Novel TRH analog improves motor and cognitive recovery after traumatic brain injury in rodents.
Thyrotropin-releasing hormone (TRH) and certain TRH analogs show substantial neuroprotective effects in experimental brain or spinal cord trauma but also have other physiological actions (autonomic, analeptic, and endocrine) that may be undesirable for the treatment of neurotrauma in humans. We developed a novel TRH analog (2-ARA-53a), with substitutions at the NH(2)-terminus and imidazole ring, that preserves the neuroprotective action of TRH-like compounds while decreasing or eliminating their autonomic, analeptic, and endocrine effects. Rats administered 2-ARA-53a (1.0 mg/kg, n = 17) intravenously 30 min after lateral fluid percussion brain injury showed marked improvement in motor recovery compared with vehicle-treated controls (n = 14). Treatment of mice subjected to moderate controlled cortical impact brain injury, at the same dose and time after trauma (n = 8), improved both motor recovery and cognitive performance in a water maze place learning task compared with vehicle-treated controls (n = 8). In injured rats, no autonomic or analeptic effects were observed with this compound, and endocrine effects were significantly reduced with 2-ARA-53a, in contrast to those found with a typical NH(2)-terminal-substituted TRH analog (YM-14673). These findings demonstrate that the neuroprotective effects of TRH-related compounds can be dissociated from their other major physiological actions and suggest a potential role for dual-substituted TRH analogs in the treatment of clinical neurotrauma.
Faden
A I
AI
Georgetown Institute for Cognitive Sciences, Department of Neurology, Georgetown University Medical Center, Washington, District of Columbia 20007-2197, USA. fadena@giccs.georgetown.edu
Fox
G B
GB
Fan
L
L
Araldi
G L
GL
Qiao
L
L
Wang
S
S
Kozikowski
A P
AP
D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects / Q000503:physiopathology; D001384:Azetidines / Q000494:pharmacology; D001930:Brain Injuries / Q000401:mortality / Q000503:physiopathology* / Q000523:psychology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects*; D004151:Dipeptides / Q000494:pharmacology; D004702:Endocrine Glands / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D009420:Nervous System / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives*
D001384:Azetidines; D000697:Central Nervous System Stimulants; D004151:Dipeptides; D013973:Thyrotropin-Releasing Hormone; C054995:azetirelin