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Objective Dihydromyricetin (DHM), a natural flavonoid, is used to reduce alcohol hangover. It has a modulatory role on GABAA receptors with significant effects on seizure and anxiety in animal models. We aimed to evaluate the effect of DHM on morphine conditioned place preference (CPP) and withdrawal sings following morphine dependence using animal models. Methods The effect of DHM (1, 2 and 5 mg/kg, intraperitoneal; ip) on the acquisition and expression of morphine-induced CPP was evaluated in male mice. Administration of morphine for three consecutive days induced physical dependence. The withdrawal signs such as jumping and defecation were precipitated by administration of naloxone (8 mg/kg, ip). The effect of DHM on the development of physical dependence was assessed by injection of DHM before morphine administrations. Results DHM, at the dose of 5 mg/kg, reduced expression of morphine CPP with an increase in the locomotor activity. DHM, at the doses of 2 and 5 mg/kg, also reduced development of morphine CPP. DHM alleviated development of morphine-induced physical dependence at the dose of 1, 2, and 5 mg/kg by decreasing jumping and defecation. Conclusion These results indicated that DHM decreased acquisition and expression of morphine CPP and inhibited development of morphine-induced physical dependence.

Neuroinflammation has a key role in seizure generation and perpetuation in the neonatal period, and toll-like receptor 4 (TLR4) pathway has a prominent role in neuroinflammatory diseases. Administration of antioxidants and targeting TLR4 in the embryonic period may protect rat offspring against the next incidence of febrile seizure and its harmful effects. Curcumin and hesperidin are natural compounds with anti-inflammatory and antioxidant properties and have an inhibitory action on TLR4 receptors. We evaluated the effect of maternal administration of curcumin and hesperidin on infantile febrile seizure and subsequent memory dysfunction in adulthood. Hyperthermia febrile seizure was induced on postnatal days 9–11 on male rat pups with 24 h intervals, in a Plexiglas box that was heated to ~45 °C by a heat lamp. We used enzyme-linked immunosorbent assay, Western blotting, malondialdehyde (MDA), and glutathione (GSH) assessment for evaluation of inflammatory cytokine levels, TLR4 protein expression, and oxidative responses in the hippocampal tissues. For assessing working memory and long-term potentiation, the double Y-maze test and Schaffer collateral-CA1 in vivo electrophysiological recording were performed, respectively Our results showed that curcumin and hesperidin decreased TNF-α, IL-10, and TLR4 protein expression and reversed memory dysfunction. However, they did not provoke a significant effect on GSH content or amplitude and slope of recorded fEPSPs in the hippocampus. In addition, curcumin, but not hesperidin, decreased interleukin-1β (IL-1β) and MDA levels. These findings imply that curcumin and hesperidin induced significant protective effects on febrile seizures, possibly via their anti-inflammatory and antioxidant properties and downregulation of TLR4.

Vincristine (VCR) induces peripheral neuropathy. We aimed to assess the efficacy of modafinil on VCR-induced neuropathy in rats. Neuropathy was induced by intraperitoneal (i.p.) injections of VCR (0.1 mg/kg). Neuropathic groups received modafinil (5, 25 and 50 mg/kg); gabapentin (20 mg/kg); and a combination of modafinil (5 and 50 mg/kg) and gabapentin (20 mg/kg,). Then, electrophysiological, behavioural, biochemical and pathological evaluations were performed. Latencies of tail-flick and von Frey filament tests, motor nerve conduction velocity (MNCV) and excitation of nerve conduction were decreased. Moreover, the transient receptor potential cation channel ankyrin 1 (TRPA1) level was increased, while TRPV1 and N-Methyl-D-aspartate (NMDA) levels remained unchanged. Tumour necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) levels were markedly elevated. Pre-treatment with modafinil prevented sensorimotor neuropathy by raising latencies, MNCV and excitation, reducing TRPA1, TNF-α and IL-1β levels. Modafinil improved behavioural, electrophysiological and pathological disturbances. The results showed that TRPA1 has a more important role than NMDA and TRPV1, in VCR-induced neuropathic pain. In addition, inflammatory mediators, TNF-α and IL-1β, were involved. Further, the combination of modafinil and gabapentin improved the neuroprotective effect of gabapentin. So, modafinil might be a neuroprotective agent in the prevention of VCR-induced neuropathy.

Neuroinflammation and fever are the main triggers in febrile seizures (FS). Focusing on inflammatory pathways and anti-inflammatory drugs could compensate for the limitations of existing medications. The aim of this study is to evaluate the neuroprotective effect of specific antagonizing Toll-like receptor 4 (TLR4), as a prominent inflammatory axis, on the consequences of FS and adulthood using animal models. Complex FS was induced on 9-11 day old male rat pups using a heated chamber. TAK-242, as a specific TLR4 inhibitor, was injected intraperitoneally before seizure induction. Seizure threshold, duration, and spike number were measured by electrocorticography. The levels of inflammatory cytokines, TLR4 protein expression, and oxidative stress markers were detected by enzyme-linked immunosorbent assay, western blotting, malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) assessments in the cortex and hippocampus. Also, spatial and non-spatial memory were evaluated using the novel object recognition test (NORT) and double Y-maze test during adulthood. The results revealed that provoked inflammatory responses in neonate rats, after FS, were associated with the increase of the tumor necrosis factor alpha, interleukin-1β, and enhanced TLR4 protein expression. Meanwhile, based on performed behavioral tests, the inflammatory process was also involved in adulthood memory deficit. Pretreatment with TAK-242 reduced the inflammatory cytokines and TLR4 protein expression in the cortex and hippocampus of neonate rats and improvement in memory deficit in NORT and double Y-maze tasks. Also, pretreatment with TAK-242 elevated seizure threshold, SOD, and CAT activities, and decreased seizure duration and MDA level with no significant change in spike number. TAK-242 possibly controlled FS via inhibiting inflammation.

Melatonin has long been known for its apparent effects on sleep and circadian rhythm. It may participate as a possible therapeutic agent in neurodegenerative, cardiovascular, and endocrine disorders as well. Autophagy is a lysosomal degradation process that occurs in response to starvation and other stresses. Recent studies have reported that melatonin may modulate the autophagy process. We reviewed the current literature that has reported on how different diseases and/or experimental models change autophagy parameters. We also discussed the effect of melatonin on autophagy parameters in the central nervous, cardiovascular, gastrointestinal and endocrine systems as reported in nonclinical studies. Moreover, the molecular targets for melatonin are discussed in details. In summary, melatonin has been reported to enhance significant protective effects in different in vitro and in vivo studies either through enhancement or inhibition of the autophagy process. Melatonin holds promise in the treatment of several major diseases. Regulation of autophagy by melatonin is a determinant parameter that should be considered in the future studies.

Snake venoms contain various active compounds including pharmacological polypeptides and proteins with various molecular weights. Some of these polypeptides and proteins are enzymatic or ac...

Cholecystokinin (CCK) is one of the most studied neuropeptides in the brain. In this study, we investigated the effects of CCK-8s and LY225910 (CCK2 receptor antagonist) on properties of neuronal r...

Exercise preconditioning has been shown to be effective in improving behavioral and neuropathological indices after cerebral ischemia. We evaluated the effect of exercise preconditioning, 17β-estradiol, and their combination on stroke outcome using an experimental model of stroke in ovariectomized (OVX) mice. OVX mice were randomly assigned to 4 groups as follows: control (stroke), exercise (exercise and stroke), estradiol (17β-estradiol and stroke), and exercise+estradiol (exercise and 17β-estradiol and stroke). Exercise preconditioning was performed on a treadmill 5 days/week, 40 min/day, at a speed of 18 m/min for 4 weeks. 17β-estradiol was gavaged (40 μg/kg per day) for 4 weeks. Stroke was induced by permanent middle cerebral artery occlusion (pMCAO), and neurological deficits were evaluated 1, 2, and 7 days after stroke. Then, the serum concentrations of matrix metalloproteinase-9 (MMP-9) and interleukin-10 (IL-10) and infarct volumes were assessed. Exercise preconditioning and 17β-estradiol induced a better outcome compared with the control ischemic mice, which was manifested by decrease in MMP-9, increase in IL-10, diminished infarct volume, and improved neurological deficits. Concomitant administration of 17β-estradiol and exercise also significantly improved these parameters. Exercise preconditioning or administration of 17β-estradiol alone or in combination before pMCAO induced significant neuroprotection in OVX mice.

There are various types of receptors in the central nervous system (CNS). G protein-coupled receptors (GPCRs) have the highest expression with a wide range of physiological functions. A newer sub group of these receptors namely orphan GPCRs have been discovered. GPR3, GPR6, GPR17, GPR26, GPR37, GPR39, GPR40, GPR50, GPR52, GPR54, GPR55, GPR85, GPR88, GPR103, and GPR139 are the selected orphan GPCRs for this article. Their roles in the central nervous system have not been understood well so far. However, recent studies show that they may have very important functions in the CNS. Hence, in the present study, we reviewed most recent findings regarding the physiological roles of the selected orphan GPCRs in the CNS. After a brief presentation of each receptor, considering the results from genetic and pharmacological manipulation of the receptors, their roles in the pathophysiology of different diseases and disorders including anxiety, depression, schizophrenia, epilepsy, Alzheimer's disease, Parkinson's disease, and substance abuse will be discussed. At present, our knowledge regarding the role of GPCRs in the brain is very limited. However, previous limited studies show that orphan GPCRs have an important place in psychopharmacology and these receptors are potential new targets for the treatment of major CNS diseases.

The immediate and the late effects of inhaled Paraquat (PQ) on systemic and lung inflammation and oxidative stress were investigated. Rats were exposed to saline (control group) and two doses of inhaled PQ (27 and 54 mg/m3) and studied variables were measured: 1) one day after the end of PQ exposure as “immediate condition”, 2) 16 days after the end of PQ exposure as “late condition”. Total and differential white blood cells (WBC) counts, lipid peroxidation and nitrite were increased but thiol, superoxide dismutase and catalase in the blood and BALF as well as methacholine EC50 was reduced in both conditions in the animals exposed to PQ compared to control groups (p

Carotenoids are a large class of natural antioxidants that occur in many vegetables, foods and other natural sources. To date, a large number of biological properties have been reported from carotenoids, particularly protective effects against diabetes mellitus (DM), cancer, and neurodegenerative, metabolic and cardiovascular diseases. However, recent studies including clinical evidences, have shown that carotenoids play a role in the treatment of diabetes via enhancing insulin sensitivity. They are also able to protect the body from long-term consequences of diabetes including infectious diseases, nephropathy, neuronal and eye abnormalities. In this review, we try to discuss the mechanisms behind the biological effects of carotenoids for the prevention and treatment of DM and its complications. The authors believe that carotenoids will have a prominent place in the treatment of DM and its complications in the future.

GABAC receptors are ligand-gated chloride channels and have important roles in some neurological functions like vision. Recent investigations demonstrated that these receptors are also expressed in the somatosensory cortex. In this study, we investigated the effect of (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) (GABAC receptor antagonist) on the properties of the neuronal response to natural stimuli (whisker deflection) in deep layers of rat barrel cortex. Twenty-eight male Wistar rats, weighing 230-260 g, were used in this study. TPMPA (100 μmol/rat) was administered intracerebroventricularly (ICV). Neuronal responses to deflection of principal (PW) and adjacent (AW) whiskers were recorded in barrel cortex using tungsten microelectrodes. A computer-controlled mechanical displacement was used to deflect whiskers individually or in combination at 30 ms inter-stimulus intervals. ON and OFF responses for PW and AW deflections were measured. A condition-test ratio (CTR) was computed to quantify neuronal responses to whisker interactions. Our data suggest that ICV administration of TPMPA increased neuronal spontaneous activity, ON and OFF responses to PW, and/or AW deflections. However, CTR for neither ON nor OFF responses changed following TPMPA administration. The results of this study demonstrated that inhibition of GABAC receptors by TPMPA can modulate neuronal response properties in rat barrel cortex.

Memantine as N-Methyl-D-Aspartic Acid (NMDA) receptor antagonist is used in some neurological disorders. Moreover, memantine presents modulatory effects on the somatosensory information processing in healthy subjects. This study investigated the effects of memantine on electrophysiological properties of barrel cortex neurons in male rats.Single unit recording was used to evaluate the electrophysiological properties of barrel cortex neurons. The neural responses to the Principal Whisker (PW), Adjacent Whisker (AW), and combined displacement of two whiskers [20 ms Inter-Stimulus Intervals (ISIs)] were recorded before and 2 hours after memantine gavage (10 mg/kg). A Condition Test Ratio (CTR) was calculated for assessing inhibitory interactions.Two hours after memantine gavage, neuronal ON and OFF responses to PW deflection were decreased. Furthermore, CTR for both ON and OFF responses was decreased following memantine administration.The current study demonstrated that memantine modified neural response properties in the rat barrel cortex.Memantine modulated excitatory receptive fields in the rat somatosensory cortex.Memantine decreased integrative receptive fields in rat somatosensory cortex.As an NMDA receptor antagonist, memantine is used to treat moderate to severe Alzheimer's disease. Memantine has beneficial effects on cognition, mood, and perform daily activities. However, the current study results suggested that memantine may affect information processing in the somatosensory system. This should be considered for future research in the clinic.

Methamphetamine (METH) is a highly potent and addictive drug with major medical, psychiatric, cognitive, socioeconomic, and legal consequences. It is well absorbed following different routes of administration and distributed throughout the body. METH is known as psychomotor stimulant with potent physiological outcomes on peripheral and central nervous systems, resulting in physical and psychological disorders. Autophagy is a highly conserved and regulated catabolic pathway which is critical for maintaining cellular energy homeostasis and regulating cell growth. The mechanism of autophagy has attracted considerable attention in the last few years because of its recognition as a vital arbiter of death/survival decisions in cells and as a critical defense mechanism in undesirable physiological conditions. The purpose of the current article was to review available evidence to find a relationship between METH toxicity and mechanisms associated with autophagy in different organs.

MicroRNAs (miRNAs) are small non-coding RNAs that act as post-transcriptional gene regulators. They are involved in the pathogenesis of different disorders including heart diseases. MiRNAs contribute to ischemia/reperfusion injury (I/RI) by altering numerous key signaling elements. Together with alterations in the various potential signaling pathways, modification in miRNA expression has been suggested as a part of the response network following ischemia/reperfusion (I/R). In addition, cardiac mitochondrial homeostasis is closely associated with cardiac function and impairment of mitochondrial activity occurred after ischemia/reperfusion injury. MiRNAs play a key role in the regulation of mitochondrial apoptotic pathway and signaling proteins. In this review, we summarize the knowledge currently available regarding the molecular mechanisms of miRNA-regulated mitochondrial functions during ischemia/reperfusion injury. This regulation occurs in different stages of mitochondrial apoptosis pathway.

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.

Background Previous studies show that some non-CB1/non-CB2 effects of cannabinoids are mediated through G protein coupled receptor 55 (GPR55). As this receptor is activated by some of cannabinoid receptor ligands and is involved in the modulation of pain, it was hypothesized that this receptor may also interact with opioids. This study examined the effect of atypical cannabinoid O-1602 as a GPR55 agonist on morphine-induced conditioned place preference (CPP) and physical dependence. Methods We used a biased CPP model to evaluate the effect of O-1602 (0.2, 1 and 5 mg/kg, intraperitoneal; ip ) on the acquisition and expression of morphine-induced CPP in male mice. The locomotor activities of mice were also recorded. Moreover, repeated administration of morphine (50, 50 and 75 mg/kg/day) for three days, induced physical dependence. The withdrawal signs such as jumps and diarrhea were precipitated by administration of naloxone (5 mg/kg, ip ). The effect of O-1602 on the development of morphine physical dependence was assessed by injection of O-1602 (0.2, 1 and 5 mg/kg) before morphine administrations. Results Morphine (40 mg/kg, subcutaneous; sc ), but not O-1602 (5 mg/kg) elicited significant preference in the post-conditioning phase. O-1602 at the doses of 0.2 and 1 mg/kg, but not 5 mg/kg reduced acquisition of morphine CPP with an increase in locomotor activity at the dose of 5 mg/kg. O-1602 at the doses of 0.2, 1 and 5 mg/kg also reduced expression of morphine CPP with an increase in locomotor activity at the dose of 5 mg/kg. O-1602 had a significant inhibitory effect on development of morphine-induced physical dependence at the dose of 5 mg/kg by decreasing jumps and diarrhea during withdrawal syndrome. Conclusions The present results indicate that O-1602 decreased acquisition and expression of morphine CPP and inhibited development of morphine-induced physical dependence.

The aim of this study was to evaluate the effects of orexin-A (OX-A) on behavioral and pathological parameters and on gene expression of some multiple sclerosis-related peptides in a model of experimental autoimmune encephalomyelitis (EAE). EAE was induced by subcutaneous administration of MOG 35-55. Following immunization, the treatment was initiated by using SB.334867 (orexin-1 receptor antagonist) and/or OX-A. Locomotor activity and exploratory behaviors were monitored using open field and T-maze continuous alternation task (T-CAT) respectively. Pain sensitivity was assessed by hot-plate test. Histopathological assessments were performed by H&E staining. The expression of TGF-β, MBP, MMP-9, IL-12, iNOS and MCP-1 were measured using real-time PCR method in lumbar spinal cord. OX-A administration in EAE mice remarkably attenuated the clinical symptoms, increased latency response in hot plate test, inhibited infiltration of inflammatory cells, up-regulated mRNA expression of TGF-β as well as MBP and down-regulated mRNA expression of iNOS, MMP-9 and IL-12. In contrast SB.334867 administration in EAE mice deteriorated the clinical symptoms, decreased the alternation in T-CAT, increased infiltration of inflammatory cells, down-regulated mRNA expression of TGF-β and MBP and up-regulated mRNA expression of iNOS. Results of this study suggest that the orexinergic system might be involved in pathological development of EAE. These findings suggest orexinergic system as a potential target for treatment of multiple sclerosis.

Transient receptor potential vanilloid channel 2 (TRPV2) is required for normal cardiac contractility. The stimulation of TRPV1 in isolated cardiomyocytes can aggravate the effect of hypoxia/ reoxygenation (H/R) on H9C2 cells. The knockout of the TRPV1 gene promotes increased tolerance of the isolated perfused heart to the impact of ischemia/reperfusion (I/R). However, activation of TRPV1 increases the resistance of the heart to I/R due to calcitonin gene-related peptide (CGRP) release from afferent nerve endings. It has been established that TRPV1 and TRPV2 are involved in the pathogenesis of myocardial infarction and, in all likelihood, ensure the cardiac tolerance to the ischemia/reperfusion. It has also been documented that the activation of TRPV4 negatively affects the stability of cardiomyocytes to the H/R. The blockade of TRPV4 can be considered as a new approach to the prevention of I/R injury of the heart. Studies also indicate that TRPV1 is involved in the pathogenesis of cardiac hypertrophy and that TRPV2 channels participate in the pathogenesis of dilated cardiomyopathy. Excessive expression of TRPV2 leads to chronic Ca2+- overload of cardiomyocytes, which may contribute to the development of cardiomyopathy.

G protein-coupled receptors (GPCRs) comprise a large number of receptors. Orphan GPCRs are divided into six families. These groups contain orphan receptors for which the endogenous ligands are unclear. They have various physiological effects in the body and have the potential to be used in the treatment of different diseases. Considering their important role in the central and peripheral nervous system, their role in the treatment of pain has been the subject of some recent studies. At present, there are effective therapeutics for the treatment of pain including opioid medications and non-steroidal anti-inflammatory drugs. However, the side effects of these drugs and the risks of tolerance and dependence remain a major problem. In addition, neuropathic pain is a condition that does not respond to currently available analgesic medications well. In the present review article, we aimed to review the most recent findings regarding the role of orphan GPCRs in the treatment of pain. Accordingly, based on the preclinical findings, the role of GPR3, GPR7, GPR8, GPR18, GPR30, GPR35, GPR40, GPR55, GPR74, and GPR147 in the treatment of pain was discussed. The present study highlights the role of orphan GPCRs in the modulation of pain and implies that these receptors are potential new targets for finding better and more efficient therapeutics for the management of pain particularly neuropathic pain.

Breast cancer and prostate cancer are the most common malignant tumors in female and men, respectively. Furthermore, lung cancer is the leading cause of cancer deaths worldwide. It is an emergency to develop a powerful strategy to treat these threatening cancers more effectively, because of low efficacy and high rates of chemotherapy effects. MicroRNAs (miRNAs), a class of small non-coding RNAs, are key regulators of gene expression via induction of translational repression or mRNA degradation. MiRNA deregulation has been linked to cancer initiation and progression. Silent Inflammation Regulator 2 (SIR2) proteins-sirtuins- are a family of histone deacetylases (HDACs) that catalyze deacetylation of both histone and non- histone lysine residues. SIRT1 can act as an oncogene. It plays a role in tumorigenesis by anti-apoptotic activity and is implicated in diverse cellular process including autophagy, senescence, apoptosis, proliferation, and aging. MicroRNAs and SIRT1 serve as tumor suppressors or tumor promotors depending on the oncogenic pathway specific to particular tumors. MicroRNAs modulate cancer development by targeting SIRT1. In this review, we underlie the specific mechanisms involved in these threatening cancers by microRNAs/SIRT1 pathways.

G-protein-coupled receptor 55 (GPR55) has been proposed as an atypical cannabinoid receptor, which is activated by lysophosphatidylinositols and some synthetic or endogenous cannabinoid molecules. The exact role of GPR55 receptors in the central nervous system especially in anxiety needs to be evaluated. In this study, the effects of intracerebroventricular (i.c.v.) administration of agonist and antagonist of GPR55 receptor on anxiety-related behaviors in rats were investigated. Here, O-1602 (GPR55 agonist) at the doses of 0.2, 1, and 5 μg/rat increased %OAT and %OAE but not the locomotor activity, showing an anxiolytic response, whereas i.c.v. injection of ML193 (GPR55 antagonist) at the doses of 0.1 and 1 μg/rat increased anxiety-like behaviors while causing locomotor impairment. The antagonistic effect of ML193 on the anxiolytic-like effect of O-1602 was also evaluated. The results showed that ML193 decreased the anxiolytic-like effect of O-1602. Based on these results, it may be concluded that central GPR55 may have a role in modulation of anxiety-like behaviors in rats. Further experiments are needed to elucidate the exact role of these receptors in anxiety.

GABA

Stroke is a prevalent and dangerous health problem, which triggers an intense inflammatory response to Toll-like receptors (TLRs) activation. TLRs are the essential components of innate immunity system response, and therefore, they are one of the key factors involved in recognizing pathogens and internal ligands. Among TLRs, TLR4 significantly participates in the induction of inflammation and brain functions, hence, it has been hypothesized that this molecule is associated with several brain immune-related diseases such as stroke. It has also been proved that animals with TLR4 deficiency have higher protection against ischemia and the absence of TLR4 reduces the neuroinflammation and injuries associated with brain trauma. TLR4 deficiency may play a neuroprotective role in the occurrence of stroke. This article will review recent information regarding the impact of TLR4 in the pathogenicity of stroke.

The use of natural products in the prevention and treatment of diseases and reduction of the adverse reactions of drugs has increased substantially during the past decade. Multiple sclerosis (MS) is described as a relapsing-remitting inflammatory and autoimmune disease of the central nervous system. It is associated with the destruction of the myelin sheaths of neurons and is one of the most common debilitating illnesses among young adults. The use of natural products and herbs in the prevention and/or treatment of MS has also increased. Furthermore, a lot of studies are devoted to evaluating the potential therapeutic effects of these products in both animals and humans. In this chapter, a brief list of the natural compounds that have been reported as effective in the treatment of MS in basic and clinical studies is prepared. This list includes selected flavonoids, phytoestrogens, alkaloids, triterpenes, polysaccharides, bee venom, and some herbs.

Inflammation and oxidative stress are two major causes of various life-threatening diseases. Hesperidin (Hsd) and its aglycone, hesperetin (Hst), are two flavonoids from citrus species that have numerous biological properties, particularly antioxidant and anti-inflammatory. New findings showed that the antioxidant activity of Hsd/Hst was not only limited to its radical scavenging activity, but it augmented the antioxidant cellular defenses via the ERK/Nrf2 signaling pathway as well. Various in vitro and in vivo studies have been conducted to evaluate Hsd, its metabolites, or its synthetic derivatives at reducing inflammatory targets including NF-κB, iNOS, and COX-2, and the markers of chronic inflammation. In this review, new findings regarding the molecular targets of Hsd and Hst in the reduction of oxidative stress are discussed. Also, in the anti-inflammatory section, we provide a summary of significant investigations concerning the mechanisms of action based on the studied inflammation models.

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel that is involved in modulation of diverse physiological processes. The role of this receptor in epilepsy has not been studied well. Therefore, we investigated the role of central TRPV1 receptors on the development of pentylenetetrazole (PTZ) and amygdala-induced kindling in rats. Male Wistar rats received subconvulsive dose of PTZ intraperitoneally, every other day. TRPV1 receptor agonist, OLDA and its antagonist, AMG-9810 were injected intracerebroventricularly 30 min prior to PTZ administration. In electrical kindling, stimulating and recording electrodes were implanted in the right amygdala of male rats. After kindling, the effect of TRPV1 receptor agonist or antagonist on afterdischarge duration (ADD), latency to the onset of bilateral forelimb clonuses (S4L) and duration of loss of equilibrium (stage 5 seizures, S5D) were measured. The results demonstrated that, OLDA at the doses of 0.01, 0.1 and 1 μg/rat, significantly accelerated the incidence of all seizure stages, increased S5D and decreased S4L in the PTZ model of kindling. Also, in amygdala kindling, S5D and ADD were significantly reduced following the administration of AMG-9810. In contrast, OLDA significantly aggravated the indices of seizure in both models of epileptic seizure. This study demonstrated that central TRPV1 receptors may be involved in the development of electrical and PTZ-induced kindling.

The purpose of this study was to assess tactile learning in the early phase of experimental autoimmune encephalomyelitis (EAE), which was induced in C57BL/6 mice by subcutaneous injections on flank of myelin oligodendrocyte glycoprotein, MOG35-55 (250 µg per mouse). Tactile learning was assessed one week after EAE induction using the novel object recognition test (NORT) in a dark room. The procedure consisted of two phases. During the training phase (T1), the animals explored two similar objects; within the test phase (T2, occurring 4 h later) the mice explored one novel and one familiar object. On average, mice developed significant behavioral disabilities related to EAE 13.2 ± 1.9 days following immunization. In the EAE group, the locomotor activity level (assessed by measuring the distance travelled) in the T1 and T2 phases did not differ significantly, as compared to the related phases in the control group (P > 0.05). Within phase T1, no reliable differences were found for the frequency (number) of visits to the sample objects and for total exploration time between experimental groups. For phase T2, no difference was also found in the discrimination ratio when comparing the control group with the EAE group. Our study demonstrates that tactile learning in male mice may not be affected 7 days after immunization with MOG35-55 (i.e., within the early EAE phase). Розвиток експериментального аутоімунного енцефаломієліту (ЕАЕ) викликали у мишей за допомогою ін’єкцій мієлінового олігодендроцитарного глікопротеїну (MOG35- 55, 250 мкг на мишу). Здатність до тактильного навчання оцінювали через один тиждень після індукції ЕАЕ, використовуючи тест впізнавання нового об’єкта (NORT) у темному приміщенні. Процедура тестування складалася з двох фаз; протягом першої з них (T1) тварини обстежували два однакових об’єкта, а в перебігу другої фази (T2) миші обстежували один новий і один раніше обстежений об’єкти. Істотні поведінкові розлади, зумовлені ЕАЕ, розвивались у мишей в середньому через 13.2 ± 1.9 доби після імунізації. У групі ЕAЕ рівень локомоторної активності (оцінюваний за відстанню, котру тварини проходили в період обстеження) в межах фаз T1 та T2 не відрізнявся істотно від такого в контрольній групі (P > 0.05). У фазі T1 не спостерігалося істотних міжгрупових різниць частоти (кількості) відвідань тест-об’єктів та загального часу, який було витрачено на ознайомлення з ними. У межах фази T2 не виявлялося також достовірних різниць величин коефіцієнта дискримінації в контрольній та ЕAЕ-групах. Отже, наші тести показали, що, видимо, тактильне навчання мишей-самцівне піддається істотним змінам через сім діб після імунізації MOG35-55 (тобто в межах ранньої фази ЕAЕ).

An efficient monitoring system for sampling, analyzing and issuing the export certificates for pistachio consignments has been established in Iran in recent years. Accordingly, 3181 commercial raw pistachio nut lots were supplied for testing for European export certification since January 2009 till December 2011. Aflatoxin analysis was carried out by high-performance liquid chromatography with fluorescence detection after immunoaffinity column clean up with recoveries ranging from 77 to 99%. Amongst 8203 sub-samples analyzed, aflatoxin B1 (AFB1) was detected in 1921 cases (23.4%) with the mean and median values of 2.18 ± 13.1 ng/g and

Stroke is a major cause of mortality and long-term disability in adults. Transient receptor potential vanilloid-1 (TRPV1) plays a crucial role in neuroinflammation. In this study, the effects of TRPV1 agonist (capsaicin) and antagonist (AMG9810) on cerebral ischemia were investigated. Forty male Wistar rats were assigned to the following experimental groups: sham, vehicle) ischemic), AMG9810 (selective TRPV1 antagonist, 0.5 mg/kg; 3 h after stroke), and capsaicin (1 mg/kg; 3 h after stroke). Stroke was induced by permanent middle cerebral artery occlusion and neurological deficits were evaluated 1, 3, and 7 days after stroke. Then, infarct volume, brain edema, body temperature, mRNA expression of TRPV1, and serum concentrations of tumor necrosis factor-alpha (TNF-α) and IL-10 were measured. Compared to the vehicle group, AMG9810 significantly decreased the infarct volume (P < 0.01). Latency for the removal of sticky labels from the forepaw and the hanging time were significantly decreased and increased, respectively, following administration of AMG9810 (P < 0.01 and P < 0.001 vs. vehicle) 3 and 7 days after stroke. Compared to the sham group, the mRNA expression of TRPV1 was significantly increased in vehicle group (P < 0.01). Administration of AMG9810 significantly increased the anti-inflammatory cytokine IL-10 and decreased the inflammatory cytokine TNF-α (P < 0.05). Moreover, our results indicate that AMG9810 might a promising candidate for the hypothermic treatment of stroke. The findings also suggest a key role for AMG9810 in reducing inflammation after stroke and imply that TRPV1 could be a potential target for the treatment of ischemic stroke.

Background The role of transient receptor potential vanilloid type 1 (TRPV1) channels in learning and memory processes has recently been recognized. In the present study, the role of this receptor in the multisensory integration process was investigated. Methods This study was done using 96 male Wistar rats, which were kept in a reverse 12–12 h dark/light cycle. Unimodal and multimodal object recognition task was performed by four variations of the spontaneous object recognition (SOR) test including standard SOR, tactile SOR, visual SOR, and cross-modal visual-tactile SOR (CMOR). AMG9810 (selective TRPV1 antagonist) was injected into the right lateral cerebral ventricle prior to sample and choice phases of SOR. A discrimination ratio was calculated to assess the preference of the animal for the novel object. Results Results demonstrated that administration of AMG9810 prior to the sample phase, as encoding phase, and prior to the choice phase, as retrieval phase, impaired discrimination between the novel and the familiar objects in all standard SOR, tactile SOR, visual SOR, and CMOR tasks (all p Conclusion The results of this study showed that TRPV1 receptors might be implicated in both unimodal and cross-modal encoding of information in rats.

Wireless internet (Wi-Fi) electromagnetic waves (2.45 GHz) have widespread usage almost everywhere, especially in our homes. Considering the recent reports about some hazardous effects of Wi-Fi signals on the nervous system, this study aimed to investigate the effect of 2.4 GHz Wi-Fi radiation on multisensory integration in rats. This experimental study was done on 80 male Wistar rats that were allocated into exposure and sham groups. Wi-Fi exposure to 2.4 GHz microwaves [in Service Set Identifier mode (23.6 dBm and 3% for power and duty cycle, respectively)] was done for 30 days (12 h/day). Cross-modal visual-tactile object recognition (CMOR) task was performed by four variations of spontaneous object recognition (SOR) test including standard SOR, tactile SOR, visual SOR, and CMOR tests. A discrimination ratio was calculated to assess the preference of animal to the novel object. The expression levels of M1 and GAT1 mRNA in the hippocampus were assessed by quantitative real-time RT-PCR. Results demonstrated that rats in Wi-Fi exposure groups could not discriminate significantly between the novel and familiar objects in any of the standard SOR, tactile SOR, visual SOR, and CMOR tests. The expression of M1 receptors increased following Wi-Fi exposure. In conclusion, results of this study showed that chronic exposure to Wi-Fi electromagnetic waves might impair both unimodal and cross-modal encoding of information.

Autophagy is a lysosomal degradation process through which long-lived and misfolded proteins and organelles are sequestered, degraded by lysosomes, and recycled. Autophagy is an essential part of cardiomyocyte homeostasis and increases the survival of cells following cellular stress and starvation. Recent studies made clear that dysregulation of autophagy in the cardiovascular system leads to heart hypertrophy and failure. In this manner, autophagy seems to be an attractive target in the new treatment of cardiovascular diseases. Although limited activation of autophagy is generally considered to be cardioprotective, excessive autophagy leads to cell death and cardiac atrophy. Natural products such as resveratrol, berberine, and curcumin that are present in our diet, can trigger autophagy via canonical (Beclin-1-dependent) and non-canonical (Beclin-1-independent) pathways. The autophagy-modifying capacity of these compounds should be taken into consideration for designing novel therapeutic agents. This review focuses on the role of autophagy in the cardioprotective effects of these compounds.

Opioids have been used as analgesics and for recreational purposes for a long time. Currently, they are the most efficacious painkillers used. However, dependence on and tolerance of their effects, especially their analgesic effect, are limiting their usage. On the other hand, the transient receptor potential vanilloid 1 (TRPV1) receptors are also involved in pain perception. Hence, the interaction of opioids and TRPV1 has been the subject of some recent studies. In this chapter, the latest findings concerning this interaction are divided into two sections: interaction in behavioral studies and interaction at the cellular level. The present review shows that the TRPV1 receptors not only interact with other addictive substances such as methamphetamine, cocaine, and ethanol but also interact with opioids both in central and peripheral nervous systems. The TRPV1 receptor also participates in opioid-induced hyperalgesia. The most important finding is the involvement of the TRPV1 receptors in opioid reward and tolerance. This implies that TRPV1 should be further considered in future pain and addiction research.

Introduction: Dimethyl sulfoxide (DMSO) is a chemical often used as a solvent for waterinsolubledrugs. In this study, we evaluated the effect of intracerebroventricular (ICV)administration of DMSO on neural response characteristics (in 1200–1500 μm depth) of the ratbarrel cortex. Methods: DMSO solution was prepared in 10% v/v concentration and injected into the lateralventricle of rats. Neuronal spontaneous activity and neuronal responses to deflection of theprincipal whisker (PW) and adjacent whisker (AW) were recorded in barrel cortex. A conditiontest ratio (CTR) was used to measure inhibitory receptive fields in barrel cortex. Results: The results showed that both PW and AW evoked ON and OFF responses, neuronalspontaneous activity and inhibitory receptive fields did not change following ICV administrationof DMSO. Conclusion: Results of this study suggest that acute ICV administration of 10% DMSO didnot modulate the electrophysiological characteristics of neurons in the l deep ayers of rat barrelcortex.

The rapid improvements in medical sciences and the ever-increasing related data, however, require novel methods of instruction. One such method, which has been given less than due attention in Iran, is problem-based learning (PBL). In this study, we aimed to evaluate the impact of study skills and the PBL methods on short and long-term retention of information provided for medical students in the course of respiratory physiology and compare it with traditional learning method. In this study, 39 medical students from Medical School of Kerman University of Medical Sciences, Kerman, Iran (2006–2010) were enrolled in the study and allocated randomly in three equal groups (13 in each group). All groups underwent a pre-test to be assessed for their basic information regarding respiratory physiology. Two groups were instructed using the traditional method, and one group used PBL. Among the two groups of the traditional method, one was instructed about study skills and the other was not. Once the PBL group took the study skill workshop, they were aided by tutors for their education. In the final term test, those students who had learned study skills and were instructed with the traditional method scored higher compared to other groups (p

Ethnopharmacological relevance Valeriana officinalis L. (valerian) root extract has been used as an antiepileptic herbal medicine in Iran. Aim of this study In the present study the effect of valerian extracts on an experimental model of temporal lobe epilepsy (TLE) was evaluated. Moreover, the involvement of adenosine system in the actions of aqueous extract of valerian was evaluated. Materials and methods Bipolar stimulating and monopolar recording electrodes were implanted stereotaxically in the right basolateral amygdala of male Sprague–Dawley rats. After kindling, the effect of aqueous (200, 500 and 800 mg/kg; intraperitoneal) and petroleum ether (PE; 50 and 100 mg/kg; intraperitoneal) extracts of valerian and CPT (selective A 1 receptor antagonist; 10 and 20 μM; intracerebroventricular) on afterdischarge duration (ADD), duration of stage 5 seizure (S5D) and latency to the onset of bilateral forelimb clonuses (S4L) were measured. The effect of CPT (10 μM) on the response of aqueous extract of valerian (500 mg/kg) was also determined. Results The results showed that aqueous extract of valerian had anticonvulsant effect. However, PE extract and CPT (20 μM) had proconvulsant effect. Administration of CPT (10 μM) before the administration of aqueous extract decreased the anticonvulsant effect of valerian. Conclusions The results showed significant anticonvulsant effect for aqueous but not PE extract of valerian. Moreover, CPT as a selective adenosine A 1 receptor antagonist decreased the anticonvulsant effect of valerian aqueous extract. Therefore, we concluded that part of anticonvulsant effect of valerian probably is mediated through activation of adenosine system.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists have been found to have potent anti-inflammatory actions and suggested as potential therapies for brain ischaemia. Glutamate is the most common excitatory neurotransmitter in the central nervous system and is released excessively during ischaemia. Stroke therapy will require combinations of drug classes, because no single drug class has yet been proven efficacious in human beings. The present study was conducted to assess whether N-methyl-d-aspartate (NMDA) receptor antagonist (MK-801) treatment can improve recovery from ischaemic brain injury and whether rosiglitazone, a PPAR-gamma ligand, can increase its neuroprotective effect in an embolic model of stroke. Stroke was induced in rats by embolizing a preformed clot into the middle cerebral artery. Rosiglitazone (0.1 mg/kg, intraperitoneally) and MK-801 (0.1 mg/kg, intravenously) were injected immediately after embolization. Forty-eight hours later, the brains were removed, sectioned and stained with triphenyltetrazolum chloride and analysed by a commercial image processing software programme. Rosiglitazone and MK-801 alone or in combination decreased infarct volume by 49.16%, 50.26% and 81.32%, respectively (P < 0.001). Moreover, the combination therapy significantly decreased the infarct volume when compared to any drug used alone (P < 0.05). MK-801 reduced the brain oedema by 68% compared to the control group (P < 0.05), but rosiglitazone or combination did not show any significant effect. The drugs alone or in combination also demonstrated improved neurological function, but combination therapy was more effective on neurological deficits improving. Our data show that the combination of MK-801 and rosiglitazone is more neuroprotective in thromboembolic stroke than given alone; this effect perhaps represents a possible additive effect in the brain infarction.

The anti-cancer properties of liquorice have been attributed, at least in part, to glycyrrhizin (GL). However, GL is not directly absorbed through the gastrointestinal tract. It is hydrolyzed to 18-β-glycyrrhetinic acid (GA), the pharmacologically active metabolite, by human intestinal microflora. GA exhibits remarkable cytotoxic and anti-tumor properties. The pro-apoptotic targets and mechanisms of action of GA have been extensively studied over the past decade. In addition, GA is an inexpensive and available triterpene with functional groups (COOH and OH) in its structure, which make it an attractive lead compound for medicinal chemists to prepare a large number of analogues. To date, more than 400 cytotoxic derivatives have been prepared on the basis of GA scaffold, including 128 cytotoxic derivatives with IC50 values less than 30 µM. Researchers have also succeeded in synthesizing very potent cytotoxic derivatives with IC50s ≤ 1 µM. Studies have shown that the introduction of a double bound at the C1-C2 position combined with an electronegative functional group, such as CN, CF3 or iodine at C2 position, and the oxidation of the hydroxyl group of C3 to the carbonyl group, significantly increased cytotoxicity. This review describes the cytotoxic and anti-tumor properties of GA and its derivatives, targets and mechanisms of action and provides insight into the structure-activity relationship of GA derivatives.

Animal models of learning and memory have been the subject of considerable research. Rodents such as mice and rats are nocturnal animals with poor vision, and their survival depends on their sense of touch. Recent reports have shown that whisker somatosensation is the main channel through which rodents collect and process environmental information. This review describes tactile learning in rodents from a neurobiological and neuropharmacological perspective, and how this is involved in memory-related processes.

Many plants produce flavonoids as secondary metabolites. These organic compounds may be involved in the defense against plant-threatening factors, such as microbes and toxins. Certain flavonoids protect their origin source against plant pathogens, but they also exhibit potential healthy properties in human organisms. Hesperidin (Hsd) and its aglycone, hesperetin (Hst), are two flavonoids from the Citrus species that exhibit various biological properties, including antioxidant, antiinflammatory and anticancer effects. Recent studies indicated that Hst and Hsd possess antimicrobial activity. Although the exact mechanisms behind their antimicrobial properties are not fully understood, several mechanisms such as the activation of the host immune system, bacterial membrane disruption, and interference with microbial enzymes, have been proposed. Hsd and Hst may also have protective effects against toxicity induced by various agents. These natural substances may contribute to the protection of cells and tissues through their antioxidant and radical scavenging activities. This review discusses the protective activities of Hsd and Hst against microbes and several toxicities induced by oxidants, chemicals, toxins, chemotherapy and radiotherapy agents, which were reported in vitro and in vivo. Furthermore, the probable mechanisms behind these activities are discussed.

Background: Stroke is a major cause of mortality and long term disability in adults. TRPV1 has a pivotal role in neuroinflammation. Among TLRs, TLR2 significantly participate in induction of inflammation in brain. In this study, the effect of TRPV1 receptor agonist and antagonist on outcome and gene expression of TLR2 in a rat model of permanent middle cerebral artery occlusion (MCAO) was investigated.Methods: Forty male rats were assigned to the following groups: sham, vehicle )stroke), AMG9810 (selective TRPV1 antagonist, 0.5 mg/kg; 3 h after stroke), and capsaicin (1 mg/kg; 3 h after stroke). Stroke was induced by permanent middle cerebral artery occlusion and behavioral functions were assessed 1, 3, and 7 days after stroke. Infarct volume, brain edema and mRNA expression of TLR2 were also evaluated at the end of the study.Results: While stroke animals showed infarctions and behavioral functions, we did not observe any cerebral infarction and behavioral functions in sham-operated animals. AMG9810 decreased neurological deficits 7 days after cerebral ischemia (P

Objective To determine whether suboptimal management in hospital could contribute to poor outcome in children admitted with meningococcal disease.

Inflammation and oxidative stress are two major causes of various life-threatening diseases. Hesperidin (Hsd) and its aglycone, hesperetin (Hst), are two flavonoids from citrus species that have numerous biological properties, particularly antioxidant and anti-inflammatory. New findings showed that the antioxidant activity of Hsd/Hst was not only limited to its radical scavenging activity, but it augmented the antioxidant cellular defenses via the ERK/Nrf2 signaling pathway as well. Various in vitro and in vivo studies have been conducted to evaluate Hsd, its metabolites, or its synthetic derivatives at reducing inflammatory targets including NF-κB, iNOS, and COX-2, and the markers of chronic inflammation. In this review, new findings regarding the molecular targets of Hsd and Hst in the reduction of oxidative stress are discussed. Also, in the anti-inflammatory section, we provide a summary of significant investigations concerning the mechanisms of action based on the studied inflammation models.

ObjectivesDopamine receptor-mediated 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent intracellular signalling is important for reward-related learning. cAMP activates cAMP-dependent protein kinase (PKA) and exchange protein directly activated by cAMP (Epac). We tested the hypothesis that reward-related learning may be mediated by Epac.MethodsWe evaluated conditioned place preference (CPP) on the basis of nucleus accumbens (NAc) injections of amphetamine (20 μg/0.5 μl/side) plus Sp-adenosine 3′,5′-cyclic monophosphorothioate triethylamanine (Sp-cAMPS) (0.1, 1.0, 10, 15, 20 μg/0.5 μl/side), an activator of both PKA and Epac, or amphetamine (20 μg) plus 8-(4-chlorophenylthio)-2′-O-methyladenosine-3′,5′-cyclic monophosphate (8-pCPT) (0.73, 1.27, 1.45, 2.89, 5.78, 11.56 μg/0.5 μl/side), an activator of Epac.ResultsIn agreement with previous results, Sp-cAMPS dose-dependently impaired CPP. 8-pCPT impaired CPP at one dose (1.45 μg/0.5 μl/side) and we replicated this effect three times.ConclusionThe results implicate Epac in the acquisition of reward-related learning.