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Background and Objective: Oxidative stress is known as the one of the causes of neuropathic pain, reactive oxygen species (ROS) has been reported to be involved in this process. Coenzyme Q10 acts as an antioxidant and is able to reduce resulting oxidative damage. This study was done to determine the effect of Coenzyme Q10 on neuropathic pain in CCI (Chronic Crash Injury) rat model. Materials and Methods: In this experimental study 30 male rats (200-250g) randomizely allocated into 3 groups each 10 rat including CCI, CCI + CoQ10 and CCI + vehicle. Neuropathic pain, was induced by Chronic Crash Injury (CCI) model for sciatic nerve. IP injection of CoQ10 (200 mg/kg) or vehicle was done daily for 10 days. Behavioral tests were done before and after surgery on day 5 and 10 respectively. Paw withdrawal threshold was assessed by Randall Selitto test, Analgesy Metter and Von Frey filaments. Data was analyzed by SPSS-14, Independent T and Mean-whatney tests. Results: Induction of nerve injury decreased pain threshold (P

Introduction: Spinal cord injury (SCI) is a significant global health challenge that results in profound physical and neurological impairments. Despite progress in medical care, the treatment options for SCI are still restricted and often focus on symptom management rather than promoting neural repair and functional recovery. This study focused on clarifying the impact of Schwann cell (SC) transplantation on the molecular, cellular, and functional basis of recovery in animal models of SCI., Material and Methods: Relevant studies were identified by conducting searches across multiple databases, which included PubMed, Web of Science, Scopus, and ProQuest. The data were analyzed via comprehensive meta-analysis software. We assessed the risk of bias via the SYRCLE method., Results: The analysis included 59 studies, 48 of which provided quantitative data. The results revealed significant improvements in various outcome variables, including protein zero structures (SMD = 1.66, 95 %CI: 0.96-2.36; p < 0.001; I 2  = 49.8 %), peripherally myelinated axons (SMD = 1.81, 95 %CI: 0.99-2.63; p < 0.001; I 2  = 39.3 %), biotinylated dextran amine-labeled CST only rostral (SMD = 1.31, 95 % CI: 0.50-2.12, p < 0.01, I 2  = 49.7 %), fast blue-labeled reticular formation (SMD = 0.96, 95 %CI: 0.43-1.49, p < 0.001, I 2  = 0.0 %), 5-hydroxytryptamine caudally (SMD = 0.83, 95 %CI: 0.36-1.29, p < 0.001, I 2  = 17.2 %) and epicenter (SMD = 0.85, 95 %CI: 0.17-1.53, p < 0.05, I 2  = 62.7 %), tyrosine hydroxylase caudally (SMD = 1.86, 95 %CI: 1.14-2.59, p < 0.001, I 2  = 0.0 %) and epicenter (SMD = 1.82, 95 %CI: 1.18-2.47, p < 0.001, I 2  = 0.0 %), cavity volume (SMD = -2.07, 95 %CI: -2.90 - -1.24, p < 0.001, I 2  = 67.2 %), and Basso, Beattie, and Bresnahan (SMD = 1.26, 95 %CI: 0.93-1.58; p < 0.001; I 2  = 79.4 %)., Conclusions: This study demonstrates the promising potential of SC transplantation as a therapeutic approach for SCI, clarifying its impact on various biological processes critical for recovery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Neuropathic pain (NeP) is a type of persistent pain initiated by diseases or injuries of the nervous system. Although the underlying pathophysiological mechanisms of NeP are poorly understood, the immune system plays a key role in this condition. M2 macrophages have a key role in tissue healing and the reduction of inflammation. This systematic study aims to provide an overview of the role and importance of M2 macrophages in NeP after spinal cord injury (SCI). A comprehensive systematic review was conducted utilizing Scopus, PubMed, Embase, and ISI Web of Science databases. Two independent reviewers conducted the article selection. All publications examine the impact of M2 macrophages on NeP following spinal cord injuries. A quality assessment was conducted on bias entities that had been predetermined. Eleven papers met the criteria. According to the findings, focusing on immune cell polarization presents viable therapeutic options for treating NeP and enhancing recovery after SCI. M2 macrophages are essential for reducing neuropathic pain and promoting recovery after spinal cord injury. The modulation of M2 macrophages by a number of therapeutic approaches, including ivermectin-functionalized MWCNTs, isorhamnetin, Neuregulin-1 administration, TMEM16F inhibition, lentivirus-mediated delivery of anti-inflammatory cytokines, epigallocatechin-3-gallate, and red-light therapy promotes neuroregeneration, decreases neuroinflammatory cytokines, and reduces NeP. The results of these preclinical investigations must, however, be interpreted with caution, according to the quality assessment and risk of bias analysis of the studies that were included. Targeting M2 macrophages may have therapeutic benefits as they are essential for the management of NeP and recovery following spinal cord damage., (© 2024. The Author(s).)

Neuropathic pain, a debilitating condition, remains a significant challenge due to the lack of effective therapeutic solutions. This study aimed to evaluate the potential of mesenchymal stromal cell (MSC)-derived conditioned medium in alleviating neuropathic pain induced by sciatic nerve compression injury in adult male rats. Forty Wistar rats were randomly assigned to four groups: control, nerve injury, nerve injury with intra-neural injection of conditioned medium, and nerve injury with intra-neural injection of culture medium. Following sciatic nerve compression, the respective groups received either 10 µl of conditioned medium from amniotic fluid-derived stem cells or an equal volume of control culture medium. Behavioral tests for cold allodynia, mechanical allodynia, and thermal hyperalgesia were conducted, and the spinal cord was analyzed using Western Blot and oxidative stress assays. The behavioral experiments showed a decrease in mechanical hyperalgesia and cold allodynia in the group receiving conditioned medium compared to the injury group and the control medium group. Western blot data revealed a decrease in the expression of the CCL2 protein and an increase in GAD65. Oxidative stress tests also showed increased levels of SOD and glutathione in conditioned media-treated animals compared to animals with nerve injury. The findings suggest that conditioned medium derived from amniotic fluid-derived stem cells can effectively reduce neuropathic pain, potentially through the provision of supportive factors that mitigate oxidative stress and inflammation in the spinal cord., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neuropathic pain (NP) following spinal cord injury (SCI) often lasts for a long time and causes a range of problems that reduce the quality of life. Current treatments are not generally effective; however, photobiomodulation therapy (PBMT) has made some progress in this area. Due to the novelty of this treatment, standard therapeutic protocols have not yet been agreed upon. In the present study, we compare the analgesic effect of two PBMT protocols (2 and 4 weeks of radiation). A total of thirty-two adult male Wistar rats were divided into four groups: control, SCI, 2 W PBMT, and 4 W PBMT. SCI was induced by an aneurism clip and PBMT used a 660-nm, initiated 30 min post-SCI, and continued daily for 2 or 4 weeks. Functional recovery, hyperalgesia, and allodynia were measured weekly. At the end of the study, the Gad65, interleukin 1-alpha (IL1α), interleukin 10 (IL10), IL4, and purinergic receptor (P2xR and P2yR) expressions were measured. Data were analyzed by Prism6. The results showed PBM irradiation for 2 and 4 weeks had the same effects in improving hyperalgesia. In the case of allodynia and functional recovery, 4 W PBMT was more effective (p<0.01). 4 W PBMT increased the Gad65 expression (p <0.001) and reduced P2Y4R (p <0.05) compared to SCI animals. The effects of 2 and 4 W PBMT were the same for IL1α, IL10, and P2X3 receptors. 4 W PBMT was more effective in reducing the complications of SCI such as pain and disability. PBMT therapy is an effective method aimed at immune system function modulation to reduce NP and motor dysfunction., (© 2023. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Few studies are conducted on the efficacy of human adipose-derived stem cells (ADSCs) in spinal cord injury (SCI) management and electrophysiological changes in the spinal cord. Therefore, the present study aimed to determine the effect of ADSCs on neuropathic pain, motor function recovery, and electrophysiology assessment. For the purpose of this study, adult male Wistar rats (weight: 140-160 gr, n = 42) were randomly allocated into five groups namely intact animals, sham-operated, SCI non-treated animals, vehicle-treated (culture media), and ADSCs treated groups. One week after clips compression SCI induction, about 1×10 6 cells were transplanted into the spinal cord. As well, both neuropathic pain (allodynia and hyperalgesia) and motor function were measured weekly. Cavity size, ADSCs survival, and electrophysiology assessments were measured at the end of the eighth week. The transplantation of ADSCs resulted in a significant improvement in the locomotion of SCI animals (p<0.0001), mechanical allodynia (p<0.0001), cold allodynia (p<0.0001), mechanical hyperalgesia (p<0.0001), and thermal hyperalgesia (p<0.0001). The cavity size was significantly smaller among the ADSCs-treated animals (p <0.0001). The single-unit recording showed that the transplantation of ADSCs decreased wide dynamic range (WDR) in neurons and it evoked potential in response to receiving signals from Aβ (p<0.0001) and Aδ (p=0.003) C-fiber (p<0.0001) neurons. Post-discharge recorded from WDR neurons decreased after the transplantation of ADSCs (p<0.0001) and wind up in the ADSCs-treated group was lower than that of the SCI group (p=0.003). Our results showed that the transplantation of ADSCs could significantly alleviate neuropathic pain, enhance motor function recovery, and improve electrophysiology findings after SCI., Competing Interests: The present study was financially supported by research affairs of Iran University of Medical Sciences [Project No 0-1-4-20000]. Competing interests The authors declared that they have no competing interests.Experimental research protocol on animals was approved by the ethics committee of the Iran University of Medical Sciences (IR.IUMS.REC.1400.513).The present study was financially supported by the research affairs of the Iran University of Medical Sciences [Project No 0-1-4-20000]., (Copyright © Journal of Stem Cells and Regenerative Medicine.)

Objectives: Tinnitus is defined as ringing of the ears that is experienced when there is no external sound source, and is an auditory phantom sensation. The insula as a multimodal cortex has been shown to be involved in the processing of auditory stimuli rather than other sensory and motor processing and reported to correlate with some aspects of tinnitus. However, its exact role is not clear. The present study aimed to investigate the effect of excitotoxic lesions limited to the insular cortex on the ability to detect a gap in background noise., Materials and Methods: Gap detection test and prepulse inhibition, two objective measurements of auditory startle response, were measured, in 33 male Wistar rats, before and up to four weeks after insular lesion in three experimental groups (sham, control, and lesion)., Results: The ability to detect the gap interposed between 60 db background noise was impaired at weeks 2, 3, and 4 following insular lesion, while prepulse inhibition remained intact up to four weeks after surgery., Conclusion: These findings indicated that excitotoxic lesions of the insular cortex may produce a tinnitus-like phenomenon in rats while sparing the hearing sensitivity; suggesting that the insular cortex may have a role in the development of tinnitus., Competing Interests: None.

Background: There are complex mechanisms for reducing intrinsic repairability and neuronal regeneration following spinal cord injury (SCI). Platelet-rich plasma (PRP) is a rich source of growth factors and has been used to motivate the regeneration of peripheral nerves in neurodegenerative disorders. However, only a few studies have shown the effects of PRP on the SCI models., Methods: We investigated whether PRP derived from human umbilical cord blood (HUCB-PRP) could recover motor function in animals with spinal cord injury. Sixty adult male Wistar rats were randomly divided into 6 groups (n=60) as control, sham (laminectomy without induction of spinal cord injury), SCI, vehicle (SCI+ Platelet-Poor Plasma), PRP2day (SCI+PRP injection 2 days after SCI), and PRP14day (SCI+PRP injection 14 days after SCI). SCI was performed at the T12-T13 level. BBB test was carried out weekly after injury for six weeks. Caspase3 expression was determined using the Immunohistochemistry technique. The expression of GSK3β, CSF-tau, and MAG was determined using the Western blot technique. Data were analyzed by PRISM & SPSS software., Results: HUCB-PRP treated animals showed a higher locomotor function recovery than those in the SCI group (p<0.0001). The level of caspase3, GSK3β and CSF- Tau reduced and the MAG level in the spinal cord increased by the injection of HUCB-PRP in SCI animals., Conclusion: Injection of HUCB-PRP enhanced hind limb locomotor performance by modulation of caspase3, GSK3β, CSF-tau, and MAG expression. Using HUCB-PRP could be a new therapeutic option for recovering motor function and axonal regeneration after SCI., (Copyright © 2022. Published by Elsevier Inc.)

This study investigated the effects of local injection of cerium oxide nanoparticles (CeONPs) in a rat spinal cord injury (SCI) model. Thirty-six adult male Wistar rats were divided into 4 groups: controls (healthy animals), sham (laminectomy), SCI (laminectomy+SCI induction), and treatment (laminectomy+SCI induction+intrathecal injection of CeONPs immediately after injury). SCI was induced using an aneurysm clip at the T12-T13 vertebral region. Motor performance and pain threshold tests were performed weekly; H&E staining and measurement of cavity sizes were performed 6 weeks after injury. The expression of granulocyte colony-stimulating factor (GCSF), P44/42 MAPK, P-P44/42 MAPK, Tau, myelin-associated glycoprotein(MAG) was evaluated after 6 weeks by Western blot. The Basso, Beattie, and Bresnahan locomotor scoring scales improved in animals receiving CeONPs compared with SCI animals. The cavity sizes were less in the treatment group. GCSF expression was similar in the animals receiving CeONPs compared with the SCI group but the expression of ERK1/ERK2 and phospho-ERK was lower than in the SCI group. Expression levels of Tau and MAG were significantly increased in treated animals compared to the SCI group. These data indicate that the use of CeONPs may improve motor functional recovery in SCI., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Spinal cord injury (SCI) causes motor deficits, urinary incontinence, and neuropathic pain. This study was designed to optimize a photobiomodulation therapy (PBMT) protocol using a continuous wave (CW) 660 nm laser in rats with SCI. Specifically, the number of days of irradiation and the daily dose of PBMT were investigated. Methods: The study was performed in two steps. In the first step, a comparison between the effects of PBMT (45 sec) daily for 2 and 4 weeks on pain and movement [Basso, Beattie, and Brenham (BBB) score] was made. In the second step, a comparison between different durations of irradiation (27, 45, 90, and 117 sec) was performed. PBMT used a 100 mW laser delivered to 9 points on and around the lesion site. Oxidative stress, fibroblast invasion, and time to achieve spontaneous urination were also assessed. Results: The improvement in movement and pain stopped with discontinuation of radiation at week 2 and fibroblast invasion resumed. No improvement was seen in movement and pain in the group receiving PBMT for 27 sec compared with the groups receiving higher doses of laser radiation. Animals receiving 117 sec of photobiomodulation showed a higher BBB score even in the first 3 days. Conclusions: The number of days is an important factor for improving mobility; however, the daily dose of radiation is more important for pain relief.

Background: Cell therapy is a promising treatment method for relieving neuropathic pain caused by spinal cord injuries (SCI). Sertoli cells (SCs) are an attractive choice given their demonstrated secretion of growth factors and immunosuppressant effect. This study mechanistically characterizes the analgesic effect of SCs transplantation., Methods: The clip compression SCI model was carried out on the T12-T13 level in male Wistar rats. One-week post-SCI, SCs were transplanted into the site of injury. Animals underwent Basso, Beattie, and Bresnahan locomotor scoring, mechanical allodynia, and thermal hyperalgesia on a weekly basis for a duration of six weeks. Histological examination of the spinal cord and molecular evaluation of Iba-1, P2Y4, TRPC6, and P-mTOR were performed. SCs survival, measured by anti-Müllerian hormone expression in the spinal cord., Results: Animals that received SCs transplantation showed improvement in motor function recovery and pain relief. Furthermore, a cavity was significantly decreased in the transplanted animals (p = 0.0024), the expression level of TRPC6 and caspase3 and the number of activated microglia decreased compared to the SCI animals, and p-mTOR and P2Y4R expression remarkably increased compared to the SCI group., Conclusion: SCs transplantation produces an analgesic effect which may represent a promising treatment for SCI-induced chronic pain., (Copyright © 2022. Published by Elsevier Inc.)

Background: Calorie Restriction (CR) is known as one of the most effective life-extending interventions. Therefore researchers are looking for other interventions or drugs to mimic the mentioned effects. Time-restricted feeding (TRF) has recently gained more attention recently as one of the CR mimetics. Here we evaluate and compare the effects of CR or TRF on cognitive function in young animals fed a high-fat diet (HFD). Methods: This is an experimental study that three-week-old male Wistar rats (n:52) were subjected to a control diet (n:11) or HFD (n:42). Then the HFD group was divided into 1) 30% calorie restriction (CR), 2) Night Intermittent Fasting (NIF), 3) Day Intermittent Fasting (DIF), and 4) Ad-Libitum (AL) with the standard diet for ten weeks (each of 9). An independent T-test or Mann-Whitney test was used for the first phase and in the second phase of the study, one-way analysis of variance (ANOVA), followed by Tukey post-hoc tests, or Kruskal-Wallis and post-hoc Bonferroni test were used. P-values of <0.05 were considered significant. Results: Deteriorated mental function was significantly lower in HFD than CON (p= 0.041). CR was still more efficient than NIF in cognitive function in obese subjects. Post-hoc test indicated that from day 2-4, escape latency was significantly shorter in NIF and CR, which was not seen in other groups (p=0.045). Conclusion: While TRF has garnered much attention recently, here we show that CR is still more efficient in learning and memory tasks. Longer fasting times and different fasting periods are recommended to study., (© 2022 Iran University of Medical Sciences.)

Background: Calorie restriction (CR) is known as a nutritional gold standard for life extension and different studies have shown that insulin-like growth factor (IGF1) reduction through CR may be involved in CR's anti-aging effects. Besides, time-restricted-feeding (TRF) is also highlighted due to more feasibility and positive health effects. We designed this study to compare the effects of CR and TRF on IGF1 and other metabolic parameters., Methods: Fifty-two male Wistar rats (3 weeks old) were subjected to either a control (CON, n = 11) diet or high-fat diet (HFD, n = 42) for 17 weeks. In the second phase of the study, the HFD group were divided into four groups ( n = 9) 1) 30% CR, 2) Night Intermittent Fasting (NIF, active phase), 3) day intermittent fasting (DIF, rest phase), and 4) Ad-Libitum (AL) with a standard diet for 10 weeks. Blood samples were collected at the end of both phases., Results: HFD increased IGF1 and deteriorated lipid profiles, except for triglycerides ( P : 0.018, 0.008.0.012, 0.032) but CR in these obese subjects could not lower the IGF1 level. HDL significantly decreased in DIF compared to CON and CR ( P ; 0.001). Meanwhile, HOMA-IR increased in DIF and was significant compared to CR ( P : 0.002). Serum glucose levels decreased in CR compared to all groups except for CON ( P : 0.001)., Conclusion: Data indicates the role of previous obesity on the effect of CR on the IGF1 level and highlights the effect of inappropriate time of food intake on HDL and APOA1., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 International Journal of Preventive Medicine.)

Introduction: The current study evaluated the analgesic effects of bumetanide as an adjunctive in the management of neuropathic pain following Spinal Cord Injury (SCI). The peripheral expression of Na-K-Cl Cotransporter-1 ( NKCC1 ) and K-Cl Cotransporter-2 ( KCC2 ) genes in polymorphonuclear lymphocytes (PMLs) was assessed as a possible biomarker indicating central mechanisms underlying the observed response., Methods: Through an open-label, single-arm, pilot trial of bumetanide (2 mg/d), an add-on treatment was conducted on 14 SCI patients for 19 weeks. This study consisted of 3 phases: pre-treatment (1 month), titration (3 weeks), and active treatment (4 months). Ultimately, 9 patients completed the study. The primary outcome variables were the endpoint pain score using the Numeric Rating Scale (NRS), and also the short-form of the McGill pain questionnaire. Secondary endpoints included the short-form of the health survey that assesses the quality of life. Blood samples were collected and used for determining the expression of NKCC1 and KCC2 genes in transcription and translation levels., Results: Bumetanide treatment significantly decreased average pain intensity according to the NRS and the short-form of the McGill pain questionnaire scores. Baseline expression of KCC2 protein was low between groups and increased significantly following treatment (P<0.05). In the current study, pain improvement was accompanied by the greater mean change from the baseline (improvement) for the overall quality of life., Conclusion: These data highlighted the analgesic effect of bumetanide on neuropathic pain and indicated the potential role of the upregulation of KCC2 protein and involvement of GABAergic disinhibition in producing neuropathic pain., Competing Interests: Conflict of interest The authors declared no conflict of interest., (Copyright© 2021 Iranian Neuroscience Society.)

Background: Memory deficit is a common cognitive comorbid in patients with neuropathic pain that need better treatment. Recent research revealed that nanocurcumin has an antinociceptive action and a protective effect against memory disorders, suggesting its possible effectiveness for the treatment of neuropathic pain and its comorbidity., Methods: Adult male albino Wistar rats (n = 32) were randomly divided into four experimental groups: CCI+ nanocurcumin, CCI + vehicle, sham + nanocurcumin, and sham + vehicle. Neuropathic pain induced by a chronic constriction injury of the sciatic nerve. Nanocurcumin or vehicle was injected intraperitoneally for 10 days. Behavioral assessment achieved to evaluate pain threshold in the von Frey test and radiant heat test, also spatial learning and memory examined by the Morris water maze (MWM) test. To explore the possible relation, IL-1β, and TNF-α levels of the hippocampus measured by enzyme-linked immunosorbent assay (ELISA)., Results: Our data showed that CCI caused neuropathic pain-related behaviors and spatial learning and memory disorders in rats. Chronic treatment with nanocurcumin significantly increased pain threshold (P < 0.001; F = 27.63, F = 20.58), improved spatial memory (P < 0.01; F = 47.37), and decreased the hippocampal levels of IL-1β (P < 0.001; F = 33.57) and TNF-α (P < 0.01; F = 7.25) in CCI rats., Conclusion: Chronic nanocurcumin can ameliorate pain-related behavior, improve spatial learning and memory deficits, and is associated with the reduction of IL-1β and TNF-α levels in the hippocampus in CCI rats. Nanocurcumin may be potentially providing a therapeutic alternative for the treatment of neuropathic pain and its memory impairment comorbidity.

Introduction: Minocycline has anti-inflammatory, anti-apoptotic, and anti-oxidant effects. Preclinical data suggest that minocycline could be beneficial for treating common neurological disorders, including Parkinson disease and multiple sclerosis., Methods: In this study, the effects of minocycline on harmaline-induced motor and cognitive impairments were studied in male Wistar rats. The rats were divided into four groups of ten animals each. Harmaline was used for the induction of Essential Tremor (ET). Minocycline (90 mg/kg, IP) was administered 30 minutes before the saline or harmaline. Tremor intensity, spontaneous locomotor activity, passive avoidance memory, anxiety-related behaviors, and motor function were assessed in the rats., Results: The results showed that minocycline could recover tremor intensity and step width but failed to recuperate the motor balance. The memory impairments observed in harmaline-treated rats were somewhat reversed by administration of minocycline. The cerebellum and inferior olive nucleus were studied for neuronal degeneration using histochemistry and transmission electron microscopy techniques. Harmaline caused ultrastructural changes and neuronal cell loss in inferior olive and cerebellar Purkinje cells. Minocycline exhibited neuroprotective changes on cerebellar Purkinje cells and inferior olivary neurons., Conclusion: These results open new therapeutic perspectives for motor and memory impairments in ET. However, further studies are needed to clarify the exact mechanisms., Competing Interests: Conflict of interest The authors declared no conflicts of interest., (Copyright© 2021 Iranian Neuroscience Society.)

Pulmonary fibrosis (PF) is an interstitial lung disease, in which the exact pathologic mechanisms are not fully understood. Drug trials for the treatment of PF have shown disappointing results and controversial. Recently, selenium nanoparticles (SeNPs) have received great attention for potential use in treatments, due to high bioactivity features and lower toxicity. This study evaluated the protective effect of SeNPs against pulmonary injury induced by bleomycin (single dose, 4 mg/kg, intratracheal) in male rats in early and late phases of the disease. The rats were treated with SeNPs by intraperitoneal injection (0.5 mg SeNP/kg) for five consecutive days in the early phase (a day after injection of bleomycin) and late phase (a week after injection of bleomycin). The results showed that injection of SeNPs in the early phase improved the degree of alveolitis and inflammation and lung structure damage. Also, led to significant decreases in density of transforming growth factor- β1 (TGF-β1) in the lung and tumor necrosis factor-α (TNF-α) levels in the serum and lung homogenates compared with bleomycin-administrated group. Notably, treatment with the SeNP during the late phase did not show any ameliorative effects. Thus, the data suggest that SeNP has a protective effect against bleomycin-induced pulmonary injury in rats in the early phase of the disease. This might mean that SeNPs may be a new therapeutic agent for the improvement of this disease in the early phases.

Background: Neuropathic pain following injury or dysfunction of the peripheral or CNS is one of the most important medical challenges to treat. Humane platelet-rich plasma (HPRP), which is a rich source of growth factors, may be able to treat and reduce pain caused by spinal cord injury (SCI). In this study, the effect of HPRP on neuropathic pain caused by SCI was investigated., Methods: Sixty adult male Wistar rats were randomly divided into 6 groups: control, sham, SCI, vehicle (SCI+platelet-poor plasma), SCI+ PRP2day (injection 48 hrs after SCI) and SCI+PRP14day (injection 14 days after SCI). SCI was induced at the T12-T13 level. Behavioral tests were conducted weekly after injury for six weeks. Allodynia and hyperalgesia were assessed using acetone drops, plantar test and von Frey filament. Cavity size and the number of fibroblasts were determined by H&E stain, and the expression of mTOR, p-mTOR, P 2 × 3 R and P 2 Y 4 R were determined using the western blot technique. Data were analyzed using PRISM & SPSS software., Results: PRP injection showed a higher pain threshold in mechanical allodynia (p<0.0001), cold allodynia (p<0.0001) and thermal hyperalgesia (p<0.0001) than those in the spinal. Animals treated with PRP also reduced cavity size, fibroblast number, p-mTOR/mTOR ratio, and P 2 × 3 R expression, and increased P 2 Y 4 R expression. The difference between the two groups was not statistically significant., Conclusions: The results showed that PRP reduced SCI-induced allodynia and hyperalgesia by regulating ATP signaling. Using HPRP can open a new window in the treatment of pain caused by damage to the nervous system., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: . The goal of the study was to test the effects of photobiomodulation therapy (PBMT) and intra-spinal injection of chondroitinase ABC (chABC) both alone and combined on pain induced by spinal cord injury (SCI) in rats., Material and Methods: SCI was induced by compression using an aneurysm clip. PBMT used a 660 nm laser starting at 30 minutes after SCI and then daily for 2 week, and at the end of 1-week ChABC was injected into the spinal cord. Allodynia (mechanical and cold), hyperalgesia (mechanical and thermal) and functional recovery were measured. Molecular levels of IL6, BDNF, GDNF and Gad65 were evaluated., Results: . Both ChABC, PBMT and the combination reduced allodynia and thermal hyperalgesia and improved functional recovery, but did not reduce mechanical hyperalgesia. Pain-related factors (BDNF and IL6) were decreased and anti-nociceptive factors (Gad65 and GDNF) were increased., Conclusion: . Treatment of SCI by PBM is a non-invasive technique, and could be improved by ChABC injection to reduce neuropathic pain and improve movement., (Copyright © 2020. Published by Elsevier Inc.)

Background and objectives: Hyperacusis is hypersensitivity and extreme response to the intensity of sound that is tolerable in normal subjects. The mechanisms underlying hyperacusis has not been well understood, specially the role of insular cortex. The aim of this study is to investigate the role of insular cortex in hyperacusis like behavior. Material and methods: The number of 33 male wistar rats weighting 170-250 gr were allocated randomly in three groups; control, sham, and insular lesion. Auditory startle responses (ASR) to different intensities of stimuli (70, 80, 90, 100, and110 dB without background noise as well as 110 dB in the presence of 70, 80 dB background noise) were measured before and up to four weeks after intervention. Results: Data analyses showed an increase in ASR to 100 dB stimulus without background noise one week after insular lesion, and increased responses to other intensities two weeks after lesion. Furthermore, there was a decrease in ASR to 110 dB stimulus with 80 dB background noise two weeks after insular lesion. However, no significant difference was observed in 70 dB background noise. The changes in ASR lasts at least four weeks. Conclusion: The findings indicated that there was an increase in ASR in the absence of background noise following cortical excititoxic lesion limited to insular cortex, while there was a decrease in responses in the presence of background noise which suggests possible increased sensitivity to sound loudness as a hyperacusis-like phenomenon. The study showed a significant relationship between insular cortex lesion and ASR in rats.

Background/objective: The current study evaluated the analgesic effects of bumetanide as an adjunctive treatment in managing neuropathic pain following spinal cord injury. The peripheral expression level of Na-K-Cl-cotransporter-1 (NKCC1) and K-Cl-cotransporter-2 (KCC2) genes in polymorphonuclear lymphocytes (PMLs) assessed as a possible biomarker indicating central underlying mechanisms., Methods: This open-label, single-arm, pilot trial of bumetanide (2 mg/day) is an add-on treatment conducted in 14 SCI patients for 19 weeks. The whole duration consisted of three phases: pre-treatment (1 month), titration (3 weeks), and active treatment (4 months). Ultimately, nine patients completed the study. The primary outcome variables were the endpoint pain score measured by the numeric rating scale (NRS), and the short-form McGill Pain Questionnaire. Secondary endpoints included the Short-Form Health Survey that measures the quality of life. Blood samples were collected and used for determining the expression of NKCC1 and KCC2 genes in transcription and translation levels., Results: Bumetanide treatment significantly reduced average pain intensity according to the NRS and the short form of the McGill Pain Questionnaire scores. The baseline expression of KCC2 protein was low between groups and increased significantly following treatment (P < 0.05). Through the current study, pain improvement accompanied by the more significant mean change from the baseline for the overall quality of life., Conclusion: These data might be a piece of preliminary evidence for the analgesic effect of bumetanide on neuropathic pain and could support the potential role of the upregulation of KCC2 protein and involvement of GABAergic disinhibition in producing neuropathic pain., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In recent years, photobiomodulation therapy (PBMT) has found many applications in various medical fields. Studies of PBMT on spinal cord injury (SCI) have mostly used laser sources in experimental animal models. The purpose of this study was to summarize studies that have employed PBMT for various kinds of SCI in animals. A thorough search in databases including MEDLINE, EMBASE, SCOPUS, and Web of Science, with the removal of unrelated articles, yielded 16 relevant articles. The meta-analysis showed that PBMT was effective in improving post-SCI movement in the first 14 days (MD = 1.593 (95% CI: 1.110 to 2.075; p <0.001, I 2  = 51.9%) and this improvement became even greater thereafter (MD = 2.086 (95% CI: 1.570 to 2.603; p = <0.001. I 2 = 90.3%). Time of irradiation (<300 sec or >300 sec), gender (male or female), injury model (contusion or compression, radiation protocol (<14 days or ≥14days), laser wavelength (<800nm or >800nm) and injury severity (moderate or severe) were found to be factors that can affect PBM efficacy for SCI treatment. PBMT has an anti-inflammatory effect, is effective in reducing the size of spinal cord lesions and helps to absorb administrated proteins and stem cells to the lesion site., Competing Interests: Declaration of Competing Interest MRH was supported by US NIH Grants R01AI050875 and R21AI121700. MRH declares the following potential conflicts of interest. Scientific Advisory Boards: Transdermal Cap Inc, Cleveland, OH; BeWell Global Inc, Wan Chai, Hong Kong; Hologenix Inc. Santa Monica, CA; LumiThera Inc, Poulsbo, WA; Vielight, Toronto, Canada; Bright Photomedicine, Sao Paulo, Brazil; Quantum Dynamics LLC, Cambridge, MA; Global Photon Inc, Bee Cave, TX; Medical Coherence, Boston MA; NeuroThera, Newark DE; JOOVV Inc, Minneapolis-St. Paul MN; AIRx Medical, Pleasanton CA; FIR Industries, Inc. Ramsey, NJ; UVLRx Therapeutics, Oldsmar, FL; Ultralux UV Inc, Lansing MI; Illumiheal & Petthera, Shoreline, WA; MB Lasertherapy, Houston, TX; ARRC LED, San Clemente, CA; Varuna Biomedical Corp. Incline Village, NV; Niraxx Light Therapeutics, Inc, Boston, MA. Consulting; Lexington Int, Boca Raton, FL; USHIO Corp, Japan; Merck KGaA, Darmstadt, Germany; Philips Electronics Nederland B.V. Eindhoven, Netherlands; Johnson & Johnson Inc, Philadelphia, PA; Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany. Stockholdings: Global Photon Inc, Bee Cave, TX; Mitonix, Newark, DE., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Several clinical and experimental studies reported the anxiety as one of the neuropathic pain comorbidities; however, the mechanisms involved in this comorbidity are incompletely cleared. The current study investigated the consequence of pain induced by peripheral neuropathy on the serotonin (5-HT) level of the CA1 region of the hippocampus, which is known as a potential reason, for anxiety associated with neuropathic pain., Methods: In this manner, 72 male rats were inconstantly subdivided into three experimental groups as follows: control, sham, and chronic constriction injury (CCI). Neuropathic pain was initiated by the CCI of the sciatic nerve, and then, mechanical allodynia, thermal hyperalgesia, and anxiety-like behavior were evaluated using the von Frey filaments, radiant heat, open field test (OFT), and elevated plus maze (EPM) respectively. To investigate the probable mechanisms, the in vivo extracellular levels of 5-HT were assessed by microdialysis and using reverse-phase high-pressure liquid chromatography (HPLC) in the CA1 region of hippocampus on days 16 and 30 post-CCI., Results: Our data suggested that CCI caused anxiety-like behavior in OFT and EPM test. 5-HT concentration in the CA1 region of the hippocampus significantly (F=43.8, p=0.000) reduced in CCI rats, when the pain threshold was minimum. Nevertheless, these alterations reversed while the pain threshold innate increased., Conclusions: Neuropathic pain, initiated by constriction of the sciatic nerve can induce anxiety-like behavior in rats. This effect accompanies the reduction in 5-HT concentration in the CA1 region of the hippocampus. When the pain spontaneously alleviated, 5-HT level increased and anxiety-like behavior relieved., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Spinal cord injury is one of the most common causes of neuropathic pain which is not responsive to common treatments. Owing to the adverse effects of drugs, it seems that the use of Calcitonin Gene-Related Protein (CGRP) receptor antagonist or Morphine and their combination could be an appropriate strategy for pain alleviation., Method: To achieve the objective, fifty six male Wistar rats were divided into seven groups. CGRP8-37 and Endomorphin-1 alone, and in combinated administration, as bolus and continues dose. Both mechanical and cold allodynia, and mechanical hyperalgesia were evaluated before and also15 and 60 min after injection to indicate the efficacy of the therapies in the acute and chronic circumstances on pain induced by spinal cord compression injury. Sigma-1 receptor experssion, oxidant and antioxidant activity after the seven days of the drug adminestration were evaluated., Result: The results showed that Endomorphin-1and CGRP8-37 injections were able to reduce neuropathic pain after spinal cord compression injury. Compared to Endomorphin-1, or CGRP8-37 monotherapy, combination therapy did not show more attenuating effects on the pain threshold. Compared to the continous administration of Endomorphin-1 alone, and CGRP8-37 alone, the continous combination therapy did not reduce the pain further. Molecular studies disclosed the increased expression of the Sigma1 receptor, in the spinal cord after administration of Endomorphin-1, and CGRP8-37 alone, as well as combination therapy. Although, an increase in GPx and SOD activity, and decrease in MDA activity was observed in the combination therapy., Conclusion: Our results demonstrate that either Endomorphin-1 or CGRP receptor antagonist is able to decrease the neuropathic pain after SCI but combination therapy by a CGRP receptor antagonist and Endomorphin-1 did not make any further reduction in pain sensation., Competing Interests: Declaration of Competing Interest No author reports having any potential conflicts of interest with this study., (Copyright © 2020. Published by Elsevier B.V.)

Introduction: Due to side effects of medications used for chronic pain, combination therapy seems to be an appropriate solution for alleviation of chronic pain and reducing the side effects. The role of inhibitory GABA system is well proven in reducing neuropathic pain. Also, special attention has been focused on endogenous morphine (endomorphins) in reducing chronic pain originates from damage to the nervous system. The purpose of this study is to investigate the analgesic effect of simultaneous administration of GABA agonist and endomorphin-1 on neuropathic pain in rat model of spinal cord injury (SCI). The role of oxidative stress, NR1 subunits of NMDA receptors, and α 2 subunits of GABA receptors in the spinal cord has also been investigated., Methods: Spinal cord at level of T6-T8 was compressed. Three weeks after spinal cord injury, muscimol and endomorphin-1 were injected (intrathecally once a day for 7 days) individually or in combination. Mechanical and cold allodynia, thermal and mechanical hyperalgesia were evaluated before injection and 15 and 60 min after injection. At the end of behavioral experiments, histological and biochemical evaluations were done on prepared spinal cord samples., Results: Isobologram results showed that combination therapy significantly increased the pain threshold comparing to injection of endomorphin-1 (EM) or muscimol alone. Histological studies indicated the increased expression of α2 subunits of GABA receptors, and NR1 subunits of NMDA receptors in the spinal cord. The combination therapy also increased the glutathione (GSH) and superoxide dismutase (SOD) level and decreased the malondialdehyde (MDA) levels in the spinal cord., Conclusion: Simultaneous administration of muscimol and endomorphine-1 could be a new candidate for alleviation of pain resulting from spinal cord injury., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

New Findings: What is the central question of this study? Can short-term high-intensity interval training (HIIT) contribute to the reduction of ischaemia-reperfusion (IR) injury by enhancing the levels of Klotho and its related axes, including myocardial TRPC6 expression, and antioxidant defence as novel possible mechanisms of exercise-induced cadioprotection (EICP) against IR injury? What is the main finding and its importance? The increase of plasma and myocardial levels of Klotho as a result of preconditioning with HIIT and prevention of a significant reduction of Klotho during IR injury can promote cardioprotection and reduce damage by attenuating myocardial TRPC6 expression and increasing antioxidant defence. The present findings may provide a new mechanism in EICP and IR injury, and provide the knowledge to develop preventive and therapeutic approaches., Abstract: Cardiovascular disease, especially coronary artery disease, remains a major cause of morbidity and mortality in the world, and ischaemia-reperfusion (IR) insult is the main pathological cause leading to death. Exercise training is associated with a reduced risk of cardiovascular disease and the development of cardioprotection against IR injury. Therefore, the purpose of this study was to investigate the effect of preconditioning with high-intensity interval training (HIIT) on myocardial and plasma levels of Klotho and its related axes as novel mechanisms of exercise-induced cardioprotection against IR injury. Seventy male Wistar rats were randomly divided into five groups of control, HIIT, sham, IR and HIIT group that underwent IR injury (H-IR). The training group performed five sessions of HIIT on the treadmill. The cardiac IR injury was induced by ligation of the left anterior descending coronary artery for 30 min followed by 24 h reperfusion. Infarct size and histopathological assessment of cardiac tissues were determined through Evans Blue-triphenyltetrazolium chloride and haematoxylin-eosin staining, respectively. We investigated lipid peroxidation and markers of cardiac injury, antioxidant enzymes and the plasma levels of Klotho using enzyme-linked immunosorbent assays. Also, myocardial levels of Klotho and TRPC6 expression were determined by western blot assays. The results demonstrated a significant increase in myocardial and plasma levels of Klotho following HIIT and a significant decrease during IR injury. Myocardial TRPC6 channel expression increased following IR. HIIT also prevented a significant reduction of Klotho during IR and consequently reduced the expression of the TRPC6 channel in the H-IR group compared with the IR group. Furthermore, HIIT decreased the infarct size, cardiac injury, lipid peroxidation, lactate dehydrogenase, creatine kinase myocardial band and cardiac troponin-I, and improved total antioxidant capacity and catalase, superoxide dismutase and glutathione peroxidase activities following IR injury. The findings of the present study suggest that HIIT improves cardioprotection against IR injury and reduces cardiac damages through an increase in myocardial and plasma levels of Klotho and its related axes (TRPC6 and antioxidant defence). These findings can help to develop preventive and therapeutic approaches., (© 2020 The Authors. Experimental Physiology © 2020 The Physiological Society.)

Background: Exercise training is known as a practical way to increase cardioprotection against stress, and it seems that stem cell recruitment is one of its mechanisms. The purpose of the present study was to investigate the effect of preconditioning with High-intensity interval training (HIIT) on tissue levels of G-CSF, its receptor and C-Kit following acute myocardial infarction in male rats., Methods: Twenty Male Wistar rats were randomly divided into 4 groups of control, MI, HIIT, and HIIT+MI. Training groups performed 2 weeks of high intensity interval training in 4 sections. The first section consisted training in 3 days and 2 sessions in each day (4 × 2 min with 35-40 m/min and 3 × 2 min with 25-30 m/min between high intervals. The second part included 2 days of training (4 × 2 min with 40 to 45 m/min and 3 × 2 min with 28 to 32 m /min). The third part was performed in 3 days with one more repetition. The fourth section consisted 2 days of training and with one more repetition compared to section 3. For induction of myocardial infarction, subcutaneous injection of isoprenaline was used. CK, total CK, LDH, and troponin T were measured in serum and G-CSF, G-CSFR and C-Kit proteins were measured by the Western Blot method in the heart tissue., Results: The results of this study showed that enzymes of CK, total CK, LDH, troponin T had a significant increase in both MI and HIIT+MI groups compared to the other two groups (P < 0.001) and these indices in the MI group were significantly higher than the HIIT+MI group. Also, the results demonstrated that G-CSF, G-CSFR and C-Kit protein expression in the heart tissue significantly increased after MI. As well as, 2 weeks of HIIT training significantly increased G-CSF and C-kit in the training group compared to the control group, but the training caused that these proteins does not increase in HIIT+MI group as much as MI group., Conclusions: Along with other protective pathways, high intensity interval training can increase cardioprotection and decrease heart injuries through the increase in G-CSF, G-CSFR and C-kit level.

Oligodendrocyte (OL) loss and demyelination occur after spinal cord injury (SCI). Stimulation of remyelination through transplantation of myelinating cells may be effective in improving function. For the repair strategy to be successful, the selection of a suitable cell and maintaining cell growth when cells are injected directly to the site of injury is important. In addition to selecting the type of cell, fibrin hydrogel was used as a suitable tissue engineering scaffold for this purpose. To test the relationship between myelination and functional improvement, the human endometrial stem cells (hEnSCs) were differentiated toward oligodendrocyte progenitor cells (OPCs) using overexpression of miR-219. Adult female Wistar rats were used to induce SCI by using a compression model and were randomly assigned to the following four experimental groups: SCI, Vehicle, hEnSC, and OPC. Ten days after injury, miR-219 overexpressed hEnSC-derived OPCs encapsulated in fibrin hydrogel, as an injectable scaffold, were injected to the injury site. In this study, with a focus on promoting functional recovery after SCI, the Basso-Beattie-Bresnahan test was performed to evaluate the recovery of motor function every week for 10 weeks and the histological assay was then performed. Results showed that the rate of motor function recovery was significantly higher in OPC group compared to SCI and vehicle groups but no marked differences were found between OPC and hEnSC groups, although, the rate of myelination in the OPC group was significantly higher than the other groups. These results demonstrated that remyelination was not the cause of recovery of motor function., (© 2019 Wiley Periodicals, Inc.)

Background: Obesity has been suggested to be well correlated with altered levels of complete blood count (CBC) parameters. In this study, the relationship of body mass index (BMI) and circulating leptin levels with CBC among obese and overweight adults was examined. Methods: CBC and biochemical parameters, WBC and hematological profiles, leptin levels, related factors to liver, and kidney and lipid profiles were measured among 184 obese and overweight people aged 18-60 years. Statistical analysis was performed using SPSS software. To assess the normality of data, the Kolmogorov-Smirnov test was used. Logarithmic transformation was performed for some variables with non-normal distribution. The association between 2 quantitative variables was measured using bivariate correlation (Pearson or Spearman). Pearson correlations and multiple regression analysis were performed to assess the correlation between variables. Simple and multiple regression analyses were performed to predict some variables. P- value <0.05 was considered significant. Results: Hematocrit, insulin, fasting blood sugar, uric acid, TG, LDL-C, VLDL-C, and ALT were positively correlated with BMI (p=0.041, r=0.149 for hematocrit; p≤0.001, r=0.520 for insulin; p≤0.001, r=0.363 for FBS; p≤0.001, r=0.309 for uric acid; p=0.015, r=0.189 for TG; p=0.030, r=161 for LDL-C; p=0.019, r=0.181 for VLDL-C; p≤0.001, r=0.299 for ALT), whereas urea and HDL-C were negatively correlated with BMI (p≤0.001, r=-0.368 for urea; p≤0.001, r=-0.297 for HDL-C). Moreover, LDL-C and insulin were positively correlated with leptin (P = 0.011, r = 0.194 for LDL-C, P = 0.013, r = 0.114 for insulin) and hematocrit, urea, creatinine, TG and VLDL-C were negatively correlated with leptin (p=0.040, r=-0.162 for hematocrit; p≤0.001, r=-0.305 for urea; p=0.007, r=-0.219 for creatinine; p=0.025, r=0.188 for TG; p=0.007, r=-0.218 for VLDL-C). Our analysis showed that white blood cell was positively correlated with leptin (β=17.36, p=0.048). Also, other CBC parameters had no significant correlations with BMI and leptin. Conclusion: According to the findings of this study, BMI had a negative association with urea and HDL-C, while BMI had a positive association with insulin, hematocrit, FBS, uric acid, TG, VLDL-C, LDL-C, and ALT. Furthermore, leptin had a negative association with hematocrit, creatinine, and urea, TG, VLDL-C and a positive association with LDL-C and insulin among the participants of this study., (© 2019 Iran University of Medical Sciences.)

Hyperacusis may be defined as diminishing tolerance to moderate and high intensity sounds in people with normal hearing sensitivity. Serotonin plays a critical role in some of auditory tasks including startle reflex and prepulse inhibition. Serotonin deficiency can cause some diseases which can coincide with hyperacusis. The aim of the present study was to investigate the probable influence of serotonergic depletion in nucleus accumbens (NAcc) on the startle reflex. The startle reflexes were examined in Wistar rats (n: 48) in different intensities with and without the background noise. The amplitude of startle reflex significantly increased in NAcc-injected rats without background noise, while this difference disappeared in the presence of background noise in all intensities. These data proposed that the injection of 5, 7-Dihydroxytryptamine (5, 7-DHT) into nucleus accumbens will cause hyperacusis-like behavior, and strengthens the possibility of the role of serotonin and nucleus accumbens in hyperacusis., (Copyright © 2019. Published by Elsevier B.V.)

Background: Evidence has suggested that human adipose-derived stem cells (hADSCs) and low-level laser has neuroprotective effects on spinal cord injury (SCI). Therefore, the combined effect of the hADSCs and laser on neuregeneration and neuropathic pain after SCI was investigated., Methods: Forty-eight adult male Wistar rats with 200-250 g weight were used. Thirty minutes after compression, injury with laser was irritated, and 1 week following SCI, about 1 × 10 6 cells were transplanted into the spinal cord. Motor function and neuropathic pain were assessed weekly. Molecular and histological studies were done at the end of the fourth week., Results: The combined application of hADSCs and laser has significantly improved motor function recovery (p = 0.0001), hyperalgesia (p < 0.05), and allodynia (p < 0.05). GDNF mRNA expression was significantly increased in hADSCs and laser+hADSC-treated animals (p < 0.001). Finally, co-administration of hADSCs and laser has enhanced the number of axons around cavity more than other treatments (p < 0.001)., Conclusions: The results showed that the combination of laser and ADSCs could significantly improve the motor function and alleviate SCI-induced allodynia and hyperalgesia. Therefore, using a combination of laser and hADSCs in future experimental and translational clinical studies is suggested.

Background: Myocardial ischemia-reperfusion (IR) injury is a leading cause of death all over the world, so developing practical approaches to promote cardioprotection against IR injury is essential. Exercise training is an effective strategy to improve cardioprotection. Hence, the purpose of this study was to investigate the effect of short-term preconditioning with two types of high-intensity interval training (HIIT) and moderate intensity continuous training (MICT) on klotho and TRPC6 mechanisms in cardioprotection., Methods: Eighty Male Wistar rats (250-300 g) were randomly divided into 7 groups, including Control, HIIT, MICT, Sham, IR, HIIT+IR, and MICT+IR. Training was performed in 5 consecutive days. HIIT protocol consisted of running on the treadmill at intervals 85-90% vo 2 max that separated by slow intensity periods at 50-60% vo 2 max. MICT program was performed at 70% VO 2 max at the same running distance with HIIT groups. The cardiac IR injury was induced by LAD occlusion followed by reperfusion. ELISA kit was used in order to measure the plasma levels of klotho, LDH and CK-MB, and TRPC6 expression was determined using the western blot technique. Data were analyzed using one way ANOVA and Tukey's post hoc tests., Results: The results of this study showed that both types of exercise training programs significantly increase plasma levels of klotho and reduce the infarct size and heart injury. In addition, the exercise training decreased the amount of TRPC6 channels expression during IR. However, the effect of HIIT on increasing the klotho and cardioprotection was greater compared to MICT., Conclusions: Based on the results, even a short-term of aerobic exercise training, especially HIIT, promotes cardioprotection against IR injury and decreases infarct size via an increase in klotho and attenuate of protein expression of myocardial TRPC6 during IR.

Background: The increase of oxidant compounds is the most well-known reasons for the tolerance to the analgesic properties of Morphine. Additionally, the production of proxy-nitrite impairs receptors, proteins and enzymes involved in the signaling pathways of analgesia, apoptosis and necrosis. Also, we revised all patents relating to opioid tolerance control methods., Objective: The aim of this study was to assess the effects of Alpha-tocopherol as an anti-oxidant agent to reduce Morphine tolerance., Method: Forty male rats randomly divided into four groups. 10 mg/kg of morphine was injected subcutaneously to create the desired level of tolerance. After modeling, 70 mg/kg Alpha- Tocopherol was injected intraperitoneal. Also, the hot plate recorded pain threshold alterations was used to evaluate the behavioral test. All tissue samples were extracted from the spinal cord, thalamus and frontal cortex for molecular and gene expression evaluations. Also, the effect of Alpha- Tocopherol on the apoptosis and necrosis parameters was analyzed using nissl staining and tunel test., Results: The time latency results showed that there were no significant differences in the different days in groups treated with Morphine plus Alpha-Tocopherol. However, our data highlighted that the pain threshold and their time latency in respond to it had substantially increased in comparison with the control group. Furthermore, we found that the Alpha-Tocopherol obviously decreased c-fos gene expression, especially in the spinal cord., Conclusion: Thus, co-administration of Alpha-Tocopherol with Morphine can decrease the adverse effects of nitrite proxy, which is released due to repeated injections of Morphine., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: and aim: Irisin is a new myokine that is secreted by myocytes during exercise, and plays a role in creating the beneficial effects of exercise on metabolism. Considering the benefits of exercise in reducing pain, this study was carried out to determine the probable effect of irisin on neuropathic pain in the chronic constriction injury (CCI) model in male rats., Methods: To induce neuropathic pain CCI model was used. Animals were divided into groups of control, CCI, sham, CCI + vehicle, and CCI + irisin. Animals that had undergone CCI were divided into 6 groups and each received a different intrathecal dose of irisin (30, 10, 3, 1, 0.3, and 0.1 μg/kg) via intrathecal administration. To evaluate the chronic effect of irisin, its effective dose was injected for 14 days in another group of animals. At the end of the experiment, animals were ranscardially perfused and their spinal cord tissue was prepared for immunohistochemical and hematoxylin-eosin staining., Results: The results showed that in acute intrathecal injection of irisin, 1 μg/kg dose has the highest analgesic effect compared to other doses. Nevertheless, in chronic administration of irisin with 1 μg/kg dose, no analgesic effect was detected. In addition, irisin administration could not increase the expression level of GABAB1 and B2 or prevent the decline in the number of neurons., Conclusion: The findings of the present study showed that acute administration of Irisin increases the pain threshold, but the chronic injection of resin does not have an effect on pain reduction and the expression of GABA receptors and it seems that this peptide is not a proper replacement for exercise in patients with neuropathic pain, who cannot exercise., (Copyright © 2018. Published by Elsevier B.V.)

There are considerable disagreements on the application of olfactory ensheathing cells (OEC) for spinal cord injury (SCI) rehabilitation. The present meta-analysis was designed to investigate the efficacy of OEC transplantation on motor function recovery and neuropathic pain alleviation in SCI animal models. Accordingly, all related studies were identified and included. Two independent researchers assessed the quality of the articles and summarized them by calculating standardized mean differences (SMD). OEC transplantation was shown to significantly improve functional recovery (SMD = 1.36; 95% confidence interval: 1.05-1.68; p < 0.001). The efficacy of this method was higher in thoracic injuries (SMD = 1.41; 95% confidence interval: 1.08-1.74; p < 0.001) and allogeneic transplants (SMD = 1.53; 95% confidence interval: 1.15-1.90; p < 0.001). OEC transplantation had no considerable effects on the improvement of hyperalgesia (SMD = -0.095; 95% confidence interval: -0.42-0.23; p = 0.57) but when the analyses were limited to studies with follow-up ≥8 weeks, it was associated with increased hyperalgesia (SMD = -0.66; 95% confidence interval: -1.28-0.04; p = 0.04). OEC transplantation did not affect SCI-induced allodynia (SMD = 0.54; 95% confidence interval: -0.80-1.87; p = 0.43). Our findings showed that OEC transplantation can significantly improve motor function post-SCI, but it has no effect on allodynia and might lead to relative aggravation of hyperalgesia.

Introduction: The effect of Low Level Laser Therapy (LLLT) as a non-invasive treatment of spinal cord injury (SCI) is still under investigation. Therefore, the present study aimed to evaluate the effectiveness of LLLT on neuropathic pain and interleukin-6 (IL-6) expression following SCI in male rats., Methods: 46 adult male rats were divided into 5 groups of control, SCI, treatment with methylprednisolone sodium succinate (MPSS), 1-week LLLT and 2-week LLLT. Animals underwent behavioral evaluations for motor behavior, level of allodynia and hyperalgesia every week. At the end, spinal cord was extracted and IL-6 level was assessed by ELISA method., Results: Treatment with MPSS and 2-week LLLT had led to motor function recovery (df: 24, 145; F=223.5; p <0.001). SCI did not affect mechanical (df: 24, 145; F=0.5; p=0.09), and cold allodynia (df: 24, 145; F=0.3; p=0.17) but significantly increased mechanical (df: 24, 145; F=21.4; p<0.001) and heat hyperalgesia (df: 24, 145; F=16.1; p<0.001). Treatment with MPSS and 1 and 2-weeks LLLT improved mechanical hyperalgesia (p<0.05) and heat hyperalgesia (p<0.01). The increased level of IL-6 following SCI was also compensated by administration of MPSS or LLLT (df: 4, 10; F=8.74; p=0.003)., Conclusion: Findings show that long periods of LLLT have better effects in improving the complication of SCI. In summation, since LLLT does not cause the side effects of MPSS, long-term use of LLLT may be a proper alternative for MPSS in decreasing post SCI side effects., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Oxidative stress in obese people is an important pathogenic mechanism of an obesity-associated metabolic syndrome. We evaluated the association between circulating leptin levels with biomarkers of oxidative stress in overweight and obese participants. Methods: This study was performed on 189 overweight and obese people aged 18-60 years old. Serum leptin, superoxide dismutase (SOD), high-sensitivity C-reactive protein (hs-CRP), homocysteine (Hcy), thiobarbituric acid reactive substances (TBARS) and amyloid A (SAA) concentrations were measured. Pearson correlation and multiple linear regressions were used to assess the relationships. Results: We found that among the biomarkers of oxidative stress and inflammation in participants, serum hs-CRP and SAA were positively correlated with BMI (β=0.003, P<0.001 and β=7.83, P<0.001, respectively). This relationship remained significant even after controlling other oxidative stress and inflammatory indicators (β=0.003, p<0.001 for hs-CRP), but this association disappeared for SAA. In addition, serum hs-CRP was positively correlated with leptin (β=0.001, p=0.003). Regression analysis showed that there was no association between serum Hcy, SAA, TBARS and SOD with serum leptin concentrations Conclusion: Overall, the current study demonstrated that serum hs-CRP and SAA levels were independently correlated with BMI. Furthermore, serum hs-CRP was positively correlated with leptin. Focusing on such strategies may lead to promises for alleviating obesity and its co-morbidities.

Background: Neuropathic pain is a chronic pain condition, which is resistant to therapy. Ascorbate was released because of the activation of glutaminergic neurons. Due to the important role of N-methyl-D-aspartate (NMDA) receptors in the pathophysiology of neuropathic pain, this study investigated the analgesic efficacy of ascorbic acid (AA) in neuropathic pain condition and the role of NMDA receptors in this effect., Methods: For this purpose, adult male rats were randomly allocated to experimental groups (n=8 in each group). Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. During the second week after CCI, animals received a single injection of 1, 3, 5, or 10 mg/kg of AA intraperitoneally and pain threshold was determined 15 and 60 min later. The antinociceptive effect of chronic administration was also evaluated by intraperitoneal injection (IP) of 3 mg/kg AA for 3 weeks. To determine the role of NMDA receptors, separate groups of animals 30 min after single injection of AA (1 mg/kg) animals received i.p. injection of ketamine (5 mg/kg), MK-801 (0.01 mg/kg), or glutamate (1000 nmol) and were tested 20 min afterwards. Data analyzed by ANOVA and Newman-Keuls tests and p<0.05 were considered as significant., Results: IP of 3, 5 and 10 mg/kg increased the pain threshold during the second week after CCI (p<0.05, F=3 in tactile allodynia and p<0.01, F=3.2 in thermal and mechanical hyperalgeisa). Chronic administration of AA also produced antinociceptive effect. Ascorbic acid (1 mg/kg, i.p.) inhibited MK-801 and ketamine-induced antinociception response significantly (p<0.001, F=2). It also prevented the analgesic effect of glutamate administration (p<0.001, F=2)., Conclusions: The results indicated that AA produced a dose-dependent antinociceptive effect that seems to mediate through its interaction with NMDA receptors.

After spinal cord injury (SCI) there are many recoveries inhibiting factors such as chondroitin sulfate proteoglycan (CSPG) and inflammation. The present study investigated the combinational effect of low level laser therapy (LLLT) as anti-inflammatory agent and Chondroitinase ABC (ChABC) enzyme as CSPG digesting factor on spinal cord after injury. This study performed on 44 male Wistar rats, spinal cord injury induced by a clip compression injury. Animals received two-weeks treatment of 660nm low level laser (LLL) and intraspinal injection of 1μg ChABC. Functional recovery, cavity size, myelination, axonal projections around the cavity, fibroblast invasion and expression of glycogen synthase kinase-3β (GSk 3β), CSPG and aquaporin 4 (AQP4) expression were evaluated. In statistical evaluation p<0.05 considered significant. Result showed the combination of LLLT and ChABC have more effect on reduction of cavity size, improvement of myelination and number of axons around the cavity and decreasing the expression of GSK3β, CSPG and AQP4 expression compared to LLLT and ChABC alone. In the laser and laser+enzyme groups AQP4 expression decreased significantly after SCI. Functional recovery, improved in LLLT and ChABC treated animals, but higher recovery belonged to the combination therapy group. The current study showed combination therapy by LLLT and ChABC is more efficient than a single therapy with each of them., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Apelin is an endogenous ligand for apelin receptor (APJ) with analgesic effect on visceral, analgesic and proanalgesic influences on acute pains in animal models. The purpose of this study was to determine the possible analgesic effects of [Pyr 1 ] apelin-13 on chronic pain after spinal cord injury (SCI) in rats. Animals were randomly divided into three major groups as intact, sham and SCI. The SCI group randomly allocated to four subgroups as no treatment, vehicle-treatment (normal saline: 10μl, intrathecally) and two subgroups with intrathecal injection (i.t) of 1μg and 5μg of [Pyr 1 ] apelin-13. After laminectomy at T6-T8 level, spinal cord compression injury was induced using an aneurysm clip. Vehicle or [Pyr 1 ] apelin-13 injected from day1 post SCI and continued for a week on a daily basis. Pain behaviors and locomotor activity were monitored up to 8weeks. At the end of the experiments, intracardial paraformaldehyde perfusion was made under deep anesthesia in some animals for histological and immunohistochemistry evaluations. Western blot technique was also done to detect caspase-3 in fresh spinal cord tissues. SCI decreased nociceptive thresholds and locomotor scores. Administration of [Pyr 1 ] apelin-13 (1μg and 5μg) improved locomotor activity and reduced pain symptoms, cavity size and caspase-3 levels. Results showed long-term beneficial effects of [Pyr 1 ] apelin-13 on neuropathic pain and locomotion. Therefore, we may suggest [Pyr 1 ] apelin-13 as a new option for further neuropathic pain research and a suitable candidate for ensuing clinical trials in spinal cord injury arena., (Copyright © 2016 Elsevier Ltd. All rights reserved.)