Osmotic Contribution of Synthesized Betaine by Choline Dehydrogenase Using In Vivo and In Vitro Models of Post-traumatic Syringomyelia

Pukale, Dipak D.; Lazarenko, Daria; Aryal, Siddhartha R.; Khabaz, Fardin; Shriver, Leah P.; Leipzig, Nic D.

doi:10.1007/s12195-022-00749-5

Cited by 2 publications

(3 citation statements)

References 64 publications

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“…The overall results from this study and our previous SM studies (19,26,27) strongly suggest an active role for betaine, alongside water regulation in terms of AQP1 and AQP4, and ion channel regulation via KCC4 in syrinx propagation following injury in the spinal cord. Regional speci c analyses show that the PTSM injured spinal cord responds with these molecular processes to local osmotic imbalances/disturbances at the expense of facilitating excess uid accumulation and syrinx formation or expansion in the tissue.…”

Section: Discussionsupporting

confidence: 77%

“…In our previous studies, we observed the expression of CHDH and BGT1 exclusively in astrocytes, with reduced or no detectable expression in other CNS populations (26,27,32). Therefore, for this study, we focused solely on examining these proteins within astrocytes while studying betaine's direct contribution to osmoregulation in SM pathophysiology via expression of its transporter BGT-1 and synthesis enzyme CHDH.…”

Section: Betaine Regulation In the Ptsm Environmentmentioning

confidence: 99%

“…10 to 12 weeks old male Wistar rats were used, and these procedures were conducted under aseptic conditions after induction of anesthesia along with iso urane for the duration of procedures. We used the PTSM rat model utilized previously in our lab (19,(26)(27)(28)(29), which is an excitotoxic injury model consisting of an parenchymal injection of 2 µL quisqualic acid (QA) (Enzo Life Sciences, Farmingdale, NY) with Evans blue followed by an injection of 5 µL kaolin (Avantor, Center Valley, PA, USA) in the subarachnoid space followed by the laminectomy at the C7 to T1 level. The endpoint for this study was 6 weeks post-injury, where syrinx size is known to be maximal (30).…”

Section: Ptsm Rat Injury Modelmentioning

confidence: 99%

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Investigating post-traumatic syringomyelia and local fluid osmoregulation via a rat model

Pukale

Adkins-Travis

Aryal

et al. 2023

Preprint

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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.

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Section: Discussionsupporting

confidence: 77%

Section: Betaine Regulation In the Ptsm Environmentmentioning

confidence: 99%

Section: Ptsm Rat Injury Modelmentioning

confidence: 99%

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Investigating post-traumatic syringomyelia and local fluid osmoregulation via a rat model

Pukale

Adkins-Travis

Aryal

et al. 2023

Preprint

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Investigating post-traumatic syringomyelia and local fluid osmoregulation via a rat model

Pukale,

Adkins-Travis,

Aryal

et al. 2024

Fluids Barriers CNS

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Background Syringomyelia (SM) is characterized by the development of fluid-filled cavities, referred to as syrinxes, within the spinal cord tissue. The molecular etiology of SM post-spinal cord injury (SCI) is not well understood and only invasive surgical based treatments are available to treat SM clinically. 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 laminectomy at the C7 to T1 level followed by a parenchymal injection of 2 μL quisqualic acid (QA) and an injection of 5 μL kaolin in the subarachnoid space was utilized 6 weeks after initial surgery, parenchymal fluid and cerebrospinal fluid (CSF) were collected, and the osmolality of fluids were analyzed. Immunohistochemistry (IHC), metabolomics analysis using LC–MS, and mass spectrometry-based imaging (MSI) were performed on injured and laminectomy-only control 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 site) 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, AQP1, AQP4, CHDH) at the syrinx site as compared to caudal and rostral sites to the injury, implying extensive local osmoregulation activities at the syrinx site. Further, metabolomics analysis corroborated alterations in osmolality at the syrinx 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 at 6 weeks following initial injury. This coincides with and may contribute to syrinx formation/expansion.

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Osmotic Contribution of Synthesized Betaine by Choline Dehydrogenase Using In Vivo and In Vitro Models of Post-traumatic Syringomyelia

Cited by 2 publications

References 64 publications

Investigating post-traumatic syringomyelia and local fluid osmoregulation via a rat model

Investigating post-traumatic syringomyelia and local fluid osmoregulation via a rat model

Investigating post-traumatic syringomyelia and local fluid osmoregulation via a rat model

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