Preemptive administration of mesenchymal stem cells-derived conditioned medium can attenuate the development of neuropathic pain in rats via downregulation of proinflammatory cytokines.

Neuropathic pain (NP) is a chronic condition characterized by persistent pain following nerve injury. It is a challenging clinical problem to manage due to limited treatment options. Mesenchymal stem cells (MSCs)-derived conditioned medium (CM) is a cell-free product that contains the secretome of MSCs and has been shown to have therapeutic potential in various inflammatory and degenerative disorders. Several animal studies have examined the antinociceptive effects of MSCs-CM on established neuropathic pain, but none have investigated the early prevention of neuropathic pain using MSCs-CM. Therefore, in this study, we tested whether preemptive administration of MSCs-CM could attenuate the development of NP in rats. To this end, NP was induced in Wistar rats using a chronic constriction injury (CCI) model (day 0), and then the animals were divided into four groups: Sham, CCI, CCI-Dulbecco's Modified Eagle Medium (DMEM), and CCI-CM. The CCI-CM group received 1 ml intraperitoneal administration of MSCs-CM on days - 1, 1, and 2, while the Sham, CCI, and CCI-DMEM groups received vehicle only (normal saline or DMEM). Mechanical withdrawal threshold and thermal withdrawal latency were assessed to evaluate pain sensitivities. In addition, the expression levels of proinflammatory cytokines (TNF-α and IL-1ß) in the spinal cord tissues were measured using quantitative real-time PCR (qRT-PCR). The results demonstrated that preemptive treatment with MSCs-CM can significantly attenuate the development of NP, as evidenced by improved mechanical withdrawal threshold and thermal withdrawal latency in the CCI-CM group compared to the CCI and CCI-DMEM groups. Furthermore, the relative gene expression of proinflammatory cytokines TNF-α and IL-1ß were significantly decreased in the spinal cord tissues of the CCI-CM group compared to the control groups. These findings suggest that preemptive administration of MSCs-CM can attenuate the development of NP in rats, partly due to the downregulation of proinflammatory cytokines.

Synbiotic supplement for treatment of iron deficiency anaemia in haemodialysis patients: A randomized controlled trial.

BACKGROUND: There is evidence that probiotics can increase the availability of iron. The aim of current study was to determine the effects of synbiotic supplementation on the haematological parameters and anaemia in haemodialysis patients. METHODS: This study was a randomized, double-blind, placebo-controlled trial. Fifty patients were randomly selected from the haemodialysis section of Vaseii Hospital, Sabzevar, Iran. Subjects in the symbiotic and control groups received 2 capsules of synbiotic supplement or placebo, respectively, once a day for 8 weeks. Blood samples were divided into two test tubes in equal volumes. Blood haemoglobin, haematocrit, transferrin saturation, red blood cells (RBCs), and total iron binding capacity (TIBC) were measured with auto-analyser. Ferritin was determined using Sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: Twenty tree patients in each group completed the study. Significant results were recorded in synbiotic groups regarding the concentration of blood haemoglobin, haematocrit, transferrin saturation, the number of RBCs, and serum ferritin compare to placebo group (P < .05). At the end of week 8, TIBC significantly decreased in synbiotic than placebo group (P < .05). CONCLUSION: Synbiotic supplementation could be a safe and promising candidate in improving anaemia in CKD patients.

The Role of 5-HT1A Receptors and Neuronal Nitric Oxide Synthase in a Seizur Induced Kindling Model in Rats.

BACKGROUND AND OBJECTIVE: Dentate gyrus (DG) has a high density of 5-HT1A receptors. It has neural nitric oxide synthase (nNOS), which is involved in neural excitability. The purpose of this study was to investigate the role of 5-HT1A receptors and nNOS of DG in perforant path kindling model of epilepsy. MATERIAL AND METHODS: To achieve this purpose, a receptor antagonist (WAY100635, 0.1 mg/kg, intracerebroventricular, i.c.v) and neuronal nitric oxide synthase inhibitor (7-NI, 15 mg/kg, intraperitoneal, i.p.) were injected during kindling aquisition. Adult male Wistar rats (280 ± 20 g) were used in this study Animals were kindled through the daily administration of brief electrical stimulations (10 stimulations per day) to the perforant pathway. Field potential recordings were performed for 20 min in DG beforehand. Additionally, glial fibrillary acidic protein (GFAP) expression rate in the DG was determined using immunohistochemistry as a highly specific marker for glia. RESULTS: WAY100635 (0.1 mg/kg) significantly attenuated the kindling threshold compared to the kindled + vehicle group (P < 0.001). The co-administration of WAY100635 with 7-NI, exerted a significant anticonvulsive effect. Furthermore, the slope of field Excitatory Post Synaptic Potentials (fEPSP) at the end of 10 days in the kindled + 7-NI + WAY100635 group was significantly lower than in the kindled + vehicle group (P < 0.001). Furthermore, immunohistochemistry showed that the density of GAFP+ cells in the kindled + 7-NI + WAY100635 group was significantly higher than in the kindled + vehicle group (P < 0.001). CONCLUSION: Our data demonstrate that antagonists of 5-HT1A receptors have proconvulsive effects and that astrocyte cells are involved in this process, while nNOS has an inhibitory effect on neuronal excitability.

Antinociceptive effect of N-acetyl glucosamine in a rat model of neuropathic pain.

OBJECTIVE: This study was aimed at evaluating the efficacy of glucosamine and potential mechanisms of actions in a neuropathic pain model in rats. METHODS: Glucosamine (500, 1000 and 2000 mg/kg) was administered via gavage route, 1 day before the chronic constriction injury (CCI) of sciatic nerve and daily for 14 days (prophylactic regimen), or from days 5 to 14 post-injury (therapeutic regimen), as the indicators of neuropathic pain, mechanical allodynia, cold allodynia and thermal hyperalgesia were assessed on days 0, 3, 5, 7, 10 and 14 after ligation. Inducible nitric oxide synthase (iNOS) and tumour necrosis factor alpha (TNF-α) gene expressions were measured by real-time polymerase chain reaction. TNF-α protein content was measured using the enzyme-linked immunosorbent assay method. RESULTS: Three days after nerve injury, the threshold of pain was declined among animals subjected to neuropathic pain. Mechanical and cold allodynia, as well as thermal hyperalgesia were attenuated by glucosamine (500, 1000, 2000 mg/kg) in the prophylactic regimen. However, existing pain was not decreased by this drug. Increased mRNA expression of iNOS and TNF-α was significantly reduced in the spinal cord of CCI animals by glucosamine (500, 1000, 2000 mg/kg) in the prophylactic regimen. The overall expression of spinal TNF-α was increased by CCI, but this increase was reduced in animals receiving glucosamine prophylactic treatment. CONCLUSION: Findings suggest that glucosamine as a safe supplement may be a useful candidate in preventing neuropathic pain following nerve injury. Antioxidant and anti-inflammatory effects may be at least in part responsible for the antinociceptive effects of this drug.

Increased Targeting Area in Tumors by Dual-Ligand Modification of Liposomes with RGD and TAT Peptides.

Modification with polyethylene glycol (PEGylation) and the use of rigid phospholipids drastically improve the pharmacokinetics of chemotherapeutics and result in more manageable or reduced side-effects. A major drawback is retarded cellular delivery of content, which, along with tumor heterogeneity, are the two main obstacles against tumor targeting. To enhance cellular delivery and reach a bigger area of a tumor, we designed liposomes decorated with two ligands: one for targeting tumor vasculature via a cyclic-pentapeptide containing arginine-glycine-aspartic acid (RGD), which impacts tumor independent of passive accumulation inside tumors, and one for extravascular targeting of tumor cells via a cell-penetrating peptide derived from human immunodeficiency virus type 1 transactivator of transcription (TAT). Liposomes with different ligand combinations were prepared and compared with respect to performance in targeting. Intravital imaging illustrates the heterogeneous behavior of RGD-liposomes in both intravascular and extravascular distribution, whereas TAT-liposomes exhibit a predictable extravascular localization but no intravascular targeting. Dual-ligand modification results in enhanced vascular targeting and a predictable extravascular behavior that improves the therapeutic efficacy of doxorubicin-loaded liposomes but also an augmented clearance rate of liposomes. However, the dual-modified liposome could be a great candidate for targeted delivery of non-toxic payloads or contrast agents for therapeutic or diagnostic purposes. Here we show that the combination of vascular-specific and tumor cell-specific ligands in a liposomal system is beneficial in bypassing the heterogeneous expression of tumor-specific markers.

The cytotoxicity and apoptotic effects of verbascoside on breast cancer 4T1 cell line.

BACKGROUND: Despite significant advancements in breast cancer therapy, novel drugs with lower side effects are still being demanded. In this regard, we investigated the anti-cancer features of verbascoside in 4 T1 mouse mammary tumor cell. METHODS: First, MTT assay was performed with various concentrations (ranging between 5 to 200 µM) of verbascoside and IC50 was calculated. Then the expression of Bax, Bcl-2, and caspase-3 was evaluated in treated 4 T1 cells. In addition, we investigated the expression of TLR4, MyD88, and NF-κB to ascertain the underlying mechanism of the anti-proliferative feature of verbascoside. Also, flow cytometry followed by double PI and Annexin V was conducted to confirm the apoptosis-inducing effect of verbascoside. RESULTS: Our results from MTT assay showed verbascoside inhibits proliferation of 4 T1 cancer cells (IC50 117 µM) while is safe for normal HEK293T cells. By qRT-PCR, we observed that verbascoside treatment (100, 117 and, 130 µM) increases the expression of caspase-3 and Bax while reduces the expression of Bcl-2. Also, verbascoside (100, 117 and, 130 µM) increased the expression of TLR4 only at 130 µM dose and the expression of MyD88 whereas reduced the expression of NF-κB at mRNA level. Flow cytometry analysis also confirmed verbascoside induces apoptosis in 4 T1 cells at 117 µM. CONCLUSION: Taken together, our data showed verbascoside is a safe natural compound for normal cells while has apoptosis-inducing feature through TLR4 axis on 4 T1 cells.

A review on the role of tau and stathmin in gastric cancer metastasis.

Gastric cancer is resistant to chemotherapy, especially in the later stages. The prevalence of gastric cancer increases after the age of 40, and its peak is in the 7th decade of life. The proteins tau (tubulin associated unit) and stathmin are overexpressed in gastric cancer and contribute to the progression of the disease by increasing cancer cell proliferation, invasion, and inducing drug resistance. This review summarizes the current knowledge on the expression of tau protein and stathmin in gastric cancer and their roles in drug resistance. Medline and PubMed databases were searched from 1990 till February 2021 for the terms "tau protein", "stathmin", and "gastric cancer." Two reviewers screened all articles and assessed prognostic studies on the role of tau and stathmin proteins in gastric cancer progression. Collectively, studies reported that both proteins are expressed at different concentrations in gastric cancer and could be significant molecular biomarkers for prognosis. Both proteins could be good candidates for targeted therapy of gastric cancer and are associated with resistance to taxanes.

Clavulanic Acid Attenuating Effect on the Diabetic Neuropathic Pain in Rats.

Diabetic neuropathy is one of the most common complications of diabetes mellitus. Excess glutamate release and oxidative stress are hypothesized to be involved in the pathophysiology of diabetes-induced neuropathy. This study was designed to investigate the effect of clavulanic acid (CLAV), a competitive beta-lactamase inhibitor, on the streptozocin (STZ)-induced neuropathic pain and possible mechanisms in the spinal cord of rats. Male Wistar rats were divided into naive group; control group which got a single dose of STZ (50 mg/kg, i.p.), as a model of diabetic neuropathic pain; prophylactic groups: animals received CLAV (10, 20 and 40 mg/kg, i.p.) 1 week after STZ for 10 days; and therapeutic group: animals received 20 mg/kg CLAV, 21 days after STZ for 10 days. Study of pain behaviors was started on days 0, 7, 14, 21, 28, 35 and 42 after STZ. The expression of the glutamate transport 1 (GLT1), genes of oxidative stress including inducible nitric oxide synthase (iNOS), proinflammatory cytokine, tumor necrosis factor alpha (TNF-α), as well as genes involved in the apoptosis including bcl2, bcl2-associated x (bax) were measured in the spinal cord tissue by Real Time PCR, on day 42. On day 21 post injection of STZ, diabetic animals showed significant mechanical allodynia, cold allodynia and thermal hyperalgesia. CLAV in all doses of 10, 20 and 40 mg/kg reduced symptoms of allodynia and hyperalgesia, in both prophylactic and therapeutic regimens. While iNOS, TNF-α, bax/bcl2 were found significantly overexpressed in spinal cord of diabetic animals, their expression in animals received CLAV had been reduced. In contrast, GLT1 that had decreased in the spinal cord of diabetic animals, significantly increased in those received CLAV. CLAV was found a promising candidate for reliving neuropathic pain in diabetes mellitus. Such beneficial effect of CLAV could be, in part, attributed to the increased expression of GLT 1, inhibition of nitrosative stress, anti-inflammation, and inhibition of some apoptotic mediators followed by administration into diabetic animals.

Local Usage of Nigella sativa Oil as an Innovative Method to Attenuate Primary Dysmenorrhea: A Randomized Double-blind Clinical Trial.

OBJECTIVES: We sought to determine the effect of topical application of Nigella sativa (black seed) oil, on the primary dysmenorrhea intensity. METHODS: We conducted a randomized, double-blind clinical trial on 124 female students, 18-22 years old, living in the dormitories of Sabzevar Universities. After a primary assessment, participants were randomly divided into two groups. The first group rubbed two drops of N. sativa oil, and the second group rubbed liquid olive oil, as the placebo. Massage was performed on the fontanel lobe 3, at night, three days before menstruation, for eight consecutive days (about five days after menses). This procedure was repeated for three menstrual cycles. After three cycles, pain severity was measured by the visual analog scale. Data analysis was carried out using the Mann-Whitney U test and analysis of covariance (ANCOVA). RESULTS: This study was conducted on 124 female students. The mean age of students, mean age of first menarche, body mass index, and pain severity were not significantly different in the two groups (p > 0.050). No adverse effects were observed during the study. The results of ANCOVA showed that pain intensity in N. sativa oil group was significantly decreased compared to that of the placebo group (0.6 score; p < 0.050). CONCLUSIONS: N. sativa could be a promising, safe, and easily available analgesic supplement in women suffering from primary dysmenorrhea.

Clavulanic acid improves ethanol withdrawal symptoms in rats.

OBJECTIVES: Ethanol withdrawal following chronic use, is an important challenge clinically. In this study, the effect of clavulanic acid was evaluated on the symptoms of ethanol withdrawal in rats. MATERIALS AND METHODS: Alcohol dependence was induced by the gavage of ethanol (10% v/v, 2 g/kg), twice daily for 10 days. Clavulanic acid (10, 20, 40, and 80 mg/kg) was administered concurrently with ethanol (sub-acute study), or a single dose after ethanol withdrawal (acute study). Six hours after the last dose of ethanol, anxiety was assessed by the elevated plus-maze (EPM). Seizure-like behavior was evaluated by a sub-convulsive dose of pentylenetetrazol (PTZ, 25 mg/kg/IP). Locomotor activity and motor coordination were measured by the open field and rotarod tests, respectively. Lipid peroxidation marker and antioxidant content were assessed through measuring malondialdehyde (MDA) and glutathione (GSH), respectively. RESULTS: The number of entries and time spent on the open arms of EPM decreased during the withdrawal state. Motor coordination and locomotor activity were significantly decreased. In the sub-acute study, clavulanic acid 80 mg/kg increased time spent and the number of entries to the open arms of EPM, in withdrawn animals. Both motor incoordination and locomotor activity reduction were normalized by clavulanic acid (10, 20, 40 and 80 mg/kg). Withdrawal-induced PTZ kindling seizure was also suppressed by all of the doses. MDA increased, while GSH decreased after withdrawal. Clavulanic acid attenuated such changes. CONCLUSION: Clavulanic acid could prevent the development of alcohol withdrawal-induced anxiety and seizure. Alcohol withdrawal causes oxidative stress which can be prevented by clavulanic acid.

Neuroprotective effects of clavulanic acid following permanent bilateral common carotid artery occlusion in rats.

We investigated whether clavulanic acid could improve learning and memory, in rats underwent bilateral occlusion of common carotid artery (2VO). Seventy male Wistar rats were subjected to 2VO, with a 1-week interval between right and left artery occlusions. After 2VO, animals received clavulanic acid (10, 20, 40 mg/kg, intraperitoneally), from day 8 to 20. Spatial memory was assessed in the Morris water maze, 1 week after the induction of 2VO (day 15). The mRNA expression levels of bcl-2, bcl2-associated x protein (bax), caspase-3, inducible nitric oxide synthase (iNOS), and amyloid beta precursor protein (APP) were measured in the neocortex and hippocampus. Clavulanic acid significantly decreased the escape latency and swimming time in the training trial days. As well, it increased time and distance percentage in the target quadrant, while it decreased such factors in the opposite quadrant in the final trial day, compared to 2VO + normal saline animals. Real time-PCR data showed a significant higher mRNA expression of bax, caspase 3, and iNOS in the hippocampus and neocortex of 2VO animal compared to nonoccluded rats. APP increased in the neocortex but not hippocampus. Compared with 2VO animals, clavulanic acid significantly down-regulated the expression of iNOS, caspase 3, and APP, accompanied by diminishing the bax/bcl2 ratio. Our results reveal a potential therapeutic use of clavulanic acid for cognitive dysfunction associated with cerebral hypoperfusion in vascular dementia and Alzheimer disease.

Ultrasensitive and Highly Selective Ni3Te2 as a Nonenzymatic Glucose Sensor at Extremely Low Working Potential.

Developing Nonenzymatic glucose biosensors has recently been at the center of attention owing to their potential application in implantable and continuous glucose monitoring systems. In this article, nickel telluride nanostructure with the generic formula of Ni3Te2 has been reported as a highly efficient electrocatalyst for glucose oxidation, functional at a low operating potential. Ni3Te2 nanostructures were prepared by two synthesis methods, direct electrodeposition on the electrode and hydrothermal method. The electrodeposited Ni3Te2 exhibited a wide linear range of response corresponding to glucose oxidation exhibiting a high sensitivity of 41.615 mA cm-2 mM-1 and a low limit of detection (LOD) of 0.43 µM. The hydrothermally synthesized Ni3Te2, on the other hand, also exhibits an ultrahigh sensitivity of 35.213 mA cm-2 mM-1 and an LOD of 0.38 µM. The observation of high efficiency for glucose oxidation for both Ni3Te2 electrodes irrespective of the synthesis method further confirms the enhanced intrinsic property of the material toward glucose oxidation. In addition to high sensitivity and low LOD, Ni3Te2 electrocatalyst also has good selectivity and long-term stability in a 0.1 M KOH solution. Since it is operative at a low applied potential of 0.35 V vs Ag|AgCl, interference from other electrochemically active species is reduced, thus increasing the accuracy of this sensor.

Assessment of anti-nociceptive effect of allopurinol in a neuropathic pain model.

BACKGROUND: This study aimed to investigate the antinociceptive effect of allopurinol, a xanthine oxidase inhibitor, in the chronic constriction injury (CCI) to sciatic nerve rat model of neuropathic pain. METHODS: Allopurinol administration (30, 60, 90 mg/kg, i.p.) was started at the time of nerve injury, and given for 14 continuous days. Behavioural tests (von Frey filaments, acetone drop, hot plate) were conducted on days 0, 3, 7, 10 and 14. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis was performed on the spinal cord of CCI animals on day 14. The contribution of adenosine (A) receptors was tested using the methylxanthine theophylline, a non-selective A receptor antagonist and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a selective A1 receptor antagonist, administered 30 min before allopurinol on day 10. RESULTS: CCI of the sciatic nerve resulted in a persistent mechanical allodynia, cold allodynia, and heat hyperalgesia, together with increased iNOS, bax/bcl2, iba-1 and TNF-α expression in the lumbar spinal cord of animals. The highest-dose group of allopurinol (90 mg/kg) attenuated pain-like behaviors compared with the normal saline treated group, and this was accompanied by normalization of iNOS, bax/bcl2, caspase 3, iba-1 and TNF-α gene expression changes. DPCPX and theophylline reversed the thermal anti-hyperalgesic effect of allopurinol. In contrast, the mechanical anti-allodynic effect was only prevented by theophylline. CONCLUSION: Allopurinol through interacting with different aspects of neuropathic pain, via anti-oxidant effects, protection against neuroinflammation, and activating adenosine receptors, could be useful in the treatment of patients with neuropathic pain.

Effects of glucosamine against morphine-induced antinociceptive tolerance and dependence in mice.

BACKGROUND: The most important limitations of morphine in pain therapy are its tolerance and dependence. In this study, we evaluated the protective effect of glucosamine against morphine-induced tolerance and dependence in mice. METHODS: Mice received twice daily morphine (20 mg/kg, s.c.) alone, or along with orally administered glucosamine (500, 1000 and 2000 mg/kg), for 9 continuous days. To assess antinociceptive effect of morphine, percentage of maximal possible effect (%MPE) of animals exposed to thermal stimulus was measured in the hot plate test, 30 min after morphine administration. Test was performed on days 1, 3, 5, 7 and 9. The effect of glucosamine on the naloxone (5 mg/kg, i.p.)-precipitated morphine withdrawal, was also evaluated. Changes in brain gene expression levels of induced nitric oxide synthase (iNOS), enzyme responsible for nitric oxide generation, as well as pro-inflammatory mediator, tumor necrosis alpha (TNF-α) were measured in morphine tolerated animals, as well as after withdrawal by real-time polymerase chain reaction (RT-PCR). Protein content of TNF-α was evaluated via ELISA assay. RESULTS: Tolerance to antinociceptive effect of morphine was developed after 7 days of morphine treatment. The concurrent administration of glucosamine (500, 1000 and 2000 mg/kg) with morphine, significantly inhibited tolerance development, on days 7 and 9. In addition, glucosamine ameliorated the naloxone-precipitated opioid withdrawal symptoms (tremor, jumping, teeth chattering, grooming). However, diarrhea was significantly improved only with the dose of 500 mg/kg. Increased mRNA expression of iNOS as well as TNF-α mRNA expression and protein, after both morphine tolerance and withdrawal, were considerably reduced by glucosamine (1000 mg/kg) in the morphine withdrawal animals. CONCLUSION: These data support the utility of glucosamine in attenuating both tolerance to nociceptive effects of morphine as well as withdrawal-induced behavioral profile. Anti-oxidant and anti-inflammatory effects are responsible, at least in part, for the protective effects of this drug.

Facile one-pot synthesis of NiCo2Se4-rGO on Ni foam for high performance hybrid supercapacitors.

A facile, innovative synthesis for the fabrication of NiCo2Se4-rGO on a Ni foam nanocomposite via a simple hydrothermal reaction is proposed. The as-prepared NiCo2Se4-rGO@Ni foam electrode was tested through pxrd, TEM, SEM, and EDS to characterize the morphology and the purity of the material. The bimetallic electrode exhibited outstanding electrochemical performance with a high specific capacitance of 2038.55 F g-1 at 1 A g-1. NiCo2Se4-rGO@Ni foam exhibits an extensive cycling stability after 1000 cycles by retaining 90% of its initial capacity. A superior energy density of 67.01 W h kg-1 along with a high power density of 903.61 W kg-1 further proved the high performance of this electrode towards hybrid supercapacitors. The excellent electrochemical performance of NiCo2Se4-rGO@Ni foam can be explained through the high electrocatalytic activity of NiCo2Se4 in combination with reduced graphene oxide which increases conductivity and surface area of the electrode. This study proved that NiCo2Se4-rGO@Ni foam can be utilized as a high energy density-high power density electrode in energy storage applications.

Involvement of Endogenous Opioid System in Swim Stress-Induced Pain Modulation During the Interphase of the Formalin Test.

INTRODUCTION: Some evidence demonstrates endogenous inhibitory pathways of pain involved in the interphase (phase between early and later phase) of the formalin test. We previously showed that swimming stress modulates the pain-related behaviors during the interphase of the formalin test. In this study, we evaluated the role of the endogenous opioid system in modulating nociceptive responses of the formalin test. METHODS: Swim stress was performed in different heights of water (5, 25, 50 cm) in a swimming tank. The mean nociceptive scores were measured during phase 1 (1-7 min), interphase (8-14 min), and phase 2 (15-90 min) of the formalin test. Opioid receptor antagonist, naloxone (3 mg/kg; IP) was injected immediately before swim stress. RESULTS: Swim stress attenuated nociceptive behaviors in the first phase and increased the duration of interphase in the formalin test in a water-height-dependent manner, compared to the control group. Naloxone significantly increased nociceptive behaviors in the first phase, interphase, and the second phase of the formalin test, compared to the control group. CONCLUSION: Stress could affect the nociceptive response. Swim stress in different heights of water could have different effects on the nociception in different phases of the formalin test. In addition, the involvement of the endogenous opioid system is further demonstrated in the swim stress-induced modulation of pain behaviors in phase 1, phase 2, as well as interphase of formalin test in rats.

Upregulation of Glutamate Transporter 1 by Clavulanic Acid Administration and Attenuation of Allodynia and Hyperalgesia in Neuropathic Rats.

INTRODUCTION: Clavulanic acid (CLAV) is structurally similar to ceftriaxone, a potent stimulator of glial GlutamateTransporter-1 (GLT-1) expression. The present study aims at exploring the anti-nociceptive effects of CLAV, a beta-lactamase inhibitor in rats underwent sciatic nerve Chronic Constriction Injury (CCI). METHODS: CLAV (12.5, 25, 50 mg/kg) was administered intraperitoneally after the surgery for 14 consecutive days. Behavioral pain parameters were evaluated before and 3, 5, 7, 10 and 14 days after injury. Spinal GLT-1 level was measured via western blotting at days 7 and 14. RESULTS: CCI led to mechanical allodynia, cold allodynia and thermal hyperalgesia which started on postoperative days 3 and continued until the end of study. We found that CLAV (12.5 and 25 mg/kg) significantly attenuated all pain related behaviors as compared to the CCI animals treated with normal saline. Protein level of GLT-1 was down-regulated on day 14 following CCI and this phenomenon was reversed by fourteen days treatment of CLAV at the low doses of 12.5 and 25 mg/kg. CONCLUSION: These results suggest that CLAV might provide a new therapeutic strategy for neuropathic pain and its effect might be partially associated with the up-regulation of GLT-1.

A non-enzymatic glucose sensor based on a CoNi2Se4/rGO nanocomposite with ultrahigh sensitivity at low working potential.

Uniform and porous CoNi2Se4 was successfully synthesized by electrodeposition onto a composite electrode comprising reduced graphene oxide (rGO) anchored on a Ni foam substrate (prepared hydrothermally). This CoNi2Se4-rGO@NF composite electrode has been employed as an electrocatalyst for the direct oxidation of glucose, thereby acting as a high-performance non-enzymatic glucose sensor. Direct electrochemical measurement with the as-prepared electrode in 0.1 M NaOH revealed that the CoNi2Se4-rGO nanocomposite has excellent electrocatalytic activity towards glucose oxidation in an alkaline medium with a sensitivity of 18.89 mA mM-1 cm-2 and a wide linear response from 1 µM to 4.0 mM at a low applied potential of +0.35 V vs. Ag|AgCl. This study also highlights the effect of decreasing the anion electronegativity on enhancing the electrocatalytic efficiency by lowering the potential needed for glucose oxidation. The catalyst composite also exhibits high selectivity towards glucose oxidation in the presence of several interferents normally found in physiological blood samples. A low glucose detection limit of 0.65 µM and long-term stability along with a short response time of approximately 4 seconds highlights the promising performance of the CoNi2Se4-rGO@NF electrode for non-enzymatic glucose sensing with high precision and reliability.

The role of serotonin and its receptors on the anticonvulsant effect of curcumin in pentylenetetrazol-induced seizures.

AIM: Curcumin, derived from turmeric, has been demonstrated to be effective in controlling seizures, although the exact mechanism is yet unknown. In this study, the role of serotonin and its receptors in the anticonvulsant effect of curcumin was evaluated in mice. MAIN METHODS: Total 110 mice were randomly divided into 11 groups (n = 10). In the first to the fourth groups, the role of curcumin (150 mg/kg, i.p) and serotonin (PCPA (100 mg/kg); was used to deplete the brain serotonin levels) was investigated. The fifth group first received NAD-299 (4 mg/kg, sc), RS-102221 (5 mg/kg, i.p), SDZ205-557 Hydrochloride (1 mg/kg, i.p), and SB 26997 (10 mg/kg, i.p), then curcumin. The sixth group received NAD-299, curcumin. The animals in the seventh to ninth groups received 5-HT2C, 5-HT4, and 5-HT7 antagonists, respectively, with curcumin. The tenth group received HTR2C antagonist and the eleventh group received HTR4 antagonist. In all animals 25 min after curcumin PTZ (80 mg/kg; i.p) was injected. KEY FINDINGS: PCPA not only inhibited the anticonvulsant action of curcumin, but also reversed some of its anticonvulsant effect. The 5-HT1A, 5-HT2C and 5-HT4 antagonists diminished but 5-HT7 antagonist strengthened the anticonvulsant effect of curcumin. Evaluation of gene expression using real-time PCR confirmed that only 5-HT7 gene expression was reduced after curcumin injection. SIGNIFICANCE: According to these results, it may be suggested that curcumin exerts anticonvulsive effects by increasing the serotonin levels in the brain that influence receptors, including 5-HT1A, 5-HT2C, and 5-HT4 and likely through the reduction of 5-HT7 gene expression.