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Cyclic AMP is an important intracellular regulator of microglial cell homeostasis and its negative perturbation through proinflammatory signaling results in microglial cell activation. Though cytokines, TNF-α and IL-1β, decrease intracellular cyclic AMP, the mechanism by which this occurs is poorly understood. The current study examined which signaling pathways are responsible for decreasing cyclic AMP in microglia following TNF-α stimulation and sought to identify the role cyclic AMP plays in regulating these pathways. In EOC2 microglia, TNF-α produced a dramatic reduction in cyclic AMP and increased cyclic AMP-dependent PDE activity that could be antagonized by Rolipram, myristoylated-PKI, PD98059, or JSH-23, implicating a role for PDE4, PKA, MEK, and NF-κB in this regulation. Following TNF-α there were significant increases in iNOS and COX-2 immunoreactivity, phosphorylated ERK1/2 and NF-κB-p65, IκB degradation, and NF-κB p65 nuclear translocation, which were reduced in the presence of high levels of cyclic AMP, indicating that reductions in cyclic AMP during cytokine stimulation are important for removing its inhibitory action on NF-κB activation and subsequent proinflammatory gene expression. Further elucidation of the signaling crosstalk involved in decreasing cyclic AMP in response to inflammatory signals may provide novel therapeutic targets for modulating microglial cell activation during neurological injury and disease. [ABSTRACT FROM AUTHOR]

Introduction:Systemic hypothermia remains a promising neuroprotective strategy. There has been recent interest in its use in patients with spinal cord injury (SCI). In this article, we describe our extended single center experience using intravascular hypothermia for the treatment of cervical SCI.Methods:Thirty-five acute cervical SCI patients received modest (33 °C) intravascular hypothermia for 48 h. Neurological outcome was assessed by the International Standards for Neurological Classification of Spinal Cord Injury scale (ISNCSCI) developed by the American Spinal Injury Association. Local and systemic complications were recorded.Results:All patients were complete ISNCSCI A on admission, but four converted to ISNCSCI B in <24 h post injury. Hypothermia was delivered in 5.76 (±0.45) hours from injury if we exclude four cases with delayed admission (>18 h). Fifteen of total 35 patients (43%) improved at least one ISNCSCI grade at latest follow up 10.07 (±1.03) months. Even excluding those patients who converted from ISNCSCI A within 24 h, 35.5% (11 out of 31) improved at least one ISNCSCI grade. Both retrospective (n=14) and prospective (n=21) groups revealed similar number of respiratory complications. The overall risk of any thromboembolic complication was 14.2%.Conclusion:The results are promising in terms of safety and improvement in neurological outcome. To date, the study represents the largest study cohort of cervical SCI patients treated by modest hypothermia. A multi-center, randomized study is needed to determine if systemic hypothermia should be a part of SCI patients' treatment for whom few options exist. [ABSTRACT FROM AUTHOR]

The article provides information on this issue of the "Journal of Rehabilitation Research and Development." It is based on the proceedings of a conference, entitled "Translational Research in Spinal Cord Injury: Avoiding Potential Pitfalls," sponsored by the Miami Veterans Affairs Rehabilitation Research and Development Center of Excellence in Spinal Cord Injury (SCI), the South Florida Model SCI System, and The Miami Project to Cure Paralysis. The meeting was held 3 April 2003 in Miami, Florida. The goal of this conference was to stimulate discussion between basic scientists and clinicians about the steps needed to move promising research related to SCI from laboratory animals into clinical trials.