The Role of Betaine Focused Fluid Osmoregulation in Syringomyelia Post Spinal Cord Injury

Autor: Pukale, Dipak Dadaso
Jazyk: angličtina
Rok vydání: 2022
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Druh dokumentu: Text
Popis: Syringomyelia (SM) is a neurological disorder in which a fluid-filled cyst (syrinx) inside the spinal cord forms due to either congenital or acquired (spinal cord injury (SCI)) causes. SM is clinically treated only when it is required depending on the severity of symptoms and syrinx extension using surgical interventions, due to high failure rates and unsatisfactory outcomes. Hence, more efforts are required to understand the molecular aspect of SM to ultimately develop non-surgical interventions. Here, an investigation of betaine, a potent osmolyte, and its roles in fluid osmoregulation in SM was conducted using in vitro and in vivo models. Investigation of the betaine regulation via its transport through betaine/γ- aminobutyric acid transporter 1 and its synthesis via choline dehydrogenase was conducted. These studies demonstrated the osmoprotectant role of betaine to support local injured/disturbed cells mainly astrocytes for cell size homeostasis that confirmed the potential involvement of betaine regulation in SM pathophysiology. Next, the osmotic condition of CSF and intraparenchymal fluid in the SM post-SCI environment were evaluated in an animal model. The elevated osmolality of intraparenchymal fluid as compared to CSF suggested an osmotic gradient in injured tissues. Tissue-level examination showed the upregulation of betaine contributing factors, along with ionic/water channels, at the injury site compared to distal tissue. During these animal studies, a new method for determining subtle and mild locomotion deficits was adapted. The detectable deficit in terms of different locomotion parameters would be utilized in the efforts for treatment development to monitor the locomotion progress over time upon treatments. Finally, a choroid plexus organoid model grown from human induced pluripotent stem cells was adapted to study fluid osmoregulation under osmotic stresses as found in SM. The results uncover the potential of this 3D system in further SM research. In general, this work sought to reveal a novel potential mechanism that the SM environment created an osmotic imbalance or disturbance leading to betaine-focused fluid osmoregulation molecular responses in local impacted cells at the expense of the excess fluid accumulation in the spinal cord tissue i.e., syrinx formation/expansion. This would help develop pharmaceutical-based treatment strategies for SM based on investigated molecular targets.
Databáze: Networked Digital Library of Theses & Dissertations
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