Oral erlotinib, but not rapamycin, causes modest acceleration of bladder and hindlimb recovery from spinal cord injury in rats

Abstract

Objectives: Erlotinib and Rapamycin are both in clinical use and experimental inhibition of their respective molecular targets, EGFR and mTORC1, has improved recovery from spinal cord injury. Our aim was to determine if daily Erlotinib or Rapamycin treatment started directly after spinal contusion injury in rats improves locomotion function or recovery of bladder function. Setting: Stockholm, Sweden Methods: Rats were subjected to contusion injuries and treated during the acute phase with either Erlotinib or Rapamycin. Recovery of bladder function was monitored by measuring residual urine volume and hindlimb locomotion assessed by open-field observations using the BBB rating scale as well as by automated registration of gait parameters. Body weights were monitored. To determine whether Erlotinib and Rapamycin inhibit the same signaling pathway, a cell culture system and western blots were used. Results: Erlotinib accelerated locomotor recovery and slightly improved bladder recovery; however, we found no long-term improvements of locomotor function. Rapamycin did neither improved locomotor function nor bladder recovery. In vitro studies confirmed that Erlotinib and Rapamycin both inhibit the EGFR-mTORC1 signaling pathway. Conclusion: We conclude that none of these two drug regimes improved long-term functional outcome in our current model of spinal cord injury. Nevertheless, oral treatment with Erlotinib may offer modest temporary advantages, whereas treatment with Rapamycin does not.

Blocking the EGFR/p38/NF-κB Signal Pathway Alleviates Disruption of BSCB and Subsequent Inflammation After Spinal Cord Injury

“…EGFR is a receptor tyrosine-protein kinase (TPK) in the plasma membranes, which plays a crucial regulatory role in cell survival, growth, differentiation, proliferation, apoptosis, and other signal pathways [36]. Recently, increasing evidence has suggested that EGFR has also been shown to participate in microvascular injury in diabetes, intestinal permeability, and BSCB permeability after SCI [12,13], indicating a role for EGFR in cellular barrier function [20]. Previous studies have demonstrated that EGFR activation was signi cant not only in astrocytes but also in microglia after SCI [17,19,28,37].…”

“…Recent studies have demonstrated that EGFR signal path is involved in functional regulation of cell barrier, including BSCB [8,14,20]. In order to assess whether blocking EGFR signal pathway could ameliorate disruption of BSCB after OGD/R injury, FITC-Dextran extravasation and TEER measurements were performed to assess permeability BSCB mode in vitro with OGD/R damage in this study.…”

“…Several studies have demonstrated activated EGFR occurrence in astrocytes, microglia, and microvascular endothelial cells during central nervous system disorders including SCI [15][16][17][18]. Meanwhile, inhibiting EGFR activation may ameliorate BSCB damage and improve neurological de cit symptoms [19,20]. Hence, EGFR activation might play a key role in BSCB damage and secondary injury after SCI [8,14,21].…”

Dietary Supplementation with Organoselenium Accelerates Recovery of Bladder Expression, but Does Not Improve Locomotor Function, following Spinal Cord Injury

“…Overall, the results do not support our hypothesis that selenium supplementation would result in improved outcomes following SCI. However, findings indicating bladder functional recovery without associated improvement in locomotor behavioral tasks suggest that these improvements in bladder function may be important markers for functional recovery[ 46 , 47 ].…”

Antibiotics with therapeutic effects on spinal cord injury: a review

“…However, long‐term functional improvement may not be feasible by mere mTOR inhibition. Rapamycin can adversely induce weight loss and affect peripheral vascular resistance or nociceptors, leading to a higher risk of cardiovascular dysfunction [124,125]. Nevertheless, as shown by Li et al (2014), lower doses of rapamycin combined with other therapeutic agents may decrease potential risks of toxicity and significantly boost its beneficial effects [111].…”