Aquaporin-4 expression and blood–spinal cord barrier permeability in canalicular syringomyelia

Abstract

<jats:sec> <jats:title>Object</jats:title> <jats:p>Noncommunicating canalicular syringomyelia occurs in up to 65% of patients with Chiari malformation Type I. The pathogenesis of this type of syringomyelia is poorly understood and treatment is not always effective. Although it is generally thought that syringomyelia is simply an accumulation of CSF from the subarachnoid space, the pathogenesis is likely to be more complex and may involve cellular and molecular processes. Aquaporin-4 (AQP4) has been implicated in numerous CNS pathological conditions involving fluid accumulation, including spinal cord edema. There is evidence that AQP4 facilitates the removal of extracellular water following vasogenic edema. The aim of this study was to investigate AQP4 expression and the structural and functional integrity of the blood–spinal cord barrier (BSCB) in a model of noncommunicating canalicular syringomyelia.</jats:p></jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>A kaolin-induced model of canalicular syringomyelia was used to investigate BSCB permeability and AQP4 expression in 27 adult male Sprague-Dawley rats. Control groups consisted of nonoperated, laminectomy-only, and saline-injected animals. The structural integrity of the BSCB was assessed using immunoreactivity to endothelial barrier antigen. Functional integrity of the BSCB was assessed by extravasation of systemically injected horseradish peroxidase (HRP) at 1, 3, 6, or 12 weeks after surgery. Immunofluorescence was used to assess AQP4 and glial fibrillary acidic protein (GFAP) expression at 12 weeks following syrinx induction.</jats:p></jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Extravasation of HRP was evident surrounding the central canal in 11 of 15 animals injected with kaolin, and in 2 of the 5 sham-injected animals. No disruption of the BSCB was observed in laminectomy-only controls. At 12 weeks the tracer leakage was widespread, occurring at every level rostral to the kaolin injection. At this time point there was a decrease in EBA expression in the gray matter surrounding the central canal from C-5 to C-7. Aquaporin-4 was expressed in gray- and white-matter astrocytes, predominantly at the glia limitans interna and externa, and to a lesser extent around neurons and blood vessels, in both control and syrinx animals. Expression of GFAP and APQ4 directly surrounding the central canal in kaolin-injected animals was variable and not significantly different from expression in controls.</jats:p></jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>This study demonstrated a prolonged disruption of the BSCB directly surrounding the central canal in the experimental model of noncommunicating canalicular syringomyelia. The disruption was widespread at 12 weeks, when central canal dilation was most marked. Loss of integrity of the barrier with fluid entering the interstitial space of the spinal parenchyma may contribute to enlargement of the canal and progression of syringomyelia. Significant changes in AQP4 expression were not observed in this model of canalicular syringomyelia. Further investigation is needed to elucidate whether subtle changes in AQP4 expression occur in canalicular syringomyelia.</jats:p></jats:sec>

Osmoregulatory Role of Betaine and Betaine/γ-Aminobutyric Acid Transporter 1 in Post-Traumatic Syringomyelia

“…An important factor for regulating cell size/volume is the maintenance of an extracellular-intracellular osmotic gradient to facilitate fluid movement through the cell membrane . Primary spinal cord injury may disrupt the osmotic environment in the vicinity of injury that leads to SM. ,, To further study this, we investigated whether betaine played an active osmolyte role in cell size regulation with rat astrocytes and HepG2 cells when exposed to isotonic, hypertonic, and hypotonic conditions. We collected live images of cells under hypertonic, hypotonic, and isotonic conditions with and without betaine (100 μM) treatment using a confocal microscope for 5 min (with a 5-s interval for the first 2 min and a 10-s interval for the next 3 min).…”

“…This osmoregulatory study was motivated by our previous system’s biology analysis of the molecular events associated with the pathophysiology of the disease syringomyelia (SM) . SM is a spinal cord disorder identified by the formation of cerebrospinal fluid (CSF)-filled cysts also known as syrinxes, coinciding with neurological diseases such as Chiari malformation I, trauma, and several other disorders. , The underlying mechanisms involved in the initiation and expansion of syrinxes are not well-understood, especially the key molecular aspects. ,, This lack of understanding of the involved basic mechanisms limits therapeutic strategies. For instance, in cases of SM, primary current clinical practice is to alleviate pressure on the spinal cord by using procedures such as decompression, duraplasty, shunting, and arachnolysis .…”

Chronic extradural compression of spinal cord leads to syringomyelia in rat model

“…These factors have limited the experimental study of the molecular mechanisms and therapeutics for syringomyelia. Previous models have used both canalicular [13,16,21,22] and noncanalicular [23] syringomyelia to mimic different causes. Most syringomyelia in humans is located in the central canal.…”

Fluids and flows in brain cancer and neurological disorders

“…The most common treatment for hydrocephalus involves the surgical implantation of a shunt, followed by endoscopic third ventriculostomy. Several studies have indicated that aquaporin channels are involved in the pathophysiology of hydrocephalus through engagement of their role in fluid homeostasis ( Desai et al, 2016 ; Hemley et al, 2012 ; Verkman et al, 2017 ). Animal studies have demonstrated that AQP1 can regulate the secretion and osmosis of CSF to control hydrocephalus ( Wang et al, 2011 ).…”