NNZ-2566, a glypromate analog, improves functional recovery and attenuates apoptosis and inflammation in a rat model of penetrating ballistic-type brain injury.

Abstract

Glycine-proline-glutamate (GPE) is an N-terminal tripeptide endogenously cleaved from insulin-like growth factor-1 in the brain and is neuroprotective against hypoxic-ischemic brain injury and neurodegeneration. NNZ-2566 is an analog of GPE designed to have improved bioavailability. In this study, we tested NNZ-2566 in a rat model of penetrating ballistic-type brain injury (PBBI) and assessed its effects on injury-induced histopathology, behavioral deficits, and molecular and cellular events associated with inflammation and apoptosis. In the initial dose-response experiments, NNZ-2566 (0.01-3 mg/kg/h x 12 h intravenous infusion) was given at 30 min post-injury and the therapeutic time window was established by delaying treatments 2-4 h post-injury, but with the addition of a 10- or 30-mg/kg bolus dose. All animals survived 72 h. Neuroprotection was evaluated by balance beam testing and histopathology. The effects of NNZ-2566 on injury-induced changes in Bax and Bcl-2 proteins, activated microgliosis, neutrophil infiltration, and astrocyte reactivity were also examined. Behavioral results demonstrated that NNZ-2566 dose-dependently reduced foot faults by 19-66% after acute treatments, and 35-55% after delayed treatments. Although gross lesion volume was not affected, NNZ-2566 treatment significantly attenuated neutrophil infiltration and reduced the number of activated microglial cells in the peri-lesion regions of the PBBI. PBBI induced a significant upregulation in Bax expression (36%) and a concomitant downregulation in Bcl-2 expression (33%), both of which were significantly reversed by NNZ-2566. Collectively, these results demonstrated that NNZ-2566 treatment promoted functional recovery following PBBI, an effect related to the modulation of injury-induced neural inflammatory and apoptotic mechanisms.

• Authors: Xi-Chun May Lu, Ren-Wu Chen, Changping Yao, Hans Wei, Xiaofang Yang, Zhilin Liao, Jitendra R Dave, Frank C Tortella
• Journal: Journal of neurotrauma (J Neurotrauma) Vol. 26 Issue 1 Pg. 141-54 (Jan 2009) ISSN: 1557-9042 [Electronic] United States
• PMID: 19119917 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Apoptosis Regulatory Proteins
• NNZ 2566
• Neuroprotective Agents
• Oligopeptides
• glycyl-prolyl-glutamic acid

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects, physiology)
• Apoptosis Regulatory Proteins (drug effects, metabolism)
• Astrocytes (drug effects, pathology)
• Brain (drug effects, pathology, physiopathology)
• Brain Injuries (drug therapy, metabolism, physiopathology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Encephalitis (drug therapy, metabolism, physiopathology)
• Gliosis (drug therapy, physiopathology, prevention & control)
• Injections, Intravenous
• Microglia (drug effects, pathology)
• Movement Disorders (drug therapy, etiology, physiopathology)
• Nerve Degeneration (drug therapy, physiopathology, prevention & control)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Oligopeptides (agonists, chemistry, pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Recovery of Function (drug effects, physiology)
• Treatment Outcome