The Therapeutic Potential and Molecular Mechanisms Underlying the Neuroprotective Effects of Sativex® - A Cannabis-derived Spray.

Sativex is a cannabis-based medicine that comes in the form of an oromucosal spray. It contains equal amounts of Δ9-tetrahydrocannabinol and cannabidiol, two compounds derived from cannabis plants. Sativex has been shown to have positive effects on symptoms of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and sleep disorders. It also has analgesic, antiinflammatory, antitumoral, and neuroprotective properties, which make it a potential treatment option for other neurological disorders. The article reviews the results of recent preclinical and clinical studies that support the therapeutic potential of Sativex and the molecular mechanisms behind its neuroprotective benefits in various neurological disorders. The article also discusses the possible advantages and disadvantages of using Sativex as a neurotherapeutic agent, such as its safety, efficacy, availability, and legal status.

Comparative Gene Signature of Nociceptors Innervating Mouse Molar Teeth, Cranial Meninges, and Cornea.

BACKGROUND: The trigeminal ganglion (TG) collects afferent sensory information from various tissues. Recent large-scale RNA sequencing of neurons of the TG and dorsal root ganglion has revealed a variety of functionally distinct neuronal subpopulations, but organ-specific information is lacking. METHODS: To link transcriptomic and tissue-specific information, we labeled small-diameter neurons of 3 specific subpopulations of the TG by local application of lipophilic carbocyanine dyes to their innervation site in the dental pulp, cornea, and meninges (dura mater). We then collected mRNA-sequencing data from fluorescent neurons. Differentially expressed genes (DEGs) were analyzed and subjected to downstream gene set enrichment analysis (GSEA), and ion channel profiling was performed. RESULTS: A total of 10,903 genes were mapped to the mouse genome (>500 reads). DEG analysis revealed 18 and 81 genes with differential expression (log 2 fold change > 2, Padj < .05) in primary afferent neurons innervating the dental pulp (dental primary afferent neurons [DPAN]) compared to those innervating the meninges (meningeal primary afferent neurons [MPAN]) and the cornea (corneal primary afferent neurons [CPAN]). We found 250 and 292 genes differentially expressed in MPAN as compared to DPAN and to CPAN, and 21 and 12 in CPAN as compared to DPAN and MPAN. Scn2b had the highest log 2 fold change when comparing DPAN versus MPAN and Mmp12 was the most prominent DEG when comparing DPAN versus CPAN and, CPAN versus MPAN. GSEA revealed genes of the immune and mitochondrial oxidative phosphorylation system for the DPAN versus MPAN comparison, cilium- and ribosome-related genes for the CPAN versus DPAN comparison, and respirasome, immune cell- and ribosome-related gene sets for the CPAN versus MPAN comparison. DEG analysis for ion channels revealed no significant differences between the neurons set except for the sodium voltage-gated channel beta subunit 2, Scn2b . However, in each tissue a few ion channels turned up with robust number of reads. In DPAN, these were Cacna1b , Trpv2 , Cnga4 , Hcn1 , and Hcn3 , in CPAN Trpa1 , Trpv1 , Cacna1a , and Kcnk13 and in MPAN Trpv2 and Scn11a . CONCLUSIONS: Our study uncovers previously unknown differences in gene expression between sensory neuron subpopulations from the dental pulp, cornea, and dura mater and provides the basis for functional studies, including the investigation of ion channel function and their suitability as targets for tissue-specific analgesia.

Antigen B modulates anti-inflammatory cytokines in the EAE model of multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is characterized by the destruction of the blood-brain barrier, loss of myelin sheath, and contribution of inflammatory interleukins such as TNF-alpha, interleukin-17, and interleukin-6. METHODS: The current study investigated the effect of antigen B of hydatid cyst fluid on the reduction of anti-inflammatory cytokines and nerve conduction velocity in rats with experimental autoimmune encephalomyelitis (EAE)-induced MS. After isolation of antigen B from sterile cyst fluid, the rats were randomly divided into four groups: saline, EAE, EAE + teriflunomide (EAE + TF), and EAE + antigen B (EAE + AngB). The EAE model was induced using cow spinal cord homogenization, in combination with Freund's complete adjuvant. The serum concentration of cytokines including IL-1B and IL-17, IL-10, IL-6, and TNF-X was measured by the ELISA method, and real-time PCR was performed to study gene expression. Electrophysiological, behavioral, and neuropathological tests were also conducted. RESULTS: Nerve conduction velocity and IL-10 concentration were increased in the antigen B group. The results of this study showed that antigen B reduced the inflammatory component of the EAE MS animal model by modulating the immune system compared to teriflunomide, which eventually led to a reduction in symptoms at the behavioral and electrophysiological level. CONCLUSIONS: It seems that antigen B plays a critical role in regulating immunity and it can be used as a possible therapeutic agent to modulate the immune system in MS patients. It might be rational to consider hydatid cyst fluid antigen as a modifier in MS.

A Review on the Disruption of Novel Object Recognition Induced by Methamphetamine.

Background: Methamphetamine (MA), is a widely abused synthetic psychostimulant that leads to irreversible brain damage manifested as cognitive impairments in humans and animals. The novel object recognition (NOR) task is a commonly used behavioral assay for the investigation of non-spatial memory in rodents. This test is based on the natural tendency of rodents to spend more time exploring a novel object than a familiar one. NOR test has been used in many studies investigating cognitive deficits caused by MA in rodents. The objective of the present study was to review neurobiological mechanisms that might be responsible for MA-induced NOR alterations. Methods: A PubMed search showed 83 publications using novel object recognition and methamphetamine as keywords in the past 10 years. Findings: The present study revealed different MA regimens cause recognition memory impairment in rodents. In addition, it was found that the main neurobiological mechanism involved in MA-induced recognition deficits is the dysfunction of monoaminergic systems. Conclusion: NOR is a useful test to assess the cognitive functions following MA administration and evaluate the efficacy of new therapeutic agents in MA-addicted individuals.

Effects of psychological or physical prenatal stress on attention and locomotion in juvenile rats.

Background: Prenatal stress has been shown to affect the cognition of offspring, including memory and learning abilities.Methods: In the current study, the long-term effects of chronic prenatal exposure to the physical or psychological stress on locomotion and attention were evaluated by using open field test (OFT) and prepulse inhibition (PPI) of the acoustic startle reflex (ASR). In addition, the level of corticosterone was measured after the ASR trial.Results: Male and female rodents that underwent prenatal physical and psychological stress had an augmented velocity in OFT, and only male animals showed an increased ASR. Neither male nor female offsprings had an alteration in the level of corticosterone and PPI values regardless of the stress type.Conclusion: Our results revealed that exposure to stress during the development of fetus increases ASR in a sex-dependent manner. This finding might implicate the effect of prenatal stress on attention in male offspring regardless of the stress type.

Nitric oxide role in anxiety-like behavior, memory and cognitive impairments in animal model of chronic migraine.

The occurrence of cognitive dysfunctions and anxiety and mood disorders has been shown to be higher in migraine patients. Nitric Oxide (NO) is a significant neurotransmitter in the pathophysiology of migraine, anxiety and neurodegenerative disorders. Therefore, the present study was conducted to evaluate the role of NO system in migraine-induced memory impairment and anxiety like behaviors. Nitroglycerin (NTG) was administered to the animals as an animal model of migraine and pretreatment with L-Arginine, L-NAME and saline were implemented to evaluate the role of NO system in possible cognitive impairments in animal model of migraine. Avoidance learning and memory performance, object recognition memory, anxiety-like behavior and motor activity were assessed using a shuttle box apparatus, novel object recognition, elevated plus-maze, and open field tests respectively. The data showed that the injection of nitroglycerin disturbs learning and memory and elicit anxiety like behavior in the animals. L-NAME administration suppressed the observed effect of nitroglycerin on memory and anxiety. Overall, the results indicated that nitric oxide system is implicated in memory impairments and anxiety like behavior in an animal model of migraine.

Hyperexcitability of VTA dopaminergic neurons in male offspring exposed to physical or psychological prenatal stress.

Prenatal stress (PS) exposure leads to cognitive and behavioral alterations in offspring including an increased risk of substance abuse and anxiety disorders. Signalling from dopamine (DA) neurons of the ventral tegmental area (VTA) in the mesoaccumbal and mesocortical pathways plays a vital role in drug dependency and anxiety behavior. To provide further knowledge about the changes in drug seeking behavior and anxiety behaviors in prenatally stressed mice, we conducted ex vivo investigations in VTA brain slices of adult male PS offspring to evaluate the effects of two types of PS (physical vs. psychological) on activity of DA neurons. Elevated plus maze (EPM) was used to assess anxiety-like behaviors and conditioned place preference (CPP) was used to evaluate drug reinforcing effects in mice. An increased anxiety-like behavior and preference to morphine was observed in prenatally stressed mice. PS VTA DA cells exhibited greater Ih current and a higher frequency and amplitude of sEPSCs, which were consistent with a greater degree of pre- or postsynaptic excitability of the VTA. This was confirmed by lower rheobase and lower firing thresholds in PS VTA neurons, as well as increases in spontaneous firing frequency. When taken together, these data suggest that alterations in VTA DA neurons in this mouse model of prenatal stress might be associated with later life alterations in drug seeking and anxiety-like behaviors through their role in mesocortical and mesoaccumbal pathways.

Chronic migraine caused a higher rate of tendency to cannabinoid agonist compared to morphine.

BACKGROUND AND AIM: Opioid and cannabinoid systems have considerable roles in modulation of chronic pain as well as regulation reward circuit and addiction responses. This study investigated the effect of nitroglycerin (NTG)-induced migraine attack on the acquisition of morphine and cannabinoid-induced conditioned place preference (CPP) in male rats. METHODS: Adult male rats (230-250 gr) were used. Experimental groups were included (n=10): control, opioid receptor agonist morphine (10mg/kg), WIN55,212-2 (1mg/kg) as a cannabinoid receptor agonist, NTG + morphine (10mg/kg) and NTG + WIN55,212-2 (1mg/kg). Nitroglycerin (10 mg/kg) was used to induce migraine attack every other day for 9 days. After migraine induction, conditioning performance was assessed by CPP test. During conditioning days, morphine and WIN55,212-2 were injected subcutaneously and intraperitoneally, respectively. Anxiety and locomotor activity were evaluated using open field test (OFT). RESULTS: According to data, conditioning score for morphine-treated rats was significantly decreased following NTG-induced migraine. However, NTG-induced migraine was able to increase the conditioning score in WIN55,212-2 as compared to control group.  In OFT, there were no significant differences in locomotor activity and grooming behaviors between experimental groups. However, time spent in the center of OFT box was significantly decreased in NTG plus morphine-treated rats as compared to control. Moreover, rearing response in NTG-treated groups which received either morphine or WIN55,212-2 decreased as compared to control group. CONCLUSION: NTG induced migraine prompts a decrease in morphine and an increase in cannabinoid performances. So, these compounds effects on drug dependency during migraine attack may occur at different mechanism or mechanisms.

Nitric oxide modulates cognitive, nociceptive and motor functions in a rat model of empathy.

Aim: Empathy is defined as the capability to comprehend and simulate the feelings of others. Though it has been considered as a human feature, recent studies have demonstrated empathy-like behaviors in other animals including rats. The objective of the current study was to evaluate the role of nitric oxide system in cognition and nociception changes following observation of cagemates in pain.Material and methods: Adult male Wistar rats were used (n = 8 for each group). One sibling received formalin injection into the hindpaw five times within a nine-day period and the other sibling observed the pain while being pretreated with saline, L-NAME or L-arginine (10 mg/kg, i.p.). Nociception, anxiety-like behavior and locomotion, balance, muscle strength, spatial and fear learning were evaluated.Results: Observing a family member (sibling) in pain increased anxiety-like behavior, led to a hyperalgesia in the observer and disruption of spatial memory. Nitric oxide system modulated these changes, so that in some paradigms the activation of NO and in some others inhibition of NO dampened the effect of observing pain in a cagemate on the evaluated features.Conclusions: Results in the current study demonstrated a modulating effect of NO on empathy induced changes in nociception, motor function and spatial memory. Further studies addressing the specific brain regions and other neurotransmitters involved are recommended.

Sensory and Affective Dimensions of Pain and Anxiety Like Behaviors Are Altered in an Animal Model of Pain Empathy.

Objective: Pain is a unique and subjective experience that has a prominent function in animals' survival. Observation of pain in others leads to alterations in pain sensation and affection, termed "Empathy for pain". The present study aimed to evaluate the effect of empathy on sensory and affective dimensions of pain and its effect on anxiety-like behaviors. Method : In this study, male Wistar rats were used. Two cage mates were selected, one of which underwent administration of a noxious stimuli for 10 days and the other observed the conspecific in pain. Hot plate, tail flick, and conditioned place aversion were used to evaluate sensory and affective dimensions of pain, respectively. Anxiety-like behavior was assayed using elevated plus maze paradigm and time spent in open and close arms and number of entrance into each arm was recorded as the anxiety indicator within a 5-minute framework. Results: Rats observing the cage mate in pain had a lower threshold to noxious stimuli in comparison to controls. They also had an increased aversion from painful stimuli, demonstrating heightened affective response to pain. Anxiety-like behavior was also enhanced in the observers. Conclusion: Results of this study demonstrate that both sensory and affective dimensions of pain are altered following observation of pain in a conspecific. Further studies evaluating the underlying mechanisms are encouraged to elucidate the role of different neurotransmitters in this phenomenon.

Role of Opioid System in Empathy-like Behaviours in Rats.

BACKGROUND: Empathy is defined as the ability to simulate the mental states of others. Recent studies have demonstrated empathy-like behaviors in other animals including rats and mice. The objective of the current study was to evaluate the effect of acute administration of morphine and naloxone on cognition and nociception changes following observing conspecifics undergoing nociceptive stimulus. METHODS: Adult male Wistar rats were used (n = 8 for each group). One cagemate received formalin injection into the hindpaw five times within a nine-day period and the other cagemate observed the pain while being pretreated with saline, morphine, or naloxone [10 mg/kg, intraperitoneal (i.p.)]. Pain behaviors, anxiety-like behaviour, locomotion, balance and muscle strength were evaluated in the observer animals. FINDINGS: Observing a cagemate in pain increased anxiety-like behavior and reduced thermal pain threshold in the observer animals. Administration of morphine reversed these effects and naloxone did not affect the responses. CONCLUSION: Results of the current study reveal an important role for opioid receptors (ORs) in empathy for pain, so that activation of this system dampens the empathy-like responses.

Role of anxiety and depression in association with migraine and myofascial pain temporomandibular disorder.

BACKGROUND: Previous studies have demonstrated a strong association between primary headaches (HAs) and temporomandibular disorders (TMDs), specifically the myofascial pain subtype of TMD (MP TMD). The role of anxiety and depression in presentation and maintenance of MP TMD and migraine is previously demonstrated. Therefore, the objective of the current study was to evaluate the modification effect of anxiety and depression on the possible association of MP TMD and migraine. METHODS: In this retrospective case-control study, individuals between 15 and 45 years old who were diagnosed with migraine HA according to the international classification of headache disorder-II (ICHD-II) were selected as case subjects (n = 65). Non-HA control subjects were matched by sex and age (n = 63). Research diagnostic criteria (RDC/TMD) (Axis I) was used to diagnose patients with MP TMD; other subtypes of RDC/TMD Axis I were excluded from the study. Subjects' anxiety and depression were screened using Persian version of Hospital Anxiety and Depression Scale-14. Chi-square and Mantel-Haenszel tests were used to analyze the data. P < 0.05 was considered statistically significant. RESULTS: A significant association was found between migraine and MP TMD so that subjects with MP TMD had a five times chance of developing HA (P < 0.001). Further analysis using stratification method revealed that anxiety and depression have a modification effect in the association of MP TMD and HA and MP TMD patients with anxiety or depression had more chance of developing migraine HA (P = 0.003). CONCLUSION: Association between HA and TMD was observed in this study. Besides, we depicted that anxiety and depression interact in this association so that patients who did not have anxiety or depression did not demonstrate an association between TMD and HA. We suggest further studies to confirm the modifying effects of anxiety and depression.

Evidence of Altered Trigeminal Nociception in an Animal Model of Fibromyalgia.

Objective: Fibromyalgia (FM) is a debilitating chronic condition that significantly affects quality of life. A strong association has been demonstrated between FM and chronic pain in the trigeminal region in clinical studies. This study was performed to evaluate the response to acute and chronic noxious stimuli applied to the facial region. Methods: Adult male Wistar rats (250-270 g, N = 10 for each group) were used in the current study. A subchronic swim stress model was used as the animal model of FM. Anxiety-like behaviors and response to acute and chronic noxious stimuli were assayed using the elevated plus maze, eye wiping test, and orofacial formalin test, respectively. Balance and motor function were evaluated using rotarod and wire grip tests. Results: An increased anxiety-like behavior was observed in swim stress rats in comparison with control and sham subjects. Response to acute and chronic noxious stimuli in the trigeminal region was increased in the stressed rats. Motor and balance function were not altered following stress. Conclusions: Results of the current study demonstrated a hyperalgesic state in the trigeminal region in a possible animal model of FM. This study provides a reliable animal model for further research on the possible mechanisms of orofacial pain in FM.

Psychological stress has a higher rate of developing addictive behaviors compared to physical stress in rat offspring.

Prenatal stress could have great influence on development of offspring and might alter cognitive function and other physiological processes of children. The current study was conducted to study the effect of physical or psychological prenatal stress on addictive and anxiety-like behavior of male and female offspring during their adolescence period (postnatal day (PND) 40). Adult female rats were exposed to physical (swimming) or psychological (observing another female rat swimming) stress from day six of gestation for 10 days. Male and female offspring were assayed for anxiety-like behavior, motor and balance function and morphine conditioned place preference using the open field, elevated plus maze (EPM), rotarod and wire grip assay and conditioned place preference. Offspring in both physical and psychological prenatal stress groups demonstrated significant increase in anxiety-like behavior in EPM paradigm, but no alterations were observed in motor and balance function of animals. Offspring in the psychological prenatal stress group had an increased preference for morphine in comparison to control and physical prenatal stress groups. Results of the current study demonstrated that animals exposed to psychological stress during fetal development are at a higher risk of developing addictive behaviors. Further research might elucidate the exact mechanisms involved to provide better preventive and therapeutic interventions.

Migraine patients have a higher prevalence of PTSD symptoms in comparison to chronic tension-type headache and healthy subjects: a case-control study.

OBJECTIVE: Headache is one of the most common disorders and has a heavy socioeconomic burden on both patients and society. Previous studies have demonstrated a high prevalence of psychological issues (e.g. depression and anxiety) in headache and especially migraine patients. The current study was designed to evaluate the prevalence of post-traumatic stress disorder (PTSD) symptomatology in chronic migraine (CM), chronic tension-type headache (CTTH) and healthy subjects. MATERIAL AND METHODS: CM and CTTH subjects were selected consecutively from patients referring to the department of neurology clinic at Shafa Hospital, Kerman University of Medical Sciences, Kerman, Iran. PTSD symptomatology was assessed using PTSD checklist civilian version-Persian edition (PCL-C). Control subjects were enrolled from the family members of headache patients who did not have any history of headache. Chi-square test was used to analyse data and p < .05 was considered statistically significant. RESULTS: Of the 60 control subjects, 5 had a PTSD symptomatology (8.3%); this prevalence was 13.3% for CTTH and 40% for CM groups. CM patients had a significantly higher prevalence of PTSD symptomatology in comparison to CTTH and control subjects (p < .05). With reference to gender, most of the subjects with PTSD symptomatology were female. CONCLUSION: Results of the current study demonstrated that CM patients have a higher prevalence of PTSD symptomatology compared to another chronic headache condition (CTTH) and healthy subjects, which should be considered while treating CM patients. Further studies in larger populations are demanded.

Simultaneous impairment of passive avoidance learning and nociception in rats following chronic swim stress.

BACKGROUND: Stress can alter response to nociception. Under certain circumstances stress enhances nociception, a phenomenon which is called stress-induced hyperalgesia (SIH). While nociception has been studied in this paradigm, possible alterations occurring in passive avoidance (PA) learning after exposing rats to this type of stress has not been studied before. MATERIALS AND METHODS: In the current study, we evaluated the effect of chronic swim stress (FS) or sham swim (SS) on nociception in both spinal (tail-flick) and supraspinal (53.5°C hot-pate) levels. Furthermore, PA task was performed to see whether chronic swim stress changes PA learning or not. Mobility of rats and anxiety-like behavior were assessed using open-field test (OFT). RESULTS: Supraspinal pain response was altered by swim stress (hot-plate test). PA learning was impaired by swim stress, rats in SS group did not show such impairments. Rats in the FS group showed increased mobility (rearing, velocity, total distant moved (TDM) and decreased anxiety-like behavior (time spent in center and grooming) compared to SS rats. CONCLUSIONS: This study demonstrated the simultaneous impairment of PA and nociception under chronic swim stress, whether this is simply a co-occurrence or not is of special interest. This finding may implicate a possible role for limbic structures, though this hypothesis should be studied by experimental lesions in different areas of rat brain to assess their possible role in the pathophysiology of SIH.

The therapeutic potential of Berberine chloride hydrate against harmaline-induced motor impairments in a rat model of tremor.

Essential tremor (ET) is a progressive neurological disorder with motor and non-motor symptoms. It has conclusively been shown that modulation of glutamate receptors could ameliorate ET. Recent studies have suggested that Berberine (BBR) has an inhibitory effect on glutamate receptors. Therefore, BBR may have therapeutic effects on ET. In this study, male Wistar rats (n=10 in each group) weighing 40-60 g were divided into control, harmaline (30 mg/kg, i.p.) and berberine (10, 20 or 50mg/kg, i.p, 15 min before harmaline injection) groups. Open field, rotarod, wire grip and foot print tests were used to evaluate motor performance. The results indicated that the administration of BBR (10 and 20mg/kg) attenuated harmaline-induced tremor in rats, but the beneficial effects of BBR could not be identified at dose 50mg/kg. In addition, BBR ameliorated gait disturbance in doses of 10 and 20mg/kg. The high dose of BBR not only failed to recover step width but also showed an adverse effect on left and right step length. The results indicate that BBR only in dose of 20mg/kg recovers mobility duration. The current study found a dose-dependent manner for the therapeutic effects of BBR in ET. Our study provides the initial evidence for the effects of BBR on motor function. Since BBR exerts its effects mainly through regulation of neurotransmitter release or blocke of NMDA receptors, thus, it is predicted that BBR ameliorate harmaline effect through blockade of NMDA receptors or glutamate release. This is an important issue for future research to evaluate the possible mechanisms involved.

Psychological or physical prenatal stress differentially affects cognition behaviors.

INTRODUCTION: Prenatal stress is proposed as a major risk factor in the development of cognitive impairments in the offspring. The objective of the current study was to evaluate the effect of prenatal physical or psychological stress on the motor and cognitive functions of male and female offspring. METHODS: Adult female rats were stressed during their conception using a novel method to induced whether physical or psychological stress. Animal offspring were then kept until adulthood. Elevated plus maze (EPM) was used to evaluate their anxiety-like behavior. Rotarod and wire grip were used to evaluate muscle strength and balance function. Morris water maze (MWM) and passive avoidance (PA) learning and memory paradigm were used to evaluate the cognitive function of the offspring. RESULTS: Female offspring of both physical and psychological stress had an increased anxiety-like behavior in the EPM test in comparison to female control rats. Balance function was impaired in physical stressed female offspring in comparison to the control and male offspring. Muscle strength was reduced in physical male and female offspring. Both male and female offspring groups that underwent prenatal physical and psychological stress had an impaired spatial learning and memory. PA learning and memory were impaired in both male and female offspring except for the psychological stress female offspring in PA learning. CONCLUSION: Results of our study revealed that prenatal physical or psychological stress have different effects on motor and cognitive functions of the offspring. Male and female offspring were differentially affected by prenatal stress. We suggest more studies to evaluate the role of sex hormones on the effects of prenatal physical or psychological stress on cognitive and motor functions of the offspring.

Exercise improves learning and memory impairments in sleep deprived female rats.

Inadequate sleep is a common problem in modern societies. It has been previously shown that female rats are more vulnerable to the deleterious effects of sleep deprivation on cognitive functions. Physical exercise has been suggested to attenuate the cognitive impairments induced by sleep deprivation in male rats. The objective of the current study was to investigate the effects of physical exercise on cognitive functions of female rats following paradoxical sleep deprivation. Intact and ovariectomized (OVX) female Wistar rats were used in the present study. The exercise protocol was 4 weeks of treadmill running. The multiple platform method was applied for the induction of 72h paradoxical sleep deprivation and the cognitive function was evaluated using Morris water maze (MWM). Plasma corticosterone level was evaluated in separate groups of study. ANOVA and repeated measures were used to analyze the data and P<0.05 was considered statistically significant. Throughout the investigation, significant learning impairment was observed in sleep-deprived OVX rats compared to the intact and the other OVX groups. Short term memory impairment was observed in both sleep-deprived OVX and intact groups. Physical exercise alleviated the PSD-induced learning and memory impairments in both intact and OVX groups. Corticosterone levels were not statistically significant among the different groups. The results of our study confirmed the negative effects of PSD on cognitive functions in female rats and regular physical exercise seems to protect rats from these effects. Further studies are suggested to be carried out in order to evaluate the possible underlying mechanisms, and also to evaluate the possible interactions between sex hormones and PSD-induced cognitive impairments.

Erythropoietin ameliorates the motor and cognitive function impairments in a rat model of hepatic cirrhosis.

Hepatic encephalopathy (HE) is a serious consequence of hepatic cirrhosis (HC). Previous studies have demonstrated cognitive impairments in both clinical and animal experiments of HC. Some potential therapeutic agents have been used to alleviate the cognitive symptoms in the animal models of HC. In the current study, the possible effect of erythropoietin (ERY) as a potent neuroprotective agent on motor and cognitive impairments induced by HC has been studied. Male Wistar rats (180-200 g) underwent bile duct ligation (BDL) or sham surgery. Administration of ERY (5,000 IU/kg, i.p., daily for three days) was initiated 2 weeks after surgery and lasted for the next 28 days. Open field, rotarod, Morris water maze and passive avoidance learning was used to evaluate the motor and cognitive function of the animals. ANOVA and repeated measures ANOVA were used to analyze the data. p < 0.05 was considered statistically significant. BDL rats had an increased level of hepatic enzymes and bilirubin. Impairment of balance function by BDL was reversed by ERY. Spatial and passive avoidance learning impairments observed in BDL rats were also reversed by chronic administration of ERY. ERY can be offered as a potential neuroprotective agent in the treatment of patients with HC that manifest mental dysfunctions. Though further studies are needed to clarify the exact mechanisms, the neuroprotective properties of ERY against BDL impairments were demonstrated in the current study.