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


METHODS
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.


CONCLUSIONS
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.
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
J
J
Kjell
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
K
K
Pernold
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
L
L
Olson
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
M B
MB
Abrams
D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D000069347:Erlotinib Hydrochloride; D005260:Female; D006614:Hindlimb / Q000503:physiopathology*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D008124:Locomotion / Q000187:drug effects* / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D020123:Sirolimus / Q000008:administration & dosage / Q000627:therapeutic use; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000503:physiopathology; D001743:Urinary Bladder / Q000187:drug effects* / Q000503:physiopathology
D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D020123:Sirolimus