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

Alan I. Faden, Gerard B. Fox, Lei Fan, Gian Luca Araldi, Lixin Qiao, Shaomeng Wang, Alan P. Kozikowski

Research output: Contribution to journalArticle

Abstract

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 NH2-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 NH2-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.

Original languageEnglish (US)
Pages (from-to)R1196-R1204
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume277
Issue number4 46-4
DOIs
StatePublished - Oct 1999

Keywords

  • Brain trauma cell culture
  • Neuroprotection rodent brain injury models
  • Thyrotropin-releasing hormone analogs

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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