression is associated with depression, which may describe the depressive signs seen in aging, chronic stress, and Alzheimer’s disease. We hypothesized that changes in expression of A2AR in nigrostriatal system may contribute in creation of depression with motor disorders.

---

Dopamine (DA) is one of the main catecholamines in the brain and is crucial for movement coordination, endocrine function, reward, mood, memory and emotions. The dopaminergic system is the primary therapeutic target in the treatment of Parkinson’s disease (PD), drug addiction and schizophrenia. Notwithstanding, dysfunction of central dopaminergic neurotransmission has also been associated to depression, which has been linked to dysregulation of DA release or alterations in dopamine receptors expression or function. studies in humans indicated that the efficacy of dopamine receptor agonists with high binding affinity to D3R compared to D2R, including aripiprazole, cariprazine and pramipexole, a drug commonly used for the treatment of motor symptoms in PD but also effective for the treatment of major depression. Furthermore, reduction of DA release at synapses leads to increased D2R/D3R binding in temporal cortex of depressive patients. Similarly, the treatment of animal models with antidepressant drugs increase the density of D2R/D3R binding sites in the nucleus accumbens without altering the density of binding sites for D1-like receptor. Interestingly, expression of D3R significantly increased in the shell of nucleus accumbens, when is used chronic administration of classical antidepressants and repeated electroconvulsive therapy in rats. This data suggested that D3R may play an important role in the pathophysiology of depression.

---

The mesolimbic dopamine (DA) system contains both D1-like and D2-like receptors, has been connected to control of locomotor behavior. An apparent role for D1 and D2 receptors throughout the mesolimbic system in the alteration of locomotor behavior has been demonstrated in pharmacological studies. The nucleus accumbens (NAc) is comprised of a core and a shell subregion, which is a component of the mesolimbic DA system, and has been specifically implicated in locomotor behavior. Intra-NAc injections of D1 and D2 agonists have been found to increase locomotor activity. The DA system also plays a role in regulating anxiety-like and fear behavior. Pharmacological studies have shown that D1 and D2 receptors are involved in anxiety-like behavior. Findings seem to be dictated by a number of factors, including strain, route of administration, ligand selected and behavioral test. Fear behavior may often be indiscernible from anxiety-like behavior in animal models though the anatomical aspects may be different. Fear cues have been shown to decrease DA transmission in the NAc core, but increase transmission in the shell. Dopamine release in the NAc also appears to assist in encoding cues that predict punishment avoidance. These data suggest a role between fear and DA transmission and suggest that there may also be a role of accumbal DA in anxiety-like behavior.

---

The prefrontal cortex (PFC) plays a central role in processing both normal and pathological affective states and it is among the brain regions most closely associated with stress-related psychopathology in humans. The ventromedial PFC (vmPFC) in particular has been shown to be required for healthy emotional regulation, social function and risk assessment and decision-making. Also this region exhibits cerebral asymmetries on measures of this sort, which appear to be sex-dependent. In these and other studies, it has been suggested that emotional processing is more strongly lateralized to right brain structures in men, while women tend to be more left-biased. In the rat, the medial PFC has long been known to be very sensitive to stress and many of these studies have focused on the mesocortical dopaminergic (DA) system, which has been shown in numerous studies to exhibit functional and neurochemical hemispheric asymmetries. Excitotoxic lesions of the right, but not left, vmPFC suppress the autonomic, neuroendocrine and behavioral responses to stressful situations, suggesting that this region normally activates physiological and behavioral responses in times of challenge. In contrast, DAergic depletion or receptor blockade of the right vmPFC results in sensitivity to stressful challenges, implying that mesocortical DA plays a protective or adaptive role in coping with stress. Behaviors improved preferentially by the left cortex thus showed less evidence of sex differences than those modulated by the right. While mesocortical DA discharge effects are lateralized, the nature of these effects can vary with sex and specific behavior. More knowledge about the relation between PFC and stress can help us to manage stress related disorders.

---

Brain injury is the leading cause of death and disability in the most active population. There is no definite clinical treatment for repair of damaged brain tissue. Application of nanoscaffolds supporting stem cells can be helpful. The present study examined the effects of autologous adult neural stem/progenitor cells (NS/PCs) seeded in PuraMatrix in acute brain injury. The right brain subventricular zone of adult wistar rats was stereotactically harvested. Then, NS/PCs were cultured using neurosphere assay. At day 45, brain injury was performed in left side of brain and PBS, PuraMatrix, NS/PCs or PuraMatrix+ NS/PCs was injected into the created cavity. The neurological status was evaluated for 4 weeks. Then, morphological and immunohistochemical studies were done. The neurologic status improved after treatment of brain injury with PuraMatrix, NS/PCs or PuraMatrix + NS/PCs. The lesion volume was decreased in PuraMatrix+ NS/PCs. By 3D transplantation of NS/PCs, not only the rate of inflammation was reduced but also the survival rate in the site of injury was increased. In addition, the transplanted cells expressed the differentiation markers after 4 weeks. Transplantation of adult NS/PCs in PuraMatrix may be a feasible method for reduction of tissue damage following brain injury.

---

Traumatic brain injury (TBI) leads to tissue damage by primary and secondary mechanisms. Several factors such as location, nature and severity of the primary injury, age, health, sex, medication, alco‌hol and drug use, and genetics influence the pathophysiology of TBI in clinic, so TBI is a heterogeneous event and consequently, TBI modeling faces some difficulties. In the fluid percussion injury model, a fluid pressure pulse is generated to the intact dura through a craniotomy and produces a combination of focal and diffuse neu‌ronal injury. The controlled cortical impact injury model uses a pneumatic or electromagnetic impact device to drive a rigid impactor onto the intact dura and creates tissue loss, haematoma, axonal injury and concussion. In the penetrating ballistic-like brain injury, projectiles are transmitted with high energy to produce a cavity in a defined area of the brain. In the weight-drop model, a weight falls from specified height. In the blast brain injury model, trauma can be caused by the primary injury related to the blast. By choosing a proper animal model, we can address the biomechanical aspects of brain injury and assess the potential treatments.

---

Brain injury is a complex event leading to tissue damage and functional deficits by primary and secondary mechanisms. Since the application of tissue engineering approaches is a new topic in the treatment of brain injury, producing a proper experimental model to evaluate the effects of tissue engineering products on damaged brain tissue is required. In the present study, a simple and reproducible model of brain injury was introduced. Adult Wistar rats were anesthetized by ketamine and xylazine and their heads were fixed in stereotaxic device. Then, after prep and drape, a midline incision was made in the skull skin by surgical knife. Using a dental drill, a rectangle window was made in the left side of the skull bone. After removing the dura mater by a micro scissors, a defined cavity was created in the cortex of the left hemisphere by slowly inserting a rotary biopsy punch with 2 mm diameter into the cortex. Following performing treatments (neural stem cells + a hydrogel scaffold), to repair of the dura and consequently prevent leakage of materials, we used a piece of the loose connective tissue located between skull bone and skin as well as a piece of dural path. Finally, the skin was closed by 2-0 surgical suture. Neurological evaluations were performed using modified neurological severity score for 28 days. Histological analysis was done after one month. This method produced a mild brain injury model and created a defined cavity in the brain cortex. The cells transplanted in the cavity survived after 28 days. We introduced an applied animal model of brain injury for evaluation of tissue engineering treatment strategies.

---

Brain injury has a multiple pathophysiology for which there is no definite treatment. In this regard, tissue engineering is one of the probable strategies for repair of damaged tissue. But creating a proper model for testing the engineered products faced some difficulties, specially, when we want to evaluate the effects of a product on the volume of injury. The current brain injury methods couldn’t provide defined brain tissue damage. We propose a new method to solve the problem. Previously, we introduced a new method for harvesting subventricular tissue from adult rat brain using a modified semi-automatic biopsy needle. We showed that a defined volume of tissue harvested from a specific area of brain without any adverse effect on other regions. We suggest using this biopsy procedure for creating a brain injury model with a defined size. Using this controllable biopsy method, we can test engineered products in a rat model of brain injury and assessed the volume of cavity after performing treatments in different groups.

---

Spinal cord injury (SCI) leads to a significant health problem associated with a broad range of secondary complications and disabilities. In this regard, animal models can help us to understand the pathobiology of SCI and evaluate the effects of potential treatments for SCI. In contusion models of SCI, different devices including surgical spring-loaded clips, balloons, forceps, weights and the computer-controlled reproducible impact contusion devices were used to create a defined lesion in the spinal cord. To evaluate treatments that target axon regeneration or in case of implantations, transection models may be utilized in which an incision is created into spinal cord. The transection may be complete or incomplete. The unilateral hemisection injury can be a good alternative to complete transection in which structural integrity, function of one side of the spinal cord and bladder and bowel function were preserved. By choosing an appropriate SCI method, we can test numerous possibilities for novel therapeutic strategies before clinical investigations.

---

Spinal cord injury (SCI) in humans remains a devastating and incurable disorder. A very important obstacle in axonal regeneration after spinal cord injury is astroglial scaring. The use of self-assembling peptide nanofiber, a hydrogel mimicking extracellular matrix, has been suggested as a scaffold for spinal cord regeneration and inhibition of astrogliosis. However, neurogenesis potential of laminim has been proved. The purpose of this study was to investigate the role of self-assembling peptide nanofiber containing long motif of laminin (SAPN-LL) in neural differentiation of human endometrial-derived stem cells (hEnSCs) in-vitro, in polymerization of tubulin isolated from sheep brain ex-vivo and assess the supportive effects of this hydrogel in an animal model of SCI. Results showed that although nanaofibers strongly differentiated hEnSC towards neuron and there were not significant differences between their neural differentiations but motor recovery results demonstrated that concentration of laminin influences motor recovery and tubulin polymerization. However, both of in-vitro and in-vivo results showed that SAPN-LL inhibited astrogenesis. Based on our results it might be concluded that, SAPN containing long motif of laminin holds great promise for spinal cord injury.

---

Traumatic brain injury (TBI) is caused by rapid deformation of the brain, resulting in a cascade of pathological events and ultimately neurodegeneration. In vitro models of TBI can help us to describe the pathobiological mechanisms. In vitro models of brain injury support a platform for performing repeatable, well-controlled, environmentally isolated experiments. Other advantages of in vitro models of injury are monitoring in real time and evaluation of specific region. Acute preparations, organotypic cultures, dissociated primary cultures, and immortalized cell line have been used to study neural injury in vitro. Several in vitro models of TBI have been designed, they include the following: Transection: in vitro transection models leading to axotomy. Compression: this model of TBI can be induced primary and secondary injury by the impactor. Hydrostatic pressure: using transient or static pressure, deformation is induced. Fluid shear stress: culture cells have been deformed using a fluid shear forces. Shear strain: in vitro shear strain model has been simulated for closed-head TBI. Stretch injury models: in vitro models of Stretch injury have been developed to reproduce the mechanics which occur during in vivo TBI. Using appropriate in vitro models, we can understand mechanisms of injury in details and evaluate the effects of potential treatments.

---

In the last century, neural stem cells are used in a lot of studies for basic and therapeutic investigations. Several sources are identified for neural stem cells including embryonic, fetal and adult stem cells. Although most of studies have focused in embryonic as well as fetal cells due to their capacity to generate progenies, these cells have some problems such as immunological, availability and ethical concerns. Among adult sources for neural stem cells, two areas in adult mammalian brain including the subventricular zone of lateral wall of lateral ventricle and the subgranular zone of hippocampus are identified as niches with neural stem/progenitor cells (NS/PCs). According to previous studies, other adult mammalian brain regions may have the quiescent cells which generate stem-like cells in vitro. To date, a few researches have addressed the isolation of NS/PCs from adult human amygdala. The aim of the present study was to evaluate the ability of human amygdala tissue to generate neurosheres. The amygdala specimens were obtained from five patients suffering from refractory temporal lobe epilepsy and subjected to amigdalo-hippocampectomy. After removing the pia mater and associated blood vessels, the tissue was dissociated enzymatically. Then, the single cells were cultured in neurosphere medium containing 20 ng/ml Fibroblast growth factor, 20 ng/ml epidermal growth factor, B27 supplement and N2 supplement in non-coated flasks. Growth factors were added twice a week. Additional neurosphere medium was administered once every week. The efficacy and number of spheres and cells were evaluated. Four days after primary culture of amygdala tissue, small free flouting spheres were appeared. The proliferation of the cells slowly continued to day 15 at which passage was done and neurospheres dissociate into single cells. The number of spheres and cells increased after each passage. Here, we showed for the first time in Iran the possibility of isolating proliferating neurospheres from patients with refractory epilepsy during interventional surgery.

---

Several sources were introduced for cell therapy after neurotrauma. There are some evidences that quiescent stem cells are located in the various regions of the adult mammalian brain including cortex, hippocampus, amygdala and striatum. But more study is needed to identify the characteristics of these cells. In the present study we investigated the possibility of isolating neural stem cells from adult human amygdala. The amygdala specimens were obtained from five patients suffering from refractory temporal lobe epilepsy and subjected to amygdalo-hippocampectomy. After removing the pia mater and associated blood vessels, the tissue was dissociated enzymatically. Then, the single cells were cultured in neurosphere medium containing 20 ng/ml Fibroblast growth factor, 20 ng/ml epidermal growth factor, B27 supplement and N2 supplement in non-coated flasks. Growth factors were added twice a week. Additional neurosphere medium was administered once every week. To characterize the isolated cells, immunocytochemistry was done against nestin, Sox2, Oct4, GFAP and MAP2. The isolated cells highly expressed neural stem cell markers nestin, Sox2 and Oct4. But there was a few cells expressed mature neuron marker MAP2 and astrocyte marker GFAP. Here, we showed for the first time in Iran the possibility of isolating neural stem-like cells from patients with refrac‌tory epilepsy during interventional surgery.

---

Luteolin, as a natural polyphenolic compound, has neuroprotective effect and exerts its function by attenuation of apoptosis and oxidative stress factors. Emerging evidences indicate that oxidative stress leads to neurodegeneration but is not the initial event and endoplasmic reticulum stress (ER) is often considered to be the stimulus event which is caused by accumulating of misfolded proteins. The activation of the unfolded protein response (UPR) outcrops as the one of early occurrence in brain injury when the agglomeration of mis- or unfolded proteins occur in the ER lumen. So, the present study try to define whether any neuroprotective effect is seen when Luteolin is administered in used H2O2–injured PC12 cells. PC12 cells were cultured and exposed to different concentrations of H2O2 with different concentrations (10, 25, 50, 100 µM) of Luteolin for 2 hr prior to our experiments, then the cells were exposed with H2O2 (150 μM) for 24 hr. Western blot analysis was performed in PC12 cells to evaluate the levels of Heat shock proteins (Hsp70 and Hsp90) and ER stress chaperon GRP78/BiP and CHOP. Cell viability was evaluated by the conventional MTT reduction assay. Pretreatment of PC12 cells with different concentration (10, 25, 50, 100 µM) of Luteolin followed by exposure to H2O2 increased cell viability (about 46, 35, 78 and 80%, respectively) relative to the H2O2-treated cells. In the group that received (25 µM) concentration of Luteolin, ER stress chaperones such as GRP78/BiP and CHOP decreased compared to H2O2 treated cells, while HSP70 increased in Luteolin treatment of 25µM. The level of hsp90 decreased in Luteolin (25µM) treatment. In conclusion, our data suggest that flavonoid has therapeutic potential following brain trauma.

---

Neuroinflamation occurring after traumatic brain injury (TBI) is a complex phenomenon comprising distinct cellular and molecular events involving the injured cerebral tissue. Mechanical injury to adult rat brain elucidated the accumulation in the affected area of trophic activity. In the tissue adjacent to the injury, trophic titers began to rise after the lesion. This study aimed to determine the effect of injured brain extract on proliferation of neonatal rat neural stem/progenitor cells (NS/PCs). NS/PCs were isolated from olfactory bulb of neonatal rat then cultured as neurospheres. After second passage, cells were seeded in PuraMatrix scaffold by injection method and incubated with intact or injured brain extracts. The proliferation assay was carried out by MTS assay 10 days later. For preparation of the injured brain extract, we used a rat brain injury model and collected the extract 48 hrs after injury. The experimental results showed that NS/PCs derived olfactory bulb have a good potential to proliferate. MTS assay demonstrated that NP/SCs proliferation rate was increased in injured brain extract. Injured brain extract could be benefit for NP/SCs proliferation.