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


CONCLUSIONS
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.
Wei
Hans H
HH
Department of Applied Neurobiology, Division of Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA. hans.wei@us.army.mil
Lu
Xi-Chun M
XC
Shear
Deborah A
DA
Waghray
Anu
A
Yao
Changping
C
Tortella
Frank C
FC
Dave
Jitendra R
JR
D000818:Animals; D008297:Male; D051381:Rats; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D016207:Cytokines / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004660:Encephalitis / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D020197:Head Injuries, Penetrating / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome; D005971:Glutamates
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D009842:Oligopeptides; D012333:RNA, Messenger; C000656362:trofinetide; D005971:Glutamates