Development of Neurogenic Detrusor Overactivity after Thoracic Spinal Cord Injury Is Accompanied by Time-Dependent Changes in Lumbosacral Expression of Axonal Growth Regulators

Abstract

Thoracic spinal cord injury (SCI) results in urinary dysfunction, which majorly affects the quality of life of SCI patients. Abnormal sprouting of lumbosacral bladder afferents plays a crucial role in this condition. Underlying mechanisms may include changes in expression of regulators of axonal growth, including chondroitin sulphate proteoglycans (CSPGs), myelin-associated inhibitors (MAIs) and repulsive guidance molecules, known to be upregulated at the injury site post SCI. Here, we confirmed lumbosacral upregulation of the growth-associated protein GAP43 in SCI animals with bladder dysfunction, indicating the occurrence of axonal sprouting. Neurocan and Phosphacan (CSPGs), as well as Nogo-A (MAI), at the same spinal segments were upregulated 7 days post injury (dpi) but returned to baseline values 28 dpi. In turn, qPCR analysis of the mRNA levels for receptors of those repulsive molecules in dorsal root ganglia (DRG) neurons showed a time-dependent decrease in receptor expression. In vitro assays with DRG neurons from SCI rats demonstrated that exposure to high levels of NGF downregulated the expression of some, but not all, receptors for those regulators of axonal growth. The present results, therefore, show significant molecular changes at the lumbosacral cord and DRGs after thoracic lesion, likely critically involved in neuroplastic events leading to urinary impairment.

Molecular Mechanism Operating in Animal Models of Neurogenic Detrusor Overactivity: A Systematic Review Focusing on Bladder Dysfunction of Neurogenic Origin

“…The vast majority of the analyzed reports, 74%, use spinal cord injury as an NDO model ( Figure 2 B). From these publications, 59% report complete transection of thoracic segments to induce SCI [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 38 , 39 , 43 , 44 , 46 , 48 , 49 , 50 , 55 , 57 , 62 , 63 ], followed by spinal contusion (13%). The use of spinal hemisections was less frequent (10%) [ 42 , 47 , 52 ], as were spinal compressions (8%) [ 32 , 36 , 54 , 56 ] and other SCI methods (10%) [ 41 , 51 , 53 , 58 ] ( Figure 3 ).…”

“…Most of the studies reporting urodynamic recordings used awake cystometry as the recording method (37%) [ 31 , 32 , 33 , 34 , 35 , 38 , 39 , 42 , 46 , 47 , 48 , 52 , 56 , 59 , 63 , 68 , 70 , 71 ]. Cystometry under anesthesia represented 26% of studies, with 16% using urethane delivered via subcutaneous [ 26 , 27 , 28 , 37 , 41 , 43 , 51 ] or intraperitoneal injection [ 57 ], 8% using zolotyl [ 53 , 58 , 61 , 74 ], and 2% referring the use of chloral hydrate as anesthetic [ 54 ]. Finally, 8% of the studies used non-invasive voiding spot assays to evaluate bladder function [ 64 , 65 , 67 , 68 ].…”

“…However, this is not the case when it comes to urological investigations. The majority of the retrieved articles in our systematic study used complete transection models [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 38 , 39 , 43 , 44 , 46 , 48 , 49 , 50 , 55 , 57 , 62 , 63 ] (58%), which may be explained by their ease of reproduction and the lower associated costs, as they do not require specific equipment. One could speculate that, when it comes to studying SCI-induced urinary dysfunction, the chosen method to reproduce SCI is not as important as it is in regenerative or tissue engineering studies.…”

“…Moreover, urethane anesthesia is limited to terminal procedures, due to its adverse post-operative health effects and carcinogenic risks [ 118 ]. One could speculate that recent papers would resort to better anesthetic options, but urethane remains the main choice for urodynamic evaluations [ 26 , 27 , 28 , 37 , 41 , 43 , 51 , 57 ], as it has low associated costs, it is easy to deliver, and there are abundant published references using this anesthetic for cystometries [ 102 , 119 ].…”

“…Astrocyte-derived chondroitin sulphate proteoglycans (CSPGs)—phosphacan and neurocan—were also included in this group, since they are the central extracellular matrix components of the spinal fibrotic scar that seals the injury site after SCI [ 28 , 127 ]. The levels of CSPGs are highly increased at the injury site after SCI [ 142 , 150 ], correlating with upregulation at the same location of S100, a glial marker [ 41 ], consistent with the accumulation of glial cells and scar formation [ 142 , 150 ].…”