Novel TRH analog improves motor and cognitive recovery after traumatic brain injury in rodents

Thyrotropin-releasing hormone (TRH) and certain TRH analogs show substantia l neuroprotective effects in experimental brain or spinal cord trauma but a lso have other physiological actions (autonomic, analeptic, and endocrine) that may be undesirable for the treatment of neurotrauma in humans. We deve loped a novel TRH analog (2-ARA-53a), with substitutions at the NH2-terminu s 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) intraven ously 30 min after lateral fluid percussion brain injury showed marked impr ovement in motor recovery compared with vehicle-treated controls (n = 14). Treatment of mice subjected to moderate controlled cortical impact brain in jury, at the same dose and time after trauma (n = 8), improved both motor r ecovery and cognitive performance in a water maze place learning task compa red 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 NH2-terminal-substituted TRH analog (YM-14673). These findings de monstrate that the neuroprotective effects of TRH-related compounds can be dissociated from their other major physiological actions and suggest a pote ntial role for dual-substituted TRH analogs in the treatment of clinical ne urotrauma.