Farinaz Nasirinezhad

The Effect of Bone Marrow–Derived Mesenchymal Stem Cell Transplantation on Allodynia and Hyperalgesia in Neuropathic Animals: A Systematic Review with Meta-Analysis

Stem cell transplantation has been considered a possible therapeutic method for neuropathic pain. However, no quantitative data synthesis of stem cell therapy for neuropathic pain exists. Therefore, the present systematic review and meta-analysis assessed the efficacy of bone marrow mesenchymal stem cell (BMMSC) transplantation on alleviating pain symptoms in animal models of neuropathic pain. In the present meta-analysis, controlled animal studies assessing the effect of administrating BMMSC on neuropathic pain were included through an extensive literature search of online databases. After collecting data, effect sizes were computed and the standardized mean difference (SMD) with 95% confidence interval (CI) was entered in all analyses. Random-effects models were used for data analysis. Sensitivity and subgroup analyses were performed to investigate expected or measured heterogeneity. Finally, 14 study were included. The analyses showed that BMMSC transplantation lead to significant improvement on allodynia (SMD = 2.06; 95% CI, 1.09 to 3.03; I(2) = 99.7%; P < .001). The type of neuropathy (P = .036), time between injury and intervention (P = .02), and the number of transplanted cells (P = .023) influence the improvement of allodynia after BMMSC transplantation. BMMSC transplantation has no effect on hyperalgesia (SMD = .3; 95% CI, -1.09 to 1.68; I(2) = 100%; P < .001) unless it occurs during the first 4 days after injury (P = .02). The present systematic review with meta-analysis suggests that BMMSC transplantation improves allodynia but does not have any significant effect on hyperalgesia unless it is given during the first 4 days after injury.

The efficacy of Schwann cell transplantation on motor function recovery after spinal cord injuries in animal models: A systematic review and meta-analysis.

AIM This article aimed to assess the efficacy of Schwann cell transplantation on motor function recovery in animal model of spinal cord injuries via meta-analysis. METHODS An extended search was carried out in the electronic databases of Medline (via PubMed), EMBASE (via OvidSP), CENTRAL, SCOPUS, Web of Science (BIOSIS), and ProQuest. Finally, 41 eligible studies conducted on 1046 animals including 517 control animals and 529 transplanted animals were included in the meta-analysis. Pooled standardized mean difference (SMD) and odds ratio (OR) with 95% confidence interval (95% CI) were reported. RESULTS The findings showed that treatment with Schwann cells leads to a modest motor function recovery after spinal cord injury (SMD=0.85; 95% CI: 0.63-1.07; p<0.001). Transplantation of these cells in acute phase of the injury (immediately after the injury) (OR=4.30; 95% CI: 1.53-12.05; p=0.007), application of mesenchymal/skin-derived precursors (OR=2.34; 95% CI: 1.28-4.29; p=0.008), and cells with human sources are associated with an increase in efficacy of Schwann cells (OR=10.96; 95% CI: 1.49-80.77; p=0.02). Finally, it seems that the efficacy of Schwann cells in mice is significantly lower than rats (OR=0.03; 95% CI: 0.003-0.41; p=0.009). CONCLUSION Transplantation of Schwann cells can moderately improve motor function recovery. It seems that inter-species differences might exist regarding the efficacy of this cells. Therefore, this should be taken into account when using Schwann cells in clinical trials regarding spinal cord injuries.

Spinal 5-HT3 receptor mediates nociceptive effect on central neuropathic pain; possible therapeutic role for tropisetron

Objectives: To test the analgesic effect of 5-HT-3 receptor antagonist, tropisetron, in a clip compression injury model of spinal cord pain in rats. Methods: Four weeks post compression of the spinal cord at lumbar level, tropisetron was administered intrathecally at 100 μg and 150 μg dosages. Behavioral tests were assessed before administration. Fifteen minutes after injection, behavioral tests were repeated. Randall-Sellitto and plantar test was used for mechanical and thermal hyperalgesia, respectively. Mechanical and cold allodynia were evaluated by Von Frey filament and acetone droplets, respectively. The analgesic effect of tropisetron was compared with intrathecal administration of salicylate. Locomotor score was evaluated by Basso, Beattie and Bresnahan (BBB) test every week after spinal cord injury. Results: Intrathecal administration of tropisetron, decreased hyperalgesia and mechanical allodynia, but not cold allodynia were observed after compression of the spinal cord. Conclusion: Blockade of 5-HT-3 receptors by tropisetron at the spinal level induces an antinociceptive effect on chronic central neuropathic pain and suggests that this compound may have potential clinical utility for the management of central neuropathic pain, particularly in patients with hyperalgesia and tactile allodynia.

Anti-allodynic Efficacy of NMDA Antagonist Peptide and Noradrenaline Alone and in Combination in Rodent Neuropathic Pain Model.

Background The present experiment was conducted to identify the cooperative effect of serine histogranin (SHG) and noradrenaline in alleviating peripheral neuropathic pain. Methods Chronic constriction injury of the right sciatic nerve was used to induce chronic neuropathic pain. For drug delivery, a PE10 tube was inserted into the subarachnoid space. Acetone drops and a 44℃ water bath were used to evaluate the cold and heat allodynia, respectively. Placing and grasping reflexes were used to assess the locomotor system. Results SHG at 0.5 and 1 µg significantly (P < 0.05) decreased the thermal allodynia. The cold allodynia was also significantly reduced by intrathecal injections of 0.5 (P < 0.05) and 1 µg (P < 0.001) of SHG. 1 µg of noradrenaline, but not 0.5 µg, significantly alleviated the cold (P < 0.01) and thermal (P < 0.05) allodynia. The ameliorating effect of noradrenaline or SHG disappeared when the two compounds were administrated in equal concentrations. A significant difference (P < 0.01 in the acetone and P < 0.05 in the heat) was observed in the groups under equal doses of the two compounds, with a lower effectiveness of the combination therapy. Conclusions Our findings suggest that the simultaneous administrations of noradrenaline and SHG do not result in synergistic analgesia, and combination therapy may not be a good approach to the treatment of chronic neuropathic pain syndrome.

Chronic administration of [Pyr1] apelin-13 attenuates neuropathic pain after compression spinal cord injury in rats

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 [Pyr1] 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 [Pyr1] apelin-13. After laminectomy at T6-T8 level, spinal cord compression injury was induced using an aneurysm clip. Vehicle or [Pyr1] 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 [Pyr1] 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 [Pyr1] apelin-13 on neuropathic pain and locomotion. Therefore, we may suggest [Pyr1] apelin-13 as a new option for further neuropathic pain research and a suitable candidate for ensuing clinical trials in spinal cord injury arena.

Transplantation of olfactory ensheathing cells on functional recovery and neuropathic pain after spinal cord injury; systematic review and meta-analysis

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.

The effect of intrathecal injection of irisin on pain threshold and expression rate of GABAB receptors in peripheral neuropathic pain model

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.

Association between the circulating leptin levels and the biomarkers of oxidative stress and inflammation among Iranian overweight and obese adults

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.

Combine effect of Chondroitinase ABC and low level laser (660 nm) on spinal cord injury model in adult male rats

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.

The role of low level laser therapy on neuropathic pain relief and interleukin-6 expression following spinal cord injury: An experimental study

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.