NNZ-2566 treatment inhibits neuroinflammation and pro-inflammatory cytokine expression induced by experimental penetrating ballistic-like brain injury in rats.

Abstract

BACKGROUND:

Inflammatory cytokines play a crucial role in the pathophysiology of traumatic brain injury (TBI), exerting either deleterious effects on the progression of tissue damage or beneficial roles during recovery and repair. NNZ-2566, a synthetic analogue of the neuroprotective tripeptide Glypromate, has been shown to be neuroprotective in animal models of brain injury. The goal of this study was to determine the effects of NNZ-2566 on inflammatory cytokine expression and neuroinflammation induced by penetrating ballistic-like brain injury (PBBI) in rats.

METHODS:

NNZ-2566 or vehicle (saline) was administered intravenously as a bolus injection (10 mg/kg) at 30 min post-injury, immediately followed by a continuous infusion of NNZ-2566 (3 mg/kg/h), or equal volume of vehicle, for various durations. Inflammatory cytokine gene expression from the brain tissue of rats exposed to PBBI was evaluated using microarray, quantitative real time PCR (QRT-PCR), and enzyme-linked immunosorbent assay (ELISA) array. Histopathology of the injured brains was examined using hematoxylin and eosin (H&E) and immunocytochemistry of inflammatory cytokine IL-1beta.

RESULTS:

NNZ-2566 treatment significantly reduced injury-mediated up-regulation of IL-1beta, TNF-alpha, E-selectin and IL-6 mRNA during the acute injury phase. ELISA cytokine array showed that NZ-2566 treatment significantly reduced levels of the pro-inflammatory cytokines IL-1beta, TNF-alpha and IFN-gamma in the injured brain, but did not affect anti-inflammatory cytokine IL-6 levels.

CONCLUSION:

Collectively, these results suggest that the neuroprotective effects of NNZ-2566 may, in part, be functionally attributed to the compound's ability to modulate expression of multiple neuroinflammatory mediators in the injured brain.

• Authors: Hans H Wei, Xi-Chun M Lu, Deborah A Shear, Anu Waghray, Changping Yao, Frank C Tortella, Jitendra R Dave
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 6 Pg. 19 (Aug 05 2009) ISSN: 1742-2094 [Electronic] England
• PMID: 19656406 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Cytokines
• Inflammation Mediators
• NNZ 2566
• Neuroprotective Agents
• Oligopeptides
• RNA, Messenger

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Brain Injuries (complications, drug therapy, physiopathology)
• Cytokines (drug effects, genetics, metabolism)
• Disease Models, Animal
• Down-Regulation (drug effects, physiology)
• Encephalitis (drug therapy, etiology, physiopathology)
• Gene Expression Regulation (drug effects, physiology)
• Head Injuries, Penetrating (complications, drug therapy, physiopathology)
• Inflammation Mediators (antagonists & inhibitors, metabolism)
• Male
• Neuroprotective Agents (pharmacology, therapeutic use)
• Oligopeptides (pharmacology, therapeutic use)
• RNA, Messenger (drug effects, metabolism)
• Rats
• Rats, Sprague-Dawley
• Treatment Outcome