gms | German Medical Science

Objective: Defining molecular targets for adjuvant therapies is one prerequisite to stabilize and improve the clinical and neurological outcome of myelomeningocele (mmc) repair-surgeries. We provide an overview of our findings on the expression-profiles of specific pro-inflammatory cytokines in neuroplacodes on fetal (rat), perinatal (rat), and early postnatal (human) time-points as well in the context of long-term mmc-sequelae.

Methods: In a first approach, pro-inflammatory cytokines and chemokines were investigated in human MMC-tissue fragments obtained during initial mmc-surgeries. Thereby, IL-1beta/IL-1R1 and TNFalpha/TNF-R1 were consistently found on elevated level in mmc-tissues compared to respective controls. To investigate if these mediators might become detectable in the prenatal time-course, similar studies* were performed in the retinoic acid mmc-rat model. Time-dated Sprague-Dawley rats received all-trans retinoic acid (RA; 60 mg/kg) at E10. Control animals received olive oil only. Fetuses were investigated at E16, E18, and E22. We than examined the expression of pro-inflammatory mediators in spinal tissue, which was obtained during surgeries of patients who suffered from secondary tethered cord syndrome in their later clinical course after MMC-repair surgeries. *To examine the cellular and anatomical expression patterns of different cytokines and chemokine, immunohistochemical procedures were applied. Amounts of expression were determined semi quantitatively by densitomtry and real-time RT-PCR.

Results: IL-1beta/IL-1R1 and TNFalpha/TNF-R1 were found on elevated immunhistochemical and mRNA-level in mmc-tissue on time-points of the later rat fetal development and in the early time-course after birth. These mediators were also detectable on high level in specimens obtained during un-tethering surgeries, which were performed in the later time-course of the affected

Conclusion: Pro-inflammatory cytokines presumably play a role in molecular cascades that are induced in the neuroplacodes during the late fetal development und probably support pathomechanisms underlying later mmc-associated sequelae. Since available biopharmaceutical agents that counteract TNF-alpha or IL-1beta activity have also beneficial effects in spinal cord injury, these cytokines provide potential targets in future approaches to protect neural components of the placode and prevent development of sequelae like secondary tethered cord syndrome.