Effects of hyperbaric oxygen therapy on autistic behaviors and GRIN2B gene expression in valproic acid-exposed rats.

Introduction: Autism is a complex neurodevelopmental condition characterized by deficits in social interaction, communication, and restricted repetitive behaviors. Hyperbaric oxygen therapy (HBOT) has emerged as a potential treatment for autism, although its effects on behavior and gene expression are not well understood. The GRIN2B gene, known for its involvement in encoding a glutamate receptor subunit crucial for neuron communication and associated with autism, was a focus of this study. Methods: Using a rat model induced by prenatal exposure to valproic acid, we examined the impact of HBOT on autism-like behaviors and GRIN2B gene expression. Male Wistar rats were categorized into four groups: control, VPA (valproic acid-exposed), VPA+HBOT [2 atmosphere absolute (ATA)], and VPA+HBOT (2.5 ATA). The rats underwent several behavioral tests to assess social behavior, anxiety, stereotype and exploratory behaviors, and learning. Following the behavioral tests, the HBOT groups received 15 sessions of HBOT at pressures of 2 and 2.5 (ATA), and their behaviors were re-evaluated. Subsequently, real-time PCR was employed to measure GRIN2B gene expression in the frontal lobe. Results: Our results indicated that HBOT significantly increased social interaction and exploratory behaviors in VPA-exposed rats, alongside elevated GRIN2B gene expression in their frontal lobe. Discussion: Our findings imply that HBOT might have a potential role in ameliorating autism-related behaviors in the VPA rat model of autism through potential modulation of GRIN2B gene expression. However, additional research is essential to fully comprehend the underlying mechanisms and refine the HBOT protocol for optimizing its effectiveness in improving autism-related symptoms.

Behavioral and electrophysiological (ECoG) effects of haplophyllum robustum and TRPA1 antagonist in adult male wistar rats.

This article aimed to investigate the effects of Haplophyllum robustum hydroalcoholic extract on animals' behavioral and electrocorticographic changes. This plant is mainly found in Turkey, Iran, and Central Asia, and is reported to have convulsive effects. In this article, we worked on the effects of its hydroalcoholic extract on electrocorticography (ECoG), along with changes induced by intracerebroventricular administration of GABAA antagonists. Furthermore, the effects of low doses of this extract on behavioral depression were examined. Four animal sets were used to compare ECoG in Wistar rats. A group of negative control, a group of positive control (PTZ), and two groups received an injection of plant extract (500 mg/kg, ip), with or without administration of Diazepam (5 mg/kg). Also, three sets were applied to compare receiving and not receiving intracerebroventricular (icv) injection of Transient receptor potential ankyrin 1 antagonist (HC-030031) (2 µg/kg) on plant-induced seizure delay and animal death. Two groups of control and a group with plant extract together with TRPA1 antagonist were administrated. Furthermore, in the present study, the forced swimming test (FST) was used as a model of depression. The behaviors of animals in three groups of negative control and positive control (Fluoxetine) and plant extract (200 mg/kg, ip) were compared. According to the ECoG, high doses of extract of plants led to seizures similar to PTZ, which were then reduced by diazepam injection. At this dose, injection of TRPA1 antagonist did not significantly delay the onset of seizures or the death of the animals. Further, a subconvulsive dose of hydroalcoholic plant extracts was equally effective in treating depression as Fluoxetine injections.

Effect of stress on spatial working memory and EEG signal dynamics in the follicular and luteal phases of the menstrual cycle in young single girls.

AIM: Women undergo behavioral changes during the menstrual cycle. This study aimed to investigate the effect of estradiol (Es) on stress and effect of stress on spatial working memory (WM) and also to investigate electroencephalogram (EEG) signal's dynamics in the early and late follicular (EF and LF) and luteal (LU) phases of unmarried girls' menstrual cycle. METHODS: Stress was induced by presentation of a short (3 min) movie clip. Simultaneous with a memory test and stress induction, EEG, serum Es levels, and galvanic skin response (GSR) were assessed. RESULTS: Serum Es concentrations were decreased in LF, LU, and EF phases. The mean GSR score decreased after stress induction in all three phases, but it increased in the LF and LU phases versus the EF phase. Spatial WM diminished after stress induction in all three phases, but it increased in the LF phase versus the two phases before and after stress induction. Average power spectrum density in all frequency bands increased after stress induction in the frontal and prefrontal channels in the spatial WM test. CONCLUSION: The results showed that stress led to spatial WM dysfunction; however, Es improved spatial WM performance in the LF phase versus the other two phases.

Long-term follow-up of intracerebroventricular injection of streptozotocin-inducing pain sensitization.

Age is known to be the major risk factor for both pain sensation and sporadic Alzheimer's disease (sAD). Pain management in AD is a critical health condition. However, assessing pain in sAD patients is challenging. The intracerebroventricularly injected streptozotocin (icv-STZ) rat model of sAD has been brought to the fore as a hopefully suitable model that could mimic some features of sAD. However, the exact mechanism by which this agent may induce AD-like pathology is largely unknown. In some studies, analgesic drugs have been suggested as possible prevention of AD and icv-STZ-induced AD-like pathology. Therefore, this study used formalin and tail-flick tests to investigate whether different doses of icv-STZ injections could affect acute and inflammatory pain sensation and edema volume over time. Behavioral responses were observed at four testing time points (1, 2.5, 3.5, and 6 months postinjection). The results indicate that icv-STZ was able to significantly decrease the animals' formalin pain threshold in both a time- and dose-dependent manner. Formalin-induced acute and chronic pain scores of animals treated with streptozotocin 3 mg/kg (STZ3) increased dramatically 2.5 months after injection and persisted thereafter. The augmentation in pain score induced by streptozotocin 1 mg/kg (STZ1) was observed from 3.5 months after STZ injection. However, the effect of streptozotocin 0.5 mg/kg (STZ0.5) was NS until 6 months after injection. However, formalin-induced paw edema occurred with a longer delay and was not detectable in STZ0.5-treated animals. In addition, only STZ3-treated animals significantly reduced the thermal pain threshold of animals 6 months after injection. These observations indicate that icv-STZ can sensitize central and/or peripheral receptors to pain. The effect of STZ is dose- and time-dependent. AD-like pathology induced by icv-STZ could be partially activated via pain processing pathways. Therefore, anti-inflammatory agents could alleviate AD-like symptoms via pain treatments.

Pharmacological upregulation of GLT-1 alleviates the cognitive impairments in the animal model of temporal lobe epilepsy.

It is known that hippocampal epileptogenesis is accompanied by hyperexcitability, glutamate-related neuronal dysfunctions and consequently cognitive deficits. However, the neuroprotective role of astrocytic glutamate uptake through the Glutamate Transporter-1 (GLT-1) remains to be unknown in these processes. Therefore, to assess the effect of glutamate uptake, pharmacological upregulation of GLT-1 using ceftriaxone administration (200 mg/kg/day, i.p, 5 days) was utilized in Li-PIL animal models of temporal lobe epilepsy (TLE). Glutamate concentration and glutamine synthetase activity were analyzed using biochemical assays. In addition, GLT-1 gene expression was assessed by RT-qPCR. Finally, cognitive function was studied using Morris water maze (MWM) test and novel object recognition task (NORT). Our results demonstrated that the acute phase of epileptogenesis (first 72 hours after Status Epilepticus) was accompanied by an increase in the hippocampal glutamate and downregulation of GLT-1 mRNA expression compared to controls. Ceftriaxone administration in epileptic animals led to a reduction of glutamate along with elevation of the level of glutamine synthetase activity and GLT-1 expression in the acute phase. In the chronic phase of epileptogenesis (4 weeks after Status Epilepticus), glutamate levels and GLT-1 expression were decreased compared to controls. Ceftriaxone treatment increased the levels of GLT-1 expression. Furthermore, impaired learning and memory ability in the chronic phase of epileptogenesis was rescued by Ceftriaxone administration. This study shows that astrocytic glutamate uptake can profoundly impact the processes of hippocampal epileptogenesis through the reduction of glutamate-induced excitotoxicity and consequently rescuing of cognitive deficits caused by epilepsy.

A Neonatal Mild Defect in Brain Insulin Signaling Predisposes a Subclinical Model of Sporadic Alzheimer's to Develop the Disease.

Brain insulin system dysfunction has been proposed as a key player in the pathogenesis of sporadic Alzheimer's disease (sAD). Given this fact, an adult rat model for sAD has been developed by intracerebroventricular injection of a subdiabetogenic streptozotocin dosage (icv-STZ). A low dose of icv-STZ in adult rats leads to a subclinical model of Alzheimer's disease. According to the brain developmental origin for sAD occurrence, the present study evaluated the effect of neonatal injection of icv-STZ on the development and progression of Alzheimer's disease later in the adult animals treated with a low dose of icv-STZ. Although no alteration was observed in the rats receiving an adult low dose of icv-STZ, these animals displayed cognitive deficits if they were also treated neonatally with icv-STZ. These impairments were associated with altered gene expression of insulin receptor, tau and choline acetyltransferase, along with increased astrocyte and dark neuron densities in the hippocampus. This study highlights neonatal brain insulin system dysfunction in the programming of brain insulin signaling sensitivity and provides more evidence for the developmental origin of sAD.

Neuroprotective effect of menaquinone-4 (MK-4) on transient global cerebral ischemia/reperfusion injury in rat.

Cerebral ischemia/reperfusion (I/R) injury causes cognitive deficits, excitotoxicity, neuroinflammation, oxidative stress and brain edema. Vitamin K2 (Menaquinone 4, MK-4) as a potent antioxidant can be a good candidate to ameliorate I/R consequences. This study focused on the neuroprotective effects of MK-4 for cerebral I/R insult in rat's hippocampus. The rat model of cerebral I/R was generated by transient bilateral common carotid artery occlusion for 20 min. Rats were divided into control, I/R, I/R+DMSO (solvent (1% v/v)) and I/R+MK-4 treated (400 mg/kg, i.p.) groups. Twenty-four hours after I/R injury induction, total brain water content, superoxide dismutase (SOD) activity, nitrate/nitrite concentration and neuronal density were evaluated. In addition to quantify the apoptosis processes, TUNEL staining, as well as expression level of Bax and Bcl2, were assessed. To evaluate astrogliosis and induced neurotoxicity by I/R GFAP and GLT-1 mRNA expression level were quantified. Furthermore, pro-inflammatory cytokines including IL-1ß, IL-6 and TNF-α were measured. Seven days post I/R, behavioral analysis to quantify cognitive function, as well as Nissl staining for surviving neuronal evaluation, were conducted. The findings indicated that administration of MK-4 following I/R injury improved anxiety-like behavior, short term and spatial learning and memory impairment induced by I/R. Also, MK-4 was able to diminish the increased total brain water content, apoptotic cell density, Bax/ Bcl2 ratio and GFAP mRNA expression following I/R. In addition, the high level of nitrate/nitrite, IL-6, IL-1ß and TNF-α induced by I/R was reduced after MK-4 administration. However, MK-4 promotes the level of SOD activity and GLT-1 mRNA expression in I/R rat model. The findings demonstrated that MK-4 can rescue transient global cerebral I/R consequences via its anti-inflammatory and anti-oxidative stress features. MK-4 administration ameliorates neuroinflammation, neurotoxicity and neuronal cell death processes and leads to neuroprotection.

Vitamin K2 protects PC12 cells against Aß (1-42) and H2O2-induced apoptosis via p38 MAP kinase pathway.

Alzheimer's is an age-related disease with a hallmark of progressive loss of memory formation followed by a damage in the brain function due to the neural degeneration and extracellular beta-amyloid (Aß) plaques accumulation. This study examines the protective effects of vitamin K2 on toxicity induced by (Aß) (1-42) and H2O2 in PC12 cells as an appropriate model of Alzheimer's cell damage. PC12 cells pretreated with vitamin K2 (5-200 µM) for 4, 24 and 48 h, and exposed to either Aß (25 µM) for 48 h or H2O2 (150 µM) for 24 h. Then the protective, antioxidant and anti-apoptotic effects of vitamin K2 in PC12 cells were investigated. Vitamin K2 pretreatment (5-200 µM) significantly decreased the Aß (1-42) and H2O2 cytotoxicity. In addition, vitamin K2 could attenuate reactive oxygen species (ROS) level after exposure of cells to H2O2 for 24 h and Aß (1-42) for 48 h. Cell apoptosis significantly increased following application of Aß (1-42) (25 µM) and H2O2 (150 µM) compared to control. However, flow cytometry histograms of PI-stained cells after pretreatment with vitamin K2 (20 and 50 µM) showed significantly reduced apoptosis. Vitamin K2 increased the amount of glutathione after exposure of cells to H2O2 for 24 h and Aß (1-42) for 48 h. Western blot analysis of PC12 cells showed that 25 µM Aß (1-42) and 150 µM H2O2 treatment could increase Bax, PARP cleavage, Phospho-p38 MAPK. Moreover, the activated form of caspase 3 proteins led to the reduction in the Bcl-2. Real-time PCR of PC12 cells showed that 150 µM H2O2 treatment increased the ratio of Bax/Bcl-2 while vitamin K2 (20 and 50 µM) reduced the rate. According to these findings, it seems that vitamin K2 possess anti-apoptotic and antioxidant effects and suggests that vitamin K2 may be a valuable protective candidate against the progression of Alzheimer's disease via inactivating p38 MAP kinase pathway.

Prenatal stress promotes icv-STZ-induced sporadic Alzheimer's pathology through central insulin signaling change.

AIM: Insulin resistance and neuroinflammation play roles in Alzheimer's (AD) etiology. Insulin receptors (IR) are developmentally expressed in neurons as well as astrocytes. Moreover, prolonged stress can induce brain insulin resistance and astrogliosis. Also, prenatal stress could advance AD-related abnormalities in a transgenic model of AD. Besides, postnatal maternal care (PMC) has antagonistic effects on prenatal stress (PS)-induced neuronal and immunological malfunctions. Using an icv-STZ subclinical model of sAD, we assessed PS and/or abnormal PMC impacts on advancing sAD-like pathology in adult male rats. We also sought astrocyte- and/or neuron-oriented change in central insulin programming. MAIN METHODS: Pregnant rats were exposed to PS. Thereafter, a group of pups was fostered onto unstressed mothers and the others remained intact. Real-time RT-PCR- for hippocampal IR, Tau, and ChAT transcripts- and immunohistochemistry analysis- for GFAP+ astrocytes- were performed at the first- and forth-postnatal-week, respectively. The other animals received icv-STZ0.5 mg/kg in adulthood and subjected to cognitive tests, molecular, and histological experiments at appropriate time-point post-injection. KEY FINDINGS: PS could advance sAD-related symptoms in icv-STZ-treated animals. PS changed expression levels of hippocampal IR in one-week-old and 5.5-month-old offspring. PS could worsen cognitive, molecular and histological impairments of icv-STZ. Adequate PMC prevented some destructive effects of PS. SIGNIFICANCE: PS can potentially change central insulin programming and induce long-lasting astrogliosis in rat hippocampus. PS-related cognitive and histological pathologies can rescue by PMC probably via IR-dependent pathways. Astrocyte involvement in AD-like neuropathology observed in stressed-animals needs more detailed investigations.

Betanin Attenuates Oxidative Stress Induced by 6-OHDA in PC12 Cells via SAPK/JNK and PI3 K Pathways.

Parkinson's disease is a neurodegenerative disorder which accompanied with cognitive decline, chorei form moves and behavioral difficulties. Oxidative stress which promote the apoptotic cell death are responsible for neurodegeneration in Parkinson. The purpose of this study is to evaluate the protective effects of betanin against toxicity and oxidative damage induced by 6-hydroxydopamine (6-OHDA) and hydrogen peroxide (H2O2) in PC12 cells as an appropriate model of Parkinson's cell damage. PC12 cells pretreated with betanin (1-200 µM) for 24 h, and exposed to either 6-OHDA (100 µM) or H2O2 (150 µM) for 24 h. Cell survival and intracellular reactive oxygen species (ROS) production analyzed by resazurin and DCF-DA assay. The anti-apoptotic effects of betanin in PC12 cells were studied using flow cytometry of PI stained cells. Also, western blot analysis of survivin, Cyt c, Phospho SAPK/JNK, SAPK/JNK, Phospho-PI3 kinase P85, PI3 kinase P85 was performed for detection of apoptosis. Betanin (1-200 µM) significantly decreased the 6-OHDA and H2O2 cytotoxicity also attenuated the ROS level. Cell apoptosis significantly increased after 6-OHDA (100 µM) treatment, compared to the control. However, pretreatment with betanin (20 and 50 µM), protected against apoptosis. Western blot analysis of PC12 cells showed that 100 µM 6-OHDA could increase the proteins involved in apoptosis signaling and betanin (20 and 50 µM), could decrease the apoptosis. The results show that betanin has antioxidant and anti-apoptotic effects and may have the ability to prevent or delay the progress of neural death in Parkinson's disease.

Protective effects of vitamin K2 on 6-OHDA-induced apoptosis in PC12 cells through modulation bax and caspase-3 activation.

Neuroprotection using compounds with dual functions of anti-apoptotic and antioxidant effects fight against neurodegeneration. Vitamin K2 acts as a cofactor in many biochemical pathways, including sphingolipid synthesis in the nervous system, which is involved in many cellular events, including proliferation, differentiation, cellular communication, and alteration. This study aimed to investigate the protective effects of vitamin K2 in PC12 cells as an in vitro model of Parkinson's disease. The protective effects of vitamin K2 against 6-OHDA-induced apoptosis in PC12 cells were assessed using resazurin for viability, DCF-DA for ROS level, DTNB for glutathione level, flow cytometry for sub G1, and western blot analysis for detecting bax and pro-caspase-3 expression level. The results showed that 6-OHDA significantly decreased cell viability, glutathione and pro-caspase-3 levels, and increased ROS, the amount of bax in PC12 cells, while the pretreatment with 5 µM vitamin K2 significantly decreased the cell death induced by 6-OHDA. Generally, the results may present a new insight about the potential protective action of vitamin K2 against the progression of Parkinson's disease. Further studies may warrant the use of vitamin K2 as an antioxidant and anti-apoptotic agent in slowing nerve injury in neurodegenerative disease, particularly in Parkinson's disease.

Celecoxib, indomethacin, and ibuprofen prevent 6-hydroxydopamine-induced PC12 cell death through the inhibition of NFκB and SAPK/JNK pathways.

OBJECTIVES: The possible action of nonsteroidal anti-inflammatory drugs (NSAIDs) in the reduction of reactive oxygen species (ROS) and also as anti-apoptotic agents may suggest them as putative agents for the treatment of neurodegenerative diseases. This study was designed to explore some pathways alterations induced by NSAIDs following 6-hydroxydopamine (6-OHDA)-induced cell death in PC12 cells as an in vitro model of Parkinson's disease (PD) and to compare the effects of celecoxib, indomethacin and ibuprofen. MATERIALS AND METHODS: The cell viability, ROS content, glutathione (GSH) level, and apoptosis were measured using resazurin, dichlorofluorescein diacetate (DCFH-DA), 5,5'-dithiobis-2-nitrobenzoic acid (DTNB), propidium iodide (PI) and flowcytometry, real-time PCR and western blot. RESULTS: Based on the results, pretreatment with celecoxib, indomethacin and ibuprofen for 24 hr significantly induced concentration and time-dependent protection against 6-OHDA-induced PC12 cell death. Cell viability (P<0.001), GSH level (P<0.01) and cytoplasmic content of nuclear factor kappa B (NFκB) (P<0.01) were increased, also ROS content (P<0.001) and apoptosis biomarkers such as the cleaved caspase-3 (P<0.001), Bax (P<0.01), phospho- stress-activated protein kinases / c-Jun N-terminal kinases (P-SAPK/JNK) (P<0.01) and cleaved poly ADP ribose polymerase (PARP) (P<0.001) protein levels were all decreased after pretreatment of cells with NSAIDs in 6-OHDA-induced PC12 cells. CONCLUSION: It is suggested that NFκB and SAPK/JNK pathways have an important role in 6-OHDA-induced cell injury. Overall, it seems that pretreatment with NSAIDs protect dopaminergic cells and may have the potential to slow the progression of PD.

Effect of swim bladder matrix treated with hyaluronic acid on wound healing: an animal model evaluation.

OBJECTIVE: To investigate the potential restorative effects of the white fish (Rutilus frisii kutum) swim bladder matrix (FSBM) treated with hyaluronic acid (HA) in the repair of skin wounds in an animal model. METHOD: Wistar rats were used to investigate the repair function of FSBM as a biological scaffold. Rats were given four round wounds on their back. Wounds were divided into four groups: control, acellular fish swim bladder matrix (AFSBM), HA and AFSBM impregnated with HA (AFSBM-HA). Macroscopic and histological studies in wound healing were investigated on days three, five and seven after injury. RESULTS: The AFSBM-HA group showed a rapid reduction in wound area compared with the other groups, indicating faster wound healing (p<0.001). At day seven after injury, the AFSBM group showed a faster process in epidermal layer formation and angiogenesis compared with the control group (p<0.001). In the AFSBM-HA group, in addition to the reduction of inflammatory cells density, a significant increase in the number of fibroblast cells and collagen synthesis was observed. An elevation in collagen synthesis and angiogenesis was also observed in the HA group compared with the control group. CONCLUSION: The findings of this study indicate that AFSBM-HA can potentially be used as a biological dressing in wound healing.

The effect of harmaline on seizures induced by amygdala kindling in rats.

OBJECTIVE: Harmaline and other beta-carbolines act as an inverse agonist for GABA-A receptors and cause central nervous system stimulation and anxiety; thus, it may act hypothetically as a potential seizure augmenter. To examine the hypothesis, the effect of harmaline during the seizures induced by amygdala kindling is investigated here. METHODS: Seven groups of male rats were kindled by daily electrical stimulation of the amygdala. After being kindled, Groups I-III, respectively, received 5, 15 and 50 mg/kg harmaline through intraperitoneal injection. The rats in Groups IV and V received vehicle daily (1 ml/kg) and harmaline (5 mg/kg) daily through intraperitoneal injection. Groups VI and VII received artificial cerebrospinal fluid and harmaline (50 mM) through intraventricular injection, respectively. RESULTS: In addition to significant increase of some seizure parameters in the fully kindled groups, harmaline significantly increased cumulative afterdischarge duration (P < 0.05) and decreased stage 1 latency (P < 0.01) in the acquisition groups (Groups V and VII). In Group VII, seizure duration showed a significant increase (P < 0.01) while stage 1 latency and stage 4 latency decreased significantly (P < 0.01). DISCUSSION: According to the results, it is suggested that harmaline may increase neuronal activity and the production of high-frequency action potentials by stimulating NMDA receptors and inhibiting GABA receptors. Overall, drugs and plants containing harmaline may be harmful to epileptic-susceptible people during some traditionally and costume treatments, so these should be avoided.

Development of a demineralized and decellularized human epiphyseal bone scaffold for tissue engineering: A histological study.

Extracellular matrix (ECM) controls cellular behaviors such as proliferation, migration, and differentiation. The decellularized matrix of mammalian tissues has been used as a scaffold for the repair and reconstruction of tissue defects. In this study, for the first time demineralized and decellularized human epiphyseal bone matrix was used as a scaffold for a bone generation. Human epiphyseal bone was demineralized by hydrochloric acid and then decellularized by three methods of physical (slow freezing and snap freeze-thaw), enzymatic (trypsin 0.25%, 18 h) and chemical sodium dodecyl sulfate (SDS),)2.5%, 26 h). The scaffolds were cultured with rat adherent bone marrow cells (RABMC). Then, the histological studies were performed on days 7, 14, 21, and 28 of the culture to observe the distribution and morphology of cells. Bone formation was also investigated using Alizarin red staining. The results of this study indicated that RABMC migrated, proliferated and separated by forming lacuna in this three-dimensional bone scaffold. In addition, the Alizarin red staining indicated the calcium deposition on the scaffold in both bone differentiation and standard culture medium. The natural characteristic of the present bone scaffold, its cell adhesion features and capability to induce bone mineralization, even in the standard culture medium, provides a potentially optimal bone scaffold for bone tissue engineering.

The effect of intracerebroventricular administration of orexin receptor type 2 antagonist on pentylenetetrazol-induced kindled seizures and anxiety in rats.

BACKGROUND: Current antiepileptic drugs are not able to prevent recurrent seizures in all patients. Orexins are excitatory hypothalamic neuropeptides that their receptors (Orx1R and Orx2R) are found almost in all major regions of the brain. Pentylenetetrazol (PTZ)-induced kindling is a known experimental model for epileptic seizures. The purpose of this study was to evaluate the effect of Orx2 receptor antagonist (TCS OX2 29) on seizures and anxiety of PTZ-kindled rats. RESULTS: Our results revealed that similar to valproate, administration of 7 µg/rat of TCS OX2 29 increased the latency period and decreased the duration time of 3rd and 4th stages of epileptiform seizures. Besides, it significantly decreased mean of seizure scores. However, TCS OX2 29 did not modulate anxiety induced by repeated PTZ administration. CONCLUSION: This study showed that blockade of Orx2 receptor reduced seizure-related behaviors without any significant effect on PTZ-induced anxiety.

A transient insulin system dysfunction in newborn rat brain followed by neonatal intracerebroventricular administration of streptozotocin could be accompanied by a labile cognitive impairment.

The early postnatal period is a critical period of hippocampus development, which is highly dependent on insulin receptor (IR) signaling and very important in cognitive function. The present study was conducted in order to present a model of neonatal transient brain insulin system dysfunction through finding an appropriate dose of injection of streptozotocin (STZ) during the neonatal period. Sixty male Wistar rat pups were divided into 4 groups of 15 and received intracerebroventricular saline or STZ (icv-STZ) (15, 20 and 25µg/kg) on postnatal day 7. Gene expression of IR and target genes for IR signaling (choline acetyltransferase (ChAT) and Tau) were measured at the ages of 2 and 7 weeks. Behavioral tests were performed at the ages of 3 and 6 weeks to assess short- and long-term cognitive function. 20µg/kg dose of icv-STZ was estimated as the optimal dose causing transient alteration in gene expression of IR, ChAT and Tau. Additionally, cognitive function of the animals restored to normal level at the age of 6 weeks. Therefore, 20µg/kg dose of icv-STZ is proposed as a new approach to generating transient brain insulin system dysfunction associated with transient cognitive impairments at a critical postnatal period of brain development.

Streptozotocin-induced hippocampal astrogliosis and insulin signaling malfunction as experimental scales for subclinical sporadic Alzheimer model.

AIMS: Insulin signaling malfunction has recently been suggested as a preliminary event involved in the etiology of Sporadic Alzheimer's disease (SAD). In order to develop insulin resistance-related SAD model, rats were treated with streptozotocin, intracerebroventricularly (icv-STZ). Nevertheless, given the lack of knowledge regarding sub-clinical stages of SAD, the current challenging issue is establishing a practical pre-clinical SAD model. Despite some proposed mechanisms, such as insulin malfunction, neuroinflammation, and gliosis, icv-STZ mechanism of action is not fully understood yet and Streptozotocin-induced rat model of Alzheimer has still major shortcomings. MAIN METHODS: Using three STZ doses (0.5, 1, and 3mg/kg) and three testing time (short-term, medium-term and long-term), we sought the best dose of STZ in order to mimic the characteristic feature of sAD in rats. So, we conducted a series of fifteen-week follow-up cognitive and non-cognitive studies. Besides, IR, tau and ChAT mRNA levels were measured, along with histological analysis of astrocyte, dark neuron numbers, and pyramidal layer thickness, in order to compare the effects of different doses of icv-STZ. KEY FINDINGS: STZ 3mg/kg caused cognitive and insulin signaling disturbance from the very first testing-time. STZ1-injected animals, however, showed an augmented hippocampal astrocyte numbers in a short time; they, also, were diagnosed with disturbed insulin signaling in medium-term post icv-STZ-injection. Moreover, behavioral, molecular and histological impairments induced by 0.5mg/kg icv-STZ were slowly progressing in comparison to high doses of STZ. SIGNIFICANCE: STZ1 and 0.5mg/kg-treated animals are, respectively, suggested as a suitable experimental model of MCI, and sub-clinical stage.

Neuroprotective Effects of Exercise on Brain Edema and Neurological Movement Disorders Following the Cerebral Ischemia and Reperfusion in Rats.

INTRODUCTION: Cerebral ischemia and reperfusion causes physiological and biochemical changes in the neuronal cells that will eventually lead to cell damage. Evidence indicates that exercise reduces the ischemia and reperfusion-induced brain damages in animal models of stroke. In the present study, the effect of exercise preconditioning on brain edema and neurological movement disorders following the cerebral ischemia and reperfusion in rats was investigated. METHODS: Twenty-one adult male wistar rats (weighing 260-300 g) were randomly divided into three groups: sham operated, exercise plus ischemia, and ischemia group (7 rats per group). The rats in exercise group were trained to run on a treadmill 5 days a week for 4 weeks. Transient focal cerebral ischemia and reperfusion were induced by middle cerebral artery occlusion (MCAO) for 60 minutes, followed by reperfusion for 23 hours. After 24 hours ischemia, movement disorders were tested by a special neurological examination. Also, cerebral edema was assessed by determining the brain water content. RESULTS: The results showed that pre-ischemic exercise significantly reduced brain edema (P<0.05). In addition, exercise preconditioning decreased the neurological movement disorders caused by brain ischemia and reperfusion (P<0.05). CONCLUSION: Preconditioning by exercise had neuroprotective effects against brain ischemia and reperfusion-induced edema and movement disorders. Thus, it could be considered as a useful strategy for prevention of ischemic injuries, especially in people at risk.

SB-334867, an orexin receptor 1 antagonist, decreased seizure and anxiety in pentylenetetrazol-kindled rats.

Convulsive seizures are due to abnormal synchronous and repetitive neuronal discharges in the central nervous system (CNS). Finding new therapeutics to overcome the side effects of the current drug therapies and to increase their effectiveness is ongoing. Orexin-A and orexin-B are brain neuropeptides originating from postero-lateral hypothalamic neurons. Studies show that orexins, through activation of OX1 and OX2 receptors, have excitatory effects in the CNS. Accordingly, this study was designed to evaluate the effect of OX1 receptor antagonist (SB-334867) on seizure- and anxiety-related behaviors of pentylenetetrazol (PTZ)-kindled rats. Kindling was induced by repeated intraperitoneal (IP) injections of PTZ (32 mg/kg) with two-day intervals for 24 days in male Wistar rats. Three groups received intracerebroventricular (ICV) injections of SB-334867 (2.5, 5, and 10 µg/rat) before PTZ injections. Two control groups received vehicle (2 µL/rat, ICV) and valproate (26 µg/rat, ICV) before PTZ injections. An extra group of control animals received saline both ICV and IP. Seizure-related behaviors were monitored for 30 min following PTZ administration. The anxiety-like behaviors were also assessed using elevated plus-maze in the first and last days of the study. The results revealed that ICV injection of SB-334867, mainly at the dose of 10 µg/rat, decreased the median of seizure stages, prolonged the latency and reduced the duration of different seizure stages, and reversed the PTZ-induced anxiety-like behaviors. Based on the presented results, it is suggested that pharmacological blockade of the OX1 receptor is a potential target in the treatment of seizure and concomitant anxiety disorders.