Basic ScienceEffect of VEGF and CX43 on the promotion of neurological recovery by hyperbaric oxygen treatment in spinal cord–injured rats
Introduction
Spinal cord injury (SCI) is a devastating condition for the individual patient and costly to society as a whole by requiring substantial long-term health-care expenditures. Trauma to the spinal cord causes both primary and secondary injury. Primary injury to the spinal cord immediately disrupts cell membranes, destroys myelin and axons, and damages microvessels, thereby triggering devastating secondary injuries [1]. Secondary injury refers to a complex array of pathophysiological processes, including ischemia, edema, local inflammation, production of free radicals, and hyperoxidation [2], [3]. The end result of SCI is that some of the neurons and glial cells die days or weeks after spinal cord injury as the result of the secondary injury, even though they survived from the initial injury [4], [5].
Numerous spinal cord protection methods, including distal aortic perfusion, reattachment of critical intercostal arteries, hypothermia, and administration of various pharmacologic agents, have been suggested to minimize the devastating complication of SCI. However, applications of these techniques had only decreased but not eliminated postoperative spinal cord dysfunction, thus further investigations are necessary to improve the treatment of SCI [6], [7]. Hyperbaric oxygen (HBO) therapy is a medical treatment that administers 100% oxygen at a controlled pressure (greater than sea level) for a prescribed period of time (60–90 minutes). Because of the capability of increasing tissue oxygenation, HBO treatment raises the tissues' tolerance to ischemia and corrects the metabolic disorders apparent in the ischemic tissue. Recent reports claimed that HBO treatment is beneficial for neurological recovery in acute and chronic SCI [8], [9], but the underlying mechanism needs to be further characterized.
In the central nervous system (CNS), vascular endothelial growth factor (VEGF) plays a pivotal role not only in vascularization, but also in neurotrophic, neuronal proliferation, and the growth of coordinated vascular and neuronal networks [10]. Gap junctions are intercellular channels that are integral for the functioning of the glial network. They allow the passage of ions, metabolites, and second messengers between neighboring cells [11]. The primary structural unit of a gap junction is a membrane protein termed connexin. Connexin43 (CX43) is the predominant protein for the formation of gap junctions in the CNS and is expressed primarily on astrocytes, activated microglia, developing neurons, the smooth muscle, and endothelial cells of blood vessels. CX43 is an important mediator of CNS injury [12]. In this study, we attempted to explore the possible mechanism of HBO treatment in SCI by measuring the expression levels of VEGF and CX43 in the injured spinal cord tissue.
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Animal care
Healthy adult male Sprague-Dawley (SD) rats, weighing 250 to 300 g at the beginning of the study, were kept two per cage for at least 5 days after their arrival at our laboratory. The rats had access to food and water ad libitum and were housed within a room with a 12:12-hour light/dark cycle. This study was performed in accordance with the ethical guidelines laid down by the Committee for the Purpose of Control and Supervision of Experiments on Animals, Capital Medical University (Beijing,
Evaluation of motor function
To evaluate the extent of motor function recovery, we used the BBB locomotor scores. The BBB scores were significantly lower in SCI and SCI+HBO groups compared with SH and SH+HBO groups (p<.01). Meanwhile, a significant gradual recovery was observed in the rats of SCI and SCI+HBO groups over time, on the 7th and 14th days postoperatively, HBO treatment caused a significant change in BBB score as compared with the SCI group values (p<.05). There was no significant difference in BBB score between
Discussion
It has been recognized that HBO treatment is beneficial in acute and chronic SCI. Gelderd et al. [14] showed that HBO treatment following SCI led to less cavitation and better vascularized scars containing densely packed collagen fibers. Al-Waili et al. [15] reported that HBO application was beneficial in patients with vascular damage in the spinal cord. HBO also reduced apoptosis following SCI [16]. Topuz et al. [17] combined HBO treatment with hypothermia in rats with SCI and found a
Conclusion
In summary, HBO treatment is found to be beneficial for neurological recovery when applied after SCI. The rats that received HBO treatment after SCI showed higher BBB scores, lower histology scores, and significant changes in VEGF and CX43 levels. These results may help to understand, in part, some of the molecular mechanisms of HBO treatment on promoting neurological recovery in SCI rats and may be useful to improve the clinical application of HBO for SCI patients. However, detailed mechanisms
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FDA device/drug status: Not applicable.
Author disclosures: XL: Grant: Beijing Natural Science Foundation (7102062) (C, Paid directly to institution/employer). YZ: Grant: Beijing Natural Science Foundation (7102062) (C, Paid directly to institution/employer). ZW: Grant: Beijing Natural Science Foundation (7102062) (C, Paid directly to institution/employer). JY: Grant: Beijing Natural Science Foundation (7102062) (C, Paid directly to institution/employer). CG: Grant: Beijing Natural Science Foundation (7102062) (C, Paid directly to institution/employer). QS: Grant: Beijing Natural Science Foundation (7102062) (C, Paid directly to institution/employer).
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