Brain-derived Neurotrophic Factor In Spinal Cord Research Articles

The effect of serotonin-noradrenaline reuptake inhibitor duloxetine on the intervertebral disk-related radiculopathy in rats.

Neuropathic pain, commonly related to intervertebral disk (IVD) degeneration, responds poorly to standard pain treatments. Serotonin-noradrenaline reuptake inhibitors (SNRIs) have been reported to reduce neuropathic pain; however their effect on radiculopathy induced by lumbar disk herniation remains unclear. The aim of this study was to investigate the effect of SNRI duloxetine in rat model of IVD-related neuropathic pain. Effects of SNRI duloxetine were tested in Sprague-Dawley rats (n = 135). Neuropathic pain was induced by applying autologous nucleus pulposus (NP) on the left L5 dorsal root ganglion (DRG). Duloxetine in concentrations 0.4 mg/kg (low dose) and 1.2 mg/kg (high dose) or saline were administered orally for 10 days. Von Frey test was carried out on post-operative days 2, 7, 14, 21, and 28 to test pain sensitivity. Immunohistochemistry of L5 DRG and L5 segment of spinal cord (SC) was performed on days 7 and 21 to examine expressions of tumor necrosis factor alpha (TNF), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and ionized calcium-binding adapter molecule 1 (Iba1). On days 14, 21, and 28, expressions of TNF in DRG as well as NGF and BDNF in SC were tested by immunoblotting. Sham-operated rats and naive rats were used as controls. Duloxetine in both concentrations significantly improved pain threshold from postoperative day 21 onward, compared to the NP + saline group (p < 0.05). High-dose duloxetine significantly inhibited the expression of TNF in DRG (day 28, p < 0.05). Both duloxetine concentrations reduced the expression of NGF in SC (day 21, p < 0.05), but the expression of BDNF remained unchanged. SNRI duloxetine inhibited neuropathic pain in rats possibly via down-regulating TNF, NGF, and microglia activation. We conclude that duloxetine, and most likely other SNRIs, may be used for the management of lumbar neuropathic pain.

Short- but Not Long-Term Melatonin Administration Reduces Central Levels of Brain-Derived Neurotrophic Factor in Rats with Inflammatory Pain

Objective: To evaluate the effect of short- and long-term administration of melatonin on central brain-derived neurotrophic factor (BDNF) levels in rats with acute and chronic inflammatory pain. Methods: The animals were allocated to one of two experiments: experiment 1 or experiment 2. In experiment 1, all animals were injected with complete Freund's adjuvant (CFA) to induce inflammation and were randomly allocated to receiving melatonin (60 mg/kg) or vehicle. Injections were administered 1 h after CFA and once daily for 2 more days (for a total of 3 days of melatonin administration). In experiment 2, fifteen days after CFA injection, the animals were treated with melatonin (50 mg/kg) or vehicle for 8 days. The animals were killed by decapitation 24 h after the last melatonin or vehicle administration, and an ELISA assay was performed to detect BDNF expression in the spinal cord, brainstem, and prefrontal cortex of the rats in both groups. Data were analyzed using Student's t test and the results are expressed as means ± SEM. Results: In the first experiment, the BDNF levels of the melatonin group were reduced in the prefrontal cortex (Student's t test, p = 0.01) and increased in the spinal cord (Student's t test, p = 0.04). In experiment 2, BDNF levels were similar in both groups for all structures (Student's t test, p > 0.00 for all). A two-way ANOVA reveled a significant effect of structures (p = 0.0001) but not of treatment (p > 0.05). The prefrontal cortex presented higher BDNF levels than other structures (ANOVA/Student-Newman-Keuls test, p = 0.0001). Considering the relationship between BDNF levels in all three structures, we found an effect of central nervous system structures (p = 0.01) and an interaction between treatment and structures (p = 0.04). Conclusion: The high spinal cord BDNF levels and the low prefrontal cortical BDNF levels observed in rats with acute CFA-induced inflammation following short-term melatonin administration may be related to the pain-modulating and neuroprotective effects of this protein. Long-term melatonin administration did not alter BDNF levels in chronic inflammation.

Chronic prenatal stress epigenetically modifies spinal cord BDNF expression to induce sex-specific visceral hypersensitivity in offspring.

Irritable bowel syndrome (IBS) is a heterogeneous disorder with abdominal pain as one of the primary symptoms. The etiology of IBS remains unknown. Epidemiological studies found that a subset of these patients have a history of adverse early-life experiences. We tested the hypothesis that chronic prenatal stress (CPS) epigenetically enhances brain-derived neurotrophic factor (BDNF) in spinal cord to aggravate colon sensitivity to colorectal distension (CRD) differentially in male and female offspring. We used heterotypic intermittent chronic stress (HeICS) protocols in pregnant dams from E11 until delivery. Chronic prenatal stress induced significant visceral hypersensitivity (VHS) to CRD in male and female offspring. A second exposure to HeICS in adult offspring exacerbated VHS greater in female offspring that persisted longer than in male offspring. Chronic prenatal stress upregulated BDNF expression in the lumbar-sacral dorsal horn that correlated with the exacerbation of VHS in female, but not in male offspring. The upregulation of BDNF was due to a significant increase in RNA Pol II binding, histone H3 acetylation, and significant decrease in histone deacetylase 1 association with the core promoter of BDNF in female offspring. Other chronic prenatal and neonatal stress protocols were less effective than HeICS. The development of VHS, which contributes to the symptom of intermittent abdominal pain, is a two-step process, chronic in utero stress followed by chronic stress in adult-life. This two-step process induces aggravated and persistent colon hypersensitivity in female than in male offspring. Our preclinical model explains several clinical features in IBS patients.

Spinal Cord Brain-Derived Neurotrophic Factor Levels Increase after Dexamethasone Treatment in Male Rats with Chronic Inflammation

Dexamethasone is widely used in the therapy of chronic inflammatory diseases for its pain-modulating effects. The objective of this study was to evaluate the effect of dexamethasone on nociception and local inflammation, and the levels of brain-derived neurotrophic factor (BDNF) in the spinal cord in male rats with chronic inflammation induced by complete Freund’s adjuvant (CFA). Rats were randomly divided into a control group (not manipulated) and 2 CFA-induced chronic inflammation groups (in the 15th post-CFA injection): 1 injected with vehicle (saline solution) and 1 received dexamethasone (0.25 mg/kg) for 8 days. The hot-plate and electronic von Frey tests were performed 24 h after the end of treatment. BDNF spinal cord levels were determined by enzyme-linked immunosorbent assay (ELISA). The level of inflammation in the tibiotarsal joint (the ankle region) was evaluated histologically at the end of treatment. Dexamethasone produced significantly increased latency in the hot-plate test (one-way ANOVA, p < 0.05) and withdrawal threshold in the electronic von Frey test (p < 0.005). The dexamethasone group showed increased spinal cord BDNF levels compared to the other groups (one-way ANOVA p, < 0.05). Histological analysis showed a local inflammatory response only in animals treated with vehicle, which demonstrated that the dexamethasone treatment decreased the inflammatory process. Our findings corroborate the antinociceptive and anti-inflammatory properties of dexamethasone. In addition, we showed that the dexamethasone treatment increased BDNF levels in the spinal cord; its pain- modulating effects can be attributed to this effect.

Study on molecular mechanism for improving neural regeneration after repair of sciatic nerve defect in rat by acellular nerve allograft

Discuss the molecular mechanism for improving neural regeneration after repair of sciatic nerve defect in rat by acellular nerve allograft (ANA). Randomly divide 36 Wistar rats into six groups as normal control group, autografting group, and bridging groups of 2, 4, 8, 12 weeks, six rats for each group. Observe the expression of brain-derived neurotrophic factor (BDNF) in L(4) spinal cord and anterior tibial muscle at the injury site, calcitonin gene-related peptide (CGRP) protein as well as mRNA, respectively. 12w after operation, histopathological observation was performed. 2w after ANA bridging the sciatic nerve defect in rats, it was observed that the expression level of BDNF in spinal cord at the injury site and CGRP protein increased, reaching the peak level at 4w, lasting till 8w, then decreased but still significantly higher than that in normal control group at 12w, and was not significantly different compared with that in autografting group. However, the expression level of BDNF in anterior tibial muscle decreased gradually within the initial 4w, then increased progressively, reaching normal level at 12w, and was not significantly different compared with that in autografting group. The expression of BDNF mRNA and CGRPmRNA was essentially the same. 12w after operation, there was nerve regeneration in bridging group of 12w and autografting group. ANA possessed fine histocompatibility, and might substitute autograft to repair long-segment defect of sciatic nerve in rats. This action might be related to upregulation of protein and mRNA expression for BDNF and CGRP in spinal cord.

Involvement of spinal cord BDNF in the generation and maintenance of chronic neuropathic pain in rats

Brain-derived neurotrophic factor (BDNF) is involved in neuronal survival and synaptic plasticity of the central and peripheral nervous system. In chronic pain, plastic changes in dorsal horn neurons contribute to a phenomenon of hypersensitivity to pain sensation that is maintained over time, known as central sensitization. This process is accompanied by BDNF overexpression, but the role of BDNF in the generation and maintenance of the hyperalgesic phenomenon is still unclear. The present study was aimed to investigate if exogenous BDNF administered to the rat spinal cord, in addition to trigger pain, participates in the maintenance of the central sensitization process (i.e., pain persistence) and to determine if the pain generated is comparable to that observed in a neuropathic pain model. Results showed that a single intrathecal injection of 0.003ng of BDNF was able to decrease the nociceptive threshold (Randall–Selitto test) in normal rats, for at least a 42-day period. Furthermore, the hyperalgesia generated was comparable to that observed in rats with a 42-day history of mononeuropathy. Increasing the dose or administering additional doses of BDNF resulted neither in additional effectiveness in reducing the pain threshold nor in the prolongation of the hyperalgesic effect, thus showing that central sensitization induced by BDNF is a dose-independent, all-or-none process. It is concluded that BDNF alone is sufficient for generating a long-lasting neural excitability change in the spinal cord via tyrosine kinase B receptor signaling, similar to that observed in chronic pain models such as neuropathy.

Contribution of the spinal cord BDNF to the development of neuropathic pain by activation of the NR2B-containing NMDA receptors in rats with spinal nerve ligation

The NMDA receptor and the brain-derived neurotrophic factor (BDNF) are involved in central sensitization and synaptic plasticity in the spinal cord. To determine whether the spinal cord BDNF contributes to the development and maintenance of neuropathic pain by activation of the dorsal horn NR2B-containing NMDA (NMDA-2B) receptors, this study was designed to investigate if alterations in BDNF and its TrkB receptor in the spinal dorsal horn would parallel the timeline of the development of neuropathic pain in lumbar 5 (L5) spinal nerve ligated (SNL) rats. The enzyme-linked immunosorbent assay (ELISA) showed that the BDNF concentration significantly increased during 24 h post-surgery, and the maximal enhancement lasted for 48 h. It declined as time progressed and returned to the level of pre-operation at 28 days after SNL. In parallel with the alteration of BDNF concentration in the spinal dorsal horn, the 50% paw withdrawal threshold (PWT) of the ipsilateral hind paw in SNL rats also showed a significant decrease during 24–48 h after SNL as compared with those in sham-operated rats. The correlation analysis revealed that the BDNF concentration had a negative correlation with 50% PWT in early stage (0–48 h) ( r = -0.974, p = 0.001), but not late stage (3–28 days) ( r = 0.3395, p = 0.6605), after SNL. Similarly, the immunohistochemical staining revealed that a significant up-regulation of BDNF expression in the spinal dorsal horn appeared as early as 12 h post-operation in SNL rats, peaked at 24–48 h, declined at 3 days and disappeared at 14 days after SNL. In contrast, an increase in NMDA-2B receptors expression in the spinal dorsal horn was delayed to 48 h after SNL. The increase reached peak at 3 days, lasted for 14 days, and returned to the control level of pre-operation at 28 days after SNL. The maximal enhancement of BDNF expression occurred in early stage (24–48 h) after nerve injury, while the peak of NMDA-2B receptors expression appeared in late stage (3–14 days) post-nerve ligation. As compared with the dynamic changes of 50% PWT in the timeline after nerve injury, the maximal enhancement of BDNF expression closely paralleled the maximal decline in the slope of 50% PWT, while the peak of NMDA-2B receptors expression corresponded with the plateau of the decreased 50% PWT. Therefore, the increased BDNF in the spinal dorsal horn was likely to be associated with the initiation of neuropathic pain in early stage (0–48 h), while the activation of NMDA-2B receptors was involved in the maintenance of persistent pain states in late stage (2–14 days) after nerve injury. Moreover, the present study also demonstrated that the BDNF/TrkB-mediated signaling pathway within the spinal cord might be involved in the induction of neuropathic pain in early stage after nerve injury, and the selective NMDA-2B receptors antagonist (Ro 25-6981) almost completely blocked the BDNF-induced mechanical allodynia in all of the tested rats. These data suggested that the BDNF/TrkB-mediated signaling pathway in the spinal cord was involved in the development of nerve injury-induced neuropathic pain through the activation of dorsal horn NMDA-2B receptors.

The effect of 4-Methylcatechol treatment in chronic constrictive injury of the rat sciatic nerve on the allodynia and spinal neurotrophic factors

Background: The effect of chronic administration of 4-methylcatechol known as a neurotrophic factor inducer on the allodynia and spinal neurotrophic factors was investigated in chronic constrictive injury of sciatic nerve in rats. Methods: With the Sprague Dawly rat, sciatic nerve was loosely ligated with 4-0 chromic catgut and neuropathic pain model was made. The threshold for tactile allodynia was measured with von Frey hair by up-down method and cold allodynia was measured by dropping 20μl of 100% acetone on the dorsum of the injured foot. 4-Methylcatechol (100μg/kg, intraperitoneal) was injected once a day for 14 days and the effect on allodynia was compared with saline injected group. At 3, 7 and 14 days after injection, lumbar spinal cord was harvested and the mRNA content of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) was measure by real time PCR. Results: Mechanical and cold allodynia improved from 7 days after 4-methylcatechol administration. NGF and BDNF in spinal cord decreased compared to sham operated group. BDNF in lumbar spinal cord has increased tendency after treatment without statistical significance. Conclusions: Chronic intraperitoneal administration of 4-methylcatechol may improve tactile and cold allodynia in chronic constrictive injury rat model of neuropathic pain. The BDNF mRNA in spinal cord might increase after 4-methylcatechol treatment.