No abstract

Background The molecular etiology of syringomyelia (SM) post-spinal cord injury (SCI) is not well understood and only invasive surgical based treatments are available to treat SM. This study builds upon our previous omics studies and in vitro cellular investigations to further understand local fluid osmoregulation in post-traumatic SM (PTSM) to highlight important pathways for future molecular interventions. Methods A rat PTSM model consisting of a parenchymal injection of 2 µL quisqualic acid (QA) and an injection of 5 µL kaolin in the subarachnoid space, followed by laminectomy at the C7 to T1 level was utilized. 6 weeks prior to the initial surgery, parenchymal fluid and cerebrospinal fluid (CSF) were collected, and the osmolality analyzed. Immunohistochemistry (IHC), metabolomics analysis using LC/MS, and mass spectrometry-based imaging (MSI) were performed on injured and laminectomy only spinal cords. Results We demonstrated that the osmolality of the local parenchymal fluid encompassing syrinxes was higher compared to control spinal cords after laminectomy, indicating a local osmotic imbalance due to SM injury. Moreover, we also found that parenchymal fluid is more hypertonic than CSF, indicating establishment of a local osmotic gradient in the PTSM injured spinal cord (syrinx area) forcing fluid into the spinal cord parenchyma to form and/or expand syrinxes. IHC results demonstrated upregulation of betaine, ions, water channels/transporters, and enzymes (BGT1, KCC4, AQP1, AQP4, CHDH) at the injury site as compared to caudal and rostral sites to the injury, implying extensive local osmoregulation activities at the injury site. Further, metabolomics analysis corroborated alterations in osmolality at the injury site by upregulation of small molecule osmolytes including betaine, carnitine, glycerophosphocholine, arginine, creatine, guanidinoacetate, and spermidine. Conclusions In summary, PTSM results in local osmotic disturbance that propagates up to 6 weeks following initial injury. This coincides with and may contribute to syrinx formation/expansion.