Formulation of Japanese Orthopaedic Association (JOA) clinical practice guideline for the management of low back pain- the revised 2019 edition.

BACKGROUND: The latest clinical guidelines are mandatory for physicians to follow when practicing evidence-based medicine in the treatment of low back pain. Those guidelines should target not only Japanese board-certified orthopaedic surgeons, but also primary physicians, and they should be prepared based entirely on evidence-based medicine. The Japanese Orthopaedic Association Low Back Pain guideline committee decided to update the guideline and launched the formulation committee. The purpose of this study was to describe the formulation we implemented for the revision of the guideline with the latest data of evidence-based medicine. METHODS: The Japanese Orthopaedic Association Low Back Pain guideline formulation committee revised the previous guideline based on a method for preparing clinical guidelines in Japan proposed by Medical Information Network Distribution Service Handbook for Clinical Practice Guideline Development 2014. Two key phrases, "body of evidence" and "benefit and harm balance" were focused on in the revised version. Background and clinical questions were determined, followed by literature search related to each question. Appropriate articles were selected from all the searched literature. Structured abstracts were prepared, and then meta-analyses were performed. The strength of both the body of evidence and the recommendation was decided by the committee members. RESULTS: Nine background and nine clinical qvuestions were determined. For each clinical question, outcomes from the literature were collected and meta-analysis was performed. Answers and explanations were described for each clinical question, and the strength of the recommendation was decided. For background questions, the recommendations were described based on previous literature. CONCLUSIONS: The 2019 clinical practice guideline for the management of low back pain was completed according to the latest evidence-based medicine. We strongly hope that this guideline serves as a benchmark for all physicians, as well as patients, in the management of low back pain.

Complications of spinal surgery for elderly patients with lumbar spinal stenosis in a super-aging country: An analysis of 8033 patients.

BACKGROUND: The Japanese Society for Spine Surgery and Related Research (JSSR) performed a third study on complications in spinal surgery in 2011. The purpose was to present information about surgery and complications in a large amount of elderly patients aged 65 years with lumbar spinal stenosis (LSS) without coexisting spondylolisthesis, spondylolysis, or scoliosis, and to compare patients aged ≥80 years to those aged 65-79 years. METHODS: A recordable optical disc for data storage was sent by JSSR in January 2012 to 1105 surgeons certified by the JSSR in order to collect surgical data. Data were returned by the end of May 2012. RESULTS: Data were accumulated for 8033 patients aged 65 years. The incidence of surgical complications was 10.8%, and did not differ significantly between age groups. The incidence of general complications was 2.7%, and differed significantly between age groups (p < 0.005). The highest incidence of surgical complications was for dural tear (DT) (3.6%), followed by deep wound infection (DWI) (1.4%), neurological complications (1.3%), and epidural hematoma (1.3%). Spinal instrumentation was applied in 30.3%. Incidences of surgical complications in instrumented and noninstrumented surgery were 17.3% and 8.8%. In instrumented surgery, incidences of surgical and general complications were higher in the ≥80 year age group than in the 65-79 year age group. Logistic regression analyses showed patients with microendoscopic surgery at increased risk of DT. Patients with diabetes mellitus and instrumented surgery showed increased risks of DWI. CONCLUSIONS: Incidences of surgical complications did not differ significantly between age groups. Attention should be paid to both surgical and general complications, particularly for postoperative mental disease in instrumented surgery for patients≥80 years old.

Altered Gene Expression of RNF34 and PACAP Possibly Involved in Mechanism of Exercise-Induced Analgesia for Neuropathic Pain in Rats.

Despite the availability of several modalities of treatment, including surgery, pharmacological agents, and nerve blocks, neuropathic pain is often unresponsive and sometimes progresses to intractable chronic pain. Although exercise therapy is a candidate for treatment of neuropathic pain, the mechanism underlying its efficacy has not been elucidated. To clarify the molecular mechanism for pain relief induced by exercise, we measured Rnf34 and Pacap mRNA levels in the spinal cord dorsal horn of SNL rats, a model of neuropathic pain. SNL model rats exhibited stable mechanical hyperalgesia for at least 6 weeks. When the rats were forced to exercise on a treadmill, mechanical and thermal hyperalgesia were significantly ameliorated compared with the non-exercise group. Accordingly, gene expression level of Rnf34 and Pacap were also significantly altered in the time course analysis after surgery. These results suggest that exercise therapy possibly involves pain relief in SNL rats by suppressing Rnf34 and Pacap expression in the spinal cord.

Japanese 2011 nationwide survey on complications from spine surgery.

BACKGROUND: The Japanese Society for Spine Surgery and Related Research (JSSR) previously carried out two nationwide surveys in 1994 and 2001 on complications from spine and spinal cord surgery. More than 10 years have now elapsed since 2001. Rapidly ageing populations have major impacts on society, particularly in the medical field. The purpose of this study was therefore to examine the present situation for spine surgery in Japan. METHODS: The JSSR research team prepared a computerized questionnaire made up of two categories in order to capture clinicopathological information and surgical information. A recordable optical disc for data storage was sent to surgeons who were certified for spine surgery by JSSR. The data was analyzed. RESULTS: The JSSR carried out a nationwide survey of complications of 31,380 patients. Patients aged 60 years or older comprised 63.1 % of the overall cohort. This was considerably higher than observed in previous surveys. Degenerative spinal diseases increased 79.7 %. With regard to surgical approach, the incidence of anterior surgery has decreased, while that of posterior surgery has increased compared to the earlier surveys (both p < 0.05). Spinal instrumentation was applied in 30.2 % cases, compared to 27.0 and 34.0 % cases in the 1994 and 2001 surveys, respectively. Intraoperative and postoperative complications were reported in 10.4 % and were slightly increased compared to 8.6 % in the earlier surveys (both p < 0.05). Diseases associated with a high incidence of complication included intramedullary tumor (29.3 %) and primary malignant tumor (22.0 %). The highest incidence of complication was dural tear (2.1 %), followed by neurological complication (1.4 %).

Evaluation of Injured Axons Using Two-Photon Excited Fluorescence Microscopy after Spinal Cord Contusion Injury in YFP-H Line Mice.

Elucidation of the process of degeneration of injured axons is important for the development of therapeutic modules for the treatment of spinal cord injuries. The aim of this study was to establish a method for time-lapse observation of injured axons in living animals after spinal cord contusion injury. YFP (yellow fluorescent protein)-H transgenic mice, which we used in this study, express fluorescence in their nerve fibers. Contusion damage to the spinal cord at the 11th vertebra was performed by IH (Infinite Horizon) impactor, which applied a pressure of 50 kdyn. The damaged spinal cords were re-exposed during the observation period under anesthesia, and then observed by two-photon excited fluorescence microscopy, which can observe deep regions of tissues including spinal cord axons. No significant morphological change of injured axons was observed immediately after injury. Three days after injury, the number of axons decreased, and residual axons were fragmented. Seven days after injury, only fragments were present in the damaged tissue. No hind-limb movement was observed during the observation period after injury. Despite the immediate paresis of hind-limbs following the contusion injury, the morphological degeneration of injured axons was delayed. This method may help clarification of pathophysiology of axon degeneration and development of therapeutic modules for the treatment of spinal cord injury.

Intravital multiphoton fluorescence imaging and optical manipulation of spinal cord in mice, using a compact fiber laser system.

BACKGROUND AND OBJECTIVE: Near-infrared ultrafast lasers are widely used for multiphoton excited fluorescence microscopy in living animals. Ti:Sapphire lasers are typically used for multiphoton excitation, but their emission wavelength is restricted below 1,000 nm. The aim of this study is to evaluate the performance of a compact Ytterbium-(Yb-) fiber laser at 1,045 nm for multiphoton excited fluorescence microscopy in spinal cord injury. MATERIALS AND METHODS: In this study, we employed a custom-designed microscopy system with a compact Yb-fiber laser and evaluated the performance of this system in in vivo imaging of brain cortex and spinal cord in YFP-H transgenic mice. RESULTS: For in vivo imaging of brain cortex, sharp images of basal dendrites, and pyramidal cells expressing EYFP were successfully captured using the Yb-fiber laser in our microscopy system. We also performed in vivo imaging of axon fibers of spinal cord in the transgenic mice. The obtained images were almost as sharp as those obtained using a conventional ultrafast laser system. In addition, laser ablation and multi-color imaging could be performed simultaneously using the Yb-fiber laser. CONCLUSION: The high-peak pulse Yb-fiber laser is potentially useful for multimodal bioimaging methods based on a multiphoton excited fluorescence microscopy system that incorporates laser ablation techniques. Our results suggest that microscopy systems of this type could be utilized in studies of neuroscience and clinical use in diagnostics and therapeutic tool for spinal cord injury in the future.

Different analgesic effects of adenosine between postoperative and neuropathic pain.

BACKGROUND: Adenosine is an endogenous neuromodulator in both the peripheral and central nervous systems. Adenosine inhibits pain signals by hyperpolarizing neuronal membrane. METHODS: To clarify the effects of adenosine on pain signals, we tested intrathecal adenosine injection in two neuropathic pains (spinal cord compression and chronic constriction of sciatic nerve) and postoperative pain (plantar incision). RESULTS: In all three kinds of pain models, significant shortening of withdrawal latencies to thermal stimulation were detected from 24 h to 1 week after the surgery. Significant improvements of pain sensation were observed in all three models after intrathecal injection of Cl-adenosine 24 h after surgery. At 72 h after surgery, intrathecal Cl-adenosine injection inhibited hyperalgesia in the two neuropathic pain models but not in the postoperative pain model. Adenosine A1R messenger RNA (mRNA) expression significantly decreased in the plantar incision model. Adenosine A1R protein levels also decreased compared with the other two models and normal control. CONCLUSIONS: These results suggest that adenosine effectively inhibits pain signals in neuropathic pain but is less effective in postoperative pain because of the decrease in adenosine A1 receptors.

3-D MRI/CT fusion imaging of the lumbar spine.

OBJECTIVE: The objective was to demonstrate the feasibility of MRI/CT fusion in demonstrating lumbar nerve root compromise. MATERIALS AND METHODS: We combined 3-dimensional (3-D) computed tomography (CT) imaging of bone with 3-D magnetic resonance imaging (MRI) of neural architecture (cauda equina and nerve roots) for two patients using VirtualPlace software. RESULTS: Although the pathological condition of nerve roots could not be assessed using MRI, myelography or CT myelography, 3-D MRI/CT fusion imaging enabled unambiguous, 3-D confirmation of the pathological state and courses of nerve roots, both inside and outside the foraminal arch, as well as thickening of the ligamentum flavum and the locations, forms and numbers of dorsal root ganglia. Positional relationships between intervertebral discs or bony spurs and nerve roots could also be depicted. CONCLUSION: Use of 3-D MRI/CT fusion imaging for the lumbar vertebral region successfully revealed the relationship between bone construction (bones, intervertebral joints, and intervertebral disks) and neural architecture (cauda equina and nerve roots) on a single film, three-dimensionally and in color. Such images may be useful in elucidating complex neurological conditions such as degenerative lumbar scoliosis(DLS), as well as in diagnosis and the planning of minimally invasive surgery.

Resolution of intraspinal retro-odontoid cyst associated with os odontoideum after posterior fixation.

STUDY DESIGN: A case report and review of previous literature. OBJECTIVES: To describe the diagnosis and successful treatment of an intraspinal retro-odontoid cyst associated with an os odontoideum. SUMMARY OF BACKGROUND DATA: Retro-odontoid cysts associated with atlantoaxial instability are extremely rare. Direct excision of the cysts has commonly been performed for the surgical treatment of myelopathy. METHODS: A retro-odontoid cyst in a 58-year-old woman with os odontoideum was treated surgically by posterior fixation between C1 and C3 without resection of the retro-odontoid mass. The patient's history, clinical examination, imaging findings, and treatment are reported. RESULTS: The patient experienced walking difficulty, numbness in the upper and lower limbs, and hypesthesia in both hands. Congenital C2/3 fusion and atlantoaxial instability associated with an os odontoideum were found in the radiographs. Magnetic resonance imaging detected a round retro-odontoid mass, which compressed the spinal cord. The mass showed uniform low intensity on T1-weighted images and uniform high signal intensity on T2-weighted images. Gadolinium-diethylenetriaminepenta-acetic acid-enhanced T1-weighted images showed rim enhancement of the mass with no internal enhancement. Three months after the operation, the mass was no longer visible in a magnetic resonance imaging examination and the patient completely recovered motor function in her extremities. CONCLUSIONS: Posterior fixation without resection was successfully used to eliminate a retro-odontoid cyst associated with atlantoaxial instability.

Risk Factors for Delirium after Spine Surgery: An Age-Matched Analysis.

STUDY DESIGN: A retrospective cohort study. PURPOSE: To investigate the risk factors for postoperative delirium after spine surgery, excluding older age, which has already been established as a strong risk factor. OVERVIEW OF LITERATURE: More than 30 risk factors have been reported for delirium after spine surgery, making it challenging to identify which factors should be prioritized. We hypothesized that risk factors could not be prioritized to date because the factor of older age is very strong and influenced other factors. To eliminate the influence of older age, we performed an age-matched group comparison analysis for the investigation of other risk factors. METHODS: This study involved 532 patients who underwent spine surgery. Two patients of the same age without delirium (delirium negative group) were matched to each patient with delirium (delirium positive group). Differences in suspected risk factors for postoperative delirium between the two groups identified from previous reports were analyzed using univariate analysis. Multivariate analysis was performed for factors that showed a significant difference between the two groups in the univariate analysis. RESULTS: Fifty-nine (11.1%) of 532 patients developed postoperative delirium after spine surgery. Large amounts of intraoperative bleeding, low preoperative concentration of serum Na, high postoperative (day after surgery) serum level of C-reactive protein, low hematocrit level, low concentration of albumin, and high body temperature were detected as significant risk factors in the univariate analysis. Large amounts of intraoperative bleeding remained a risk factor for postoperative delirium in the multivariate analysis. CONCLUSIONS: We should pay attention to and take precautions against the occurrence of postoperative delirium after spine surgery in patients of older age or those who experience severe intraoperative bleeding.

A periosteal chondroma in the lumbar spinal canal. Case report.

Periosteal chondromas located in the spine are rare. The authors document a case of periosteal chondroma in the lumbar spinal canal of a 77-year-old man. The patient had severe pain in his right leg and used a wheelchair because of weakness in both legs. Magnetic resonance imaging revealed a round tumor that was hypo- or isointense on T1-weighted images and uniformly hyperintense on T2-weighted images. Administration of gadolinium-diethylenetriamine pentaacetic acid resulted in margin enhancement on T1-weighted images. During the operation, a round tumor 1.5 cm in diameter was found on the surface of the anterior wall of the L-3 lamina. Histological examination revealed that the tumor consisted of chondroid tissue with typical chondrocytes, indicating that it was a periosteal chondroma.

Spinal fusion in a patient with Fukuyama congenital muscular dystrophy.

Many studies have evaluated surgical treatments for spinal deformities in patients with neuromuscular disease. However, few reports have described patients with Fukuyama congenital muscular dystrophy (FCMD). A 13-year-old boy with FCMD was unable to sit for long periods or sleep in the supine position because of progressive scoliosis. His Cobb angle worsened from 27° to 41° in 5months. He underwent standard posterior spinal fusion and pedicle-screw-alone fixation from T5 to S1. Postoperatively, his Cobb angle improved from 41° to 25° without exacerbation for 2years. After the surgery, he was able to sit for longer periods without pain, and he and his family were satisfied with the efficacy of the spinal fusion. Some patients with mild FCMD can sit at the age of puberty, but progression to scoliosis is possible. Therefore, spinal fusion for progressive scoliosis in patients with FCMD should be considered.

Surgical and general complications in 2,961 Japanese patients with cervical spondylotic myelopathy: Comparison of different age groups.

Introduction: Details of surgical and general complications for patients with cervical spondylotic myelopathy (CSM) are still uncertain. The purpose of this study was to describe surgeries and their complications among Japanese patients with CSM. Methods: The Japanese Society for Spine Surgery and Related Research performed a nationwide survey on spine surgery and complications in 2011. Data of patients with 2,961 CSM >40 years old were included. The clinicopathological variables were basic demographic and clinical information, surgical information, and surgical and general complications. To examine the influence of age, variables were compared among three age groups: patients 40-64 (n=1,123), 65-74 (n=966), and ≥75 (n=872) years of age. Results: The study included 1,970 males and 991 females and the mean age was 64.3 years old. There were 168 anterior (5.7%) and 2,770 posterior (94.2%) approach surgeries. The vast majority of patients with CSM were treated using the posterior approach, 89.4% of whom had decompression surgery only. Anterior surgeries were more common in the younger age group, but posterior surgeries were equally distributed. The incidence of total complications including surgical/general complications was similar for the anterior (16/168; 9.5%) and posterior (295/2,770; 10.6%) approaches. No patient died on the operating table, but four patients (0.1%) died within one month after surgery. No association was detected between complications and age, comorbidity, and other surgical factors. The incidence of complications was similar for the different age groups. However general complications were predominantly observed in the older group and those who had instrumented surgery. Conclusions: The results indicate that the indication and surgical performance for patients with CSM is favorable in Japan, despite the super-aging population. Few serious complications were reported in this study. However, more detailed informed consent about surgical and, in particular, general complications is necessary for the older patients with CSM.

Eight years of follow-up after laminectomy of calcium pyrophosphate crystal deposition in the cervical yellow ligament of patient with Coffin-Lowry syndrome: A case report.

BACKGROUND: We report 8 years of follow-up after decompression to treat cervical myelopathy in a patient with Coffin-Lowry syndrome (CLS). CLS is a rare X-linked semidominant syndrome associated with growth and psychomotor retardation, general hypotonia, and skeletal abnormalities. In this patient, the spinal cord was compressed by calcium pyrophosphate crystal deposition in the cervical yellow ligament (YL). To date, only 1 report has described clinical features after surgery for calcified cervical YL in CLS. METHODS: A 15-year-old male with tetraplegia secondary to compression of the cervical spinal cord induced by a hypoplastic posterior arch of C1 and calcification of the YL from C2 to C7 was treated surgically with laminectomy from C1 to C7. The patient's history, clinical examination, imaging findings, and treatment are reported. The patient was incapable of speech because of mental retardation, so he could not describe his symptoms. Gait disturbance worsened over the 2 months before admission to our hospital. At admission, the patient could not move his extremities, and tendon reflexes of the upper and lower extremities were significantly increased. Computed tomography of the cervical spine showed YL calcification from C2 to C7. Magnetic resonance imaging showed consecutive compression of the cervical spinal cord. We diagnosed quadriplegia secondary to cervical cord damage and performed emergency surgery. RESULTS: During C1-C7 laminectomy, YL calcification in C2-C7 was observed. The calcification was confirmed as calcium pyrophosphate by crystal analysis. Quadriplegia gradually resolved, and almost disappeared by 2 weeks after the operation. Cervical hyperlordosis was observed in radiographs starting from 1 month after the operation, but it has not progressed and is not associated with any symptoms. CONCLUSIONS: The efficacy of decompression continued, and no postoperative complications have occurred during at least 8 years of follow-up.

Continuous intrathecal infusion of SB203580, a selective inhibitor of p38 mitogen-activated protein kinase, reduces the damage of hind-limb function after thoracic spinal cord injury in rat.

P38 mitogen-activated protein kinase (MAPK) is one of the key enzymes in apoptosis induction pathways. We tested continuous intrathecal infusion of SB203580, a selective inhibitor of p38-MAPK, after spinal cord compression injury by a 20 g weight for 40 min at the 11th vertebra level-thoracic spinal cord. SB203580 (1 microg/day) was infused for 1 week after the compression. Hind-limb function was evaluated by measuring the frequency of 'standing' posture; raising fore limbs and sustaining body weight with hind-limbs. One-week after the compression, frequency of standing spinal cord injured rat was decreased to about half of that in sham operated animals which underwent laminectomy without compression. The frequency of standing in rats infused SB203580 recovered 2-3 weeks after the spinal cord injury, on the other hand, vehicle animals infused with saline did not recover. Myelin staining by Luxol fast blue showed severe myelin degradation in vehicle animals in lateral and dorsal funiculi. Apoptotic cells, detected by TUNEL staining, appeared in lateral funiculi of spinal cord injured rats. The application of SB203580 decreased the number of apoptotic cells. The SB203580-treated animals showed no significant degeneration of myelin structure. These results suggest that inhibition of p38-MAPK is one candidate for therapeutic agents against neurological deficits after spinal cord injury.

Delayed neuronal damage related to microglia proliferation after mild spinal cord compression injury.

In order to investigate the mechanism of delayed progressive or secondary neuronal damage after the spinal cord injury, we developed a mild-compression injury model in the rat thoracic spinal cord. Our compression device consists of a soft silicone point of contact to the dura, in order to prevent violent injury that may cause axonal tears or hemorrhages in the spinal cord. Since rats often assume a 'standing' posture, i.e. raising head with lifting their fore-limbs, damage to the thoracic spinal cord was evaluated by measuring the frequency of 'standing', which effectively indicates hind limb function. Twenty-four hours after compression by a 20 g weight for 10 or 20 min, the standing frequency of the injured rat was almost the same as that of sham animals that underwent laminectomy without compression. However, the standing frequency decreased with time; the frequency of standing at 72 h was approximately 30-50% that of sham animals. In the compressed spinal cord tissue, microglial cells, detected by lectin staining, proliferated with time. An enormous amount of microglia was observed at 48 and 72 h after compression, although only a small amount of cells were positive to lectin staining at 24 h after the compression. These results suggest that our mild-compression spinal cord injury model showed late-onset or delayed neuronal damage that may be related to pathological microglia proliferation.

Serotonergic signaling inhibits hyperalgesia induced by spinal cord damage.

Although dysesthesia is one of the most serious problems in patients with spinal cord injury, most of them being unresponsive to conventional treatments. In this study, we established a rat thoracic spinal cord mild-compression model that revealed thermal hyperalgesia in the hind limb. The thoracic spinal cord was compressed gently, using a 20 g weight for 20 min. The withdrawal latency of the thermal stimulation of the bilateral hind-limb was monitored using Hargreaves' Plantar test apparatus. In this model, thermal-hyperalgesia was observed for 1 week after the injury. The spinal cord injury-induced thermal-hyperalgesia was mimicked by the intrathecal application of metergoline, a non-selective 5-HT antagonist, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido) butyl]-piperazine hydrobromide (NAN190), a selective 5-HT1 antagonist, and 3-tropanyl-3,5-dichlorobenzoate (MDL72222), a selective 5-HT3 antagonist. Intraperitoneal application of fluvoxamine maleate, a selective serotonin reuptake inhibitor, reduced the intensity of hyperalgesia induced by spinal cord injury. The inhibitory effect of fluvoxamine maleate on thermal hyperalgesia was prevented by the application of the aforementioned nonselective or selective 5-HT receptor antagonists. Intrathecal application of fluvoxamine maleate and selective 5-HT receptor agonists, i.e., 8-hydroxy-2-(di-n-proplyamino)-tetralin hydrobromide (8-OH-DPAT: 5HT-1 selective) and 2-methyl-5-hydroxytryptamine maleate (2-m-5-HT: 5HT-3 selective), inhibited the spinal cord injury-induced hyperalgesia. These results suggest that the change in the descending serotonergic signal plays an important role in hyperalgesia after the spinal cord injury, and that the application of selective serotonin reuptake inhibitors will be one of the candidates for new therapeutic methods against post-spinal cord injury dysesthesia.

Adenosine triphosphate inhibits cytokine release from lipopolysaccharide-activated microglia via P2y receptors.

Microglial proliferation and activation have been reported to occur after several central nervous system injuries. In this study, we tested the effects of adenosine triphosphate (ATP) on cultured microglia obtained from the spinal cord of rat embryos. The amounts of tumor necrosis factor alpha (TNF-alpha), interleukin 1beta and interleukin 6 released from the microglia, which were stimulated by lipopolysaccharide (LPS; 100 ng/ml), were inhibited by the simultaneous addition of ATP in a dose dependent manner (10-300 microM). We examined the effect of several endogenous purines (ATP, ADP, CTP, UDP, UTP) and P(2)y receptor agonists (ADPbetaS and 2-methylthio-ATP) on LPS-induced TNF-alpha release. The rank order of inhibitory potency of endogenous purines on TNF-alpha release was: ATP>ADP>>UTP>UDP>CTP. The latter three were much less potent than the former two. The addition of 10 microM 2-methylthio-ATP showed a potency similar to 100 microM ATP. The addition of ADPbetaS, however, showed less effect. These endogenous purines and selective ATP receptor agonists showed a similar inhibitory effect in their rank order on LPS-induced interleukin 6 release. We demonstrate that ATP inhibits cytokine release from LPS-activated microglia via metabotropic receptors. The application of P(2)y receptor agonists might be considered as a pharmacological treatment of several pathological conditions of the spinal cord, including toxic immunoreactions.

Prostaglandin E1 analog inhibits the microglia function: suppression of lipopolysaccharide-induced nitric oxide and TNF-alpha release.

Release of nitric oxide and TNF-alpha, a toxic cytokine, have been reported to accelerate neuronal damage under several pathological conditions, such as trauma or ischemia in the central nervous system. In the present study, we tested the effect of alprostadil alfadex, a prostaglandin E1 analog, on cultured microglia from the rat spinal cord. The cultured microglia were exposed to lipopolysaccharide (LPS) (100 ng/ml), an endotoxin, for 24 h, then the released nitric oxide and TNF-alpha in the culture media was analyzed. The released nitric oxide was detected by the Griess reaction and released TNF-alpha was measured using ELISA method. The LPS-induced nitric oxide release was inhibited by the simultaneous addition of alprostadil alfadex in a dose-dependent manner (0.1-100 microM). The LPS-induced TNF-alpha release was also inhibited by alprostadil alfadex addition (0.1-100 microM). The IC50 values of alprostadil alfadex on nitric oxide and TNF-alpha release were about 1 and 10 microM, respectively. These results suggest that prostaglandin E1 possibly protects spinal cord neurons from several types of neurodegenerative damage, not only via increased blood supply, but also via inhibition of pathological immunoreactions of activated microglia.