The impact of phosphodiesterase inhibition on neurobehavioral outcomes in preclinical models of traumatic and non-traumatic spinal cord injury: a systematic review.

Study design: Systematic review. Objective: The objective of this study was to evaluate the impact of phosphodiesterase (PDE) inhibitors on neurobehavioral outcomes in preclinical models of traumatic and non-traumatic spinal cord injury (SCI). Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and was registered with PROSPERO (CRD42019150639). Searches were performed in MEDLINE and Embase. Studies were included if they evaluated the impact of PDE inhibitors on neurobehavioral outcomes in preclinical models of traumatic or non-traumatic SCI. Data were extracted from relevant studies, including sample characteristics, injury model, and neurobehavioral assessment and outcomes. Risk of bias was assessed using the SYRCLE checklist. Results: The search yielded a total of 1,679 studies, of which 22 met inclusion criteria. Sample sizes ranged from 11 to 144 animals. PDE inhibitors used include rolipram (n = 16), cilostazol (n = 4), roflumilast (n = 1), and PDE4-I (n = 1). The injury models used were traumatic SCI (n = 18), spinal cord ischemia (n = 3), and degenerative cervical myelopathy (n = 1). The most commonly assessed outcome measures were Basso, Beattie, Bresnahan (BBB) locomotor score (n = 13), and grid walking (n = 7). Of the 22 papers that met the final inclusion criteria, 12 showed a significant improvement in neurobehavioral outcomes following the use of PDE inhibitors, four papers had mixed findings and six found PDE inhibitors to be ineffective in improving neurobehavioral recovery following an SCI. Notably, these findings were broadly consistent across different PDE inhibitors and spinal cord injury models. Conclusion: In preclinical models of traumatic and non-traumatic SCI, the administration of PDE inhibitors appeared to be associated with statistically significant improvements in neurobehavioral outcomes in a majority of included studies. However, the evidence was inconsistent with a high risk of bias. This review provides a foundation to aid the interpretation of subsequent clinical trials of PDE inhibitors in spinal cord injury. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=150639, identifier: CRD42019150639.

Existing Funding Sources in Degenerative Cervical Myelopathy Research: Scoping Review.

BACKGROUND: Degenerative cervical myelopathy (DCM) is a common, disabling condition of symptomatic cervical spinal cord compression that requires significant research advances to improve patient outcomes. A James Lind Alliance Partnership recently identified the top research priorities for DCM. To effectively address these priorities, appropriate funding of DCM research is essential. OBJECTIVE: The aim of this paper is to review current funding in DCM research and highlight future research funding opportunities. METHODS: A systematic search of Web of Science for "cervical AND myelopathy" was conducted. Papers exclusively studying DCM with declared funding and published between January 1, 1995, and March 21, 2020, were considered eligible. Funding sources were classified by country of origin and organization type. A grant search was also conducted using Dimensions.ai (Digital Science Ltd). RESULTS: A total of 621 papers were included, with 300 unique funding bodies. The top funders were AO Spine (n=87); National Institutes of Health, USA (n=63); and National Natural Science Foundation, China (n=63). Funding sources in the USA (n=242) supported the most DCM research, followed by China (n=209) and Japan (n=116). Funding in the USA was primarily provided by corporate or nonprofit organizations (146/242, 60.3%), while in China, the majority of funding was from institutions (208/209, 99.5%). Dimensions.ai gives an estimate for the total declared grant funding awards for DCM-specific research. Data here showed 180 grants awarded specifically for DCM research, with a total value of US $45.6 million since 1996. CONCLUSIONS: DCM funding appears to be predominantly from the USA, China, and Japan, aligning with areas of high DCM research activity and underpinning the importance of funding to increasing research capacity. The existing funding sources differ from medical research in general, representing opportunities for future investment in DCM.

Systematic review of the impact of cannabinoids on neurobehavioral outcomes in preclinical models of traumatic and nontraumatic spinal cord injury.

STUDY DESIGN: Systematic review. OBJECTIVES: To evaluate the impact of cannabinoids on neurobehavioral outcomes in preclinical models of nontraumatic and traumatic spinal cord injury (SCI), with the aim of determining suitability for clinical trials involving SCI patients. METHODS: A systematic search was performed in MEDLINE and Embase databases, following registration with PROPSERO (CRD42019149671). Studies evaluating the impact of cannabinoids (agonists or antagonists) on neurobehavioral outcomes in preclinical models of nontraumatic and traumatic SCI were included. Data extracted from relevant studies, included sample characteristics, injury model, neurobehavioural outcomes assessed and study results. PRISMA guidelines were followed and the SYRCLE checklist was used to assess risk of bias. RESULTS: The search returned 8714 studies, 19 of which met our inclusion criteria. Sample sizes ranged from 23 to 390 animals. WIN 55,212-2 (n = 6) and AM 630 (n = 8) were the most used cannabinoid receptor agonist and antagonist respectively. Acute SCI models included traumatic injury (n = 16), ischaemia/reperfusion injury (n = 2), spinal cord cryoinjury (n = 1) and spinal cord ischaemia (n = 1). Assessment tools used assessed locomotor function, pain and anxiety. Cannabinoid receptor agonists resulted in statistically significant improvement in locomotor function in 9 out of 10 studies and pain outcomes in 6 out of 6 studies. CONCLUSION: Modulation of the endo-cannabinoid system has demonstrated significant improvement in both pain and locomotor function in pre-clinical SCI models; however, the risk of bias is unclear in all studies. These results may help to contextualise future translational clinical trials investigating whether cannabinoids can improve pain and locomotor function in SCI patients.

Research activity amongst DCM research priorities.

INTRODUCTION: Degenerative cervical myelopathy (DCM) is a progressive neurodegenerative disorder. DCM is common (estimated prevalence, 2% of adults) and significantly impacts quality of life. The AO Spine RECODE-DCM (Research Objectives and Common Data Elements in DCM) project has recently established the top research priorities for DCM. This article examines the extent to which existing research activity aligns with the established research priorities. METHODS: A systematic review of MEDLINE and Embase for "Cervical" AND "Myelopathy" was conducted following PRISMA guidelines. Full-text papers in English, exclusively studying DCM, published between January 1, 1995 and August 08, 2020 were considered eligible. Extracted data for each study included authors, journal, year of publication, location, sample size and study design. Each study was then analysed for alignment to the established research priorities. RESULTS: In total, 2261 papers with a total of 1,323,979 patients were included. Japan published more papers (625) than any other country. Moreover, 2005 (89%) of 2261 papers were aligned to at least one research priority. The alignment of papers to the different research priorities was unequal, with 1060 papers on the most researched priority alone (#15, predictors of outcome after treatment), but only 64 total papers on the least-researched 10 priorities. The comparative growth of research in the different priorities was also unequal, with some priorities growing and others plateauing over the past 5 years. DISCUSSION: Research activity in DCM continues to grow, and the focus of this research remains on surgery. The established research priorities therefore represent a new direction for the field.