Mechanism of Action for NNZ-2566 Anti-inflammatory Effects Following PBBI Involves Upregulation of Immunomodulator ATF3

@article{Cartagena2013MechanismOA,
  title={Mechanism of Action for NNZ-2566 Anti-inflammatory Effects Following PBBI Involves Upregulation of Immunomodulator ATF3},
  author={Casandra M Cartagena and Katie L. Phillips and Garry L. Williams and Melissa A. Konopko and Frank C. Tortella and Jitendra R. Dave and Kara E. Schmid},
  journal={NeuroMolecular Medicine},
  year={2013},
  volume={15},
  pages={504-514}
}
The tripeptide glycine–proline–glutamate analogue NNZ-2566 (Neuren Pharmaceuticals) demonstrates neuroprotective efficacy in models of traumatic brain injury. In penetrating ballistic-like brain injury (PBBI), it significantly decreases injury-induced upregulation of inflammatory cytokines including TNF-α, IFN-γ, and IL-6. However, the mechanism by which NNZ-2566 acts has yet to be determined. The activating transcription factor-3 (ATF3) is known to repress expression of these inflammatory… 
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  • Biology, Medicine
    Experimental Neurology
  • 2016
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...
1
2
3
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References

SHOWING 1-10 OF 56 REFERENCES
NNZ-2566 treatment inhibits neuroinflammation and pro-inflammatory cytokine expression induced by experimental penetrating ballistic-like brain injury in rats
TLDR
The 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.
NNZ-2566, a glypromate analog, improves functional recovery and attenuates apoptosis and inflammation in a rat model of penetrating ballistic-type brain injury.
TLDR
It is demonstrated that NNZ-2566 treatment promoted functional recovery following PBBI, an effect related to the modulation of injury-induced neural inflammatory and apoptotic mechanisms.
Neuroprotective effects of Gly-Pro-Glu, the N-terminal tripeptide of IGF-1, in the hippocampus in vitro.
TLDR
A neuroprotective role for GPE tripeptide is reported, with enhanced survival of the CA1-2 hippocampal neurons following an excitotoxic insult in vitro, which could lead to new strategies to reduce neuronal death after injury and in disease.
Negative Regulation of TLR-Signaling Pathways by Activating Transcription Factor-31
TLDR
ATF3 behaves as a negative regulatory transcription factor in TLR pathways and, accordingly, deficiency in atf3 alters responses to immunological challenges in vivo, which merits further exploration in diseases such as type I diabetes and cancer.
Astrocytes produce and release interleukin-1, interleukin-6, tumor necrosis factor alpha and interferon-gamma following traumatic and metabolic injury.
  • L. Lau, A. Yu
  • Biology, Medicine
    Journal of neurotrauma
  • 2001
TLDR
This study provides the first evidence that astrocytes, without the influence from other cell types, can produce and release cytokines following mechanical and ischemic injury.
Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4
TLDR
Cluster analysis of a comprehensive set of transcriptomic data derived from Toll-like receptor-activated macrophages is used to identify a prominent group of genes that appear to be regulated by activating transcription factor 3 (ATF3), a member of the CREB/ATF family of transcription factors.
Cortical injury increases cholesterol 24S hydroxylase (Cyp46) levels in the rat brain.
TLDR
The data suggest that increased microglial Cyp46 activity is part of a system for removal of damaged cell membranes post-injury, by conversion of cholesterol to 24-hydroxycholesterol and by activation of LXR-regulated gene transcription.
Distinct cellular patterns of upregulated chemokine expression supporting a prominent inflammatory role in traumatic brain injury.
TLDR
It is shown that following TBI, secondary injury chiefly involves inflammatory processes and chemokine signaling, which comprise putative targets for pharmaceutical neuroprotection.
T-cell cytokines in injury-induced neural damage and repair
TLDR
The role of interferon-γ, interleukin (IL)-2,IL-4, IL-6, and IL-10 in autoimmune diseases such as multiple sclerosis, and primarily “non-immune” injury of the central nervous system (CNS), in particular focal ischemia and trauma is reviewed.
...
1
2
3
4
5
...