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

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 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.

Multifunctional Drugs for Head Injury

“…Alternative TRH analogs were designed to largely eliminate the undesirable physiological actions while preserving the neuroprotective effects, 196 and in so doing, the compounds have become even more of a multifactorial drug, now with nootropic actions, but without the adverse side effects. As a class of compounds, these more recent analogs have been shown to reduce cell death, protect against glutamate toxicity and ␤-amyloidinduced injury, reduce lesion volume, and produce highly significant improvements in motor and cognitive function in both in vitro and in vivo models of neurotrauma.…”

Kinetic Investigation of the Specificity of Porcine Brain Thyrotropin-releasing Hormone-degrading Ectoenzyme for Thyrotropin-releasing Hormone-like Peptides

“…Based on its central nervous system effects, TRH has been found to have potential use in the treatment of brain and spinal injury (18,19) and several central nervous system disorders, including spinocerebellar degeneration, cognitive deficits, and spinal cord pain transmission (16,17). The mechanisms by which TRH improves these conditions are not fully elucidated but appear to involve the potentiation by TRH of other neurotransmitter systems.…”

Comparing the Predictive Value of Multiple Cognitive, Affective, and Motor Tasks after Rodent Traumatic Brain Injury

“…It results in consistent histological damage and sustained behavioral deficits. [6][7][8][9] CCI can cause intracerebral hemorrhage, cytotoxic and vasogenic brain edema, neuronal loss, and motor and cognitive deficits. [10][11][12][13][14][15][16] Both behavioral and histological outcomes are injury-severity dependent, as demonstrated by varying impact depth and/or velocity in rats, 17,18 or mice.…”