Novel diketopiperazine enhances motor and cognitive recovery after traumatic brain injury in rats and shows neuroprotection in vitro and in vivo.

Abstract

The authors developed a novel diketopiperazine that shows neuroprotective activity in a variety of in vitro models, as well as in a clinically relevant experimental model of traumatic brain injury (TBI) in rats. Treatment with 1-ARA-35b (35b), a cyclized dipeptide derived from a modified thyrotropin-releasing hormone (TRH) analog, significantly reduced cell death associated with necrosis (maitotoxin), apoptosis (staurosporine), or mechanical injury in neuronal-glial cocultures. Rats subjected to lateral fluid percussion-induced TBI and then treated with 1 mg/kg intravenous 35b thirty minutes after trauma showed significantly improved motor recovery and spatial learning compared with vehicle-treated controls. Treatment also significantly reduced lesion volumes as shown by magnetic resonance imaging, and decreased the number of TUNEL-positive neurons observed in ipsilateral hippocampus. Unlike TRH or traditional TRH analogs, 35b treatment did not change mean arterial pressure, body temperature, or thyroid-stimulating hormone release, and did not have analeptic activity. Moreover, in contrast to TRH or typical TRH analogs, 35b administration after TBI did not alter free-magnesium concentration or cellular bioenergetic state. Receptor-binding studies showed that 35b did not act with high affinity at 50 classical receptors, channels, or transporters. Thus, 35b shows none of the typical physiologic actions associated with TRH, but possesses neuroprotective actions in vivo and in vitro, and appears to attenuate both necrotic and apoptotic cell death.

• Authors: Alan I Faden, Susan M Knoblach, Ibolja Cernak, Lei Fan, Robert Vink, Gian Luca Araldi, Stanley T Fricke, Bryan L Roth, Alan P Kozikowski
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 23 Issue 3 Pg. 342-54 (Mar 2003) ISSN: 0271-678X [Print] United States
• PMID: 12621309 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 1-ARA-35b
• Central Nervous System Stimulants
• Dipeptides
• Neuroprotective Agents
• Peptides, Cyclic
• Piperazines
• Receptors, Cell Surface

Topics

• Animals
• Autonomic Nervous System (drug effects, physiopathology)
• Brain Injuries (diagnosis, physiopathology, psychology)
• Cells, Cultured
• Central Nervous System Stimulants (pharmacology)
• Coculture Techniques
• Cognition (drug effects)
• Dipeptides (metabolism, pharmacology)
• In Situ Nick-End Labeling
• Magnetic Resonance Imaging
• Magnetic Resonance Spectroscopy
• Male
• Motor Activity (drug effects)
• Neuroprotective Agents (pharmacology)
• Peptides, Cyclic (metabolism, pharmacology)
• Piperazines (metabolism, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Cell Surface (metabolism)
• Recovery of Function
• Wounds, Nonpenetrating (diagnosis, physiopathology, psychology)