June 14, 2013 Journal article Open Access

Cartagena, Casandra M.; Phillips, Katie L.; Williams, Garry L.; Konopko, Melissa; Tortella, Frank C.; Dave, Jitendra R.; Schmid, Kara E.

Citation Style Language JSON Export

{
  "DOI": "10.1007/s12017-013-8236-z", 
  "author": [
    {
      "family": "Cartagena, Casandra M."
    }, 
    {
      "family": "Phillips, Katie L."
    }, 
    {
      "family": "Williams, Garry L."
    }, 
    {
      "family": "Konopko, Melissa"
    }, 
    {
      "family": "Tortella, Frank C."
    }, 
    {
      "family": "Dave, Jitendra R."
    }, 
    {
      "family": "Schmid, Kara E."
    }
  ], 
  "issued": {
    "date-parts": [
      [
        2013, 
        6, 
        14
      ]
    ]
  }, 
  "abstract": "The tripeptide glycine\u2013proline\u2013glutamate 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-\u03b1, IFN-\u03b3, 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 cytokines and was increased at the mRNA and protein level 24-h post-PBBI. This study investigated whether 12 h of NNZ-2566 treatment following PBBI alters atf3 expression. PBBI alone significantly increased atf3 mRNA levels by 13-fold at 12 h and these levels were increased by an additional fourfold with NNZ-2566 treatment. To confirm that changes in mRNA translated to changes in protein expression, ATF3 expression levels were determined in vivo in microglia/macrophages, T cells, natural killer cells (NKCs), astrocytes, and neurons. PBBI alone significantly increased ATF3 in microglia/macrophages (820 %), NKCs (58 %), and astrocytes (51 %), but decreased levels in T cells (48 %). NNZ-2566 treatment further increased ATF3 protein expression in microglia/macrophages (102 %), NKCs (308 %), and astrocytes (13 %), while reversing ATF3 decreases in T cells. Finally, PBBI increased ATF3 levels by 55 % in neurons and NNZ-2566 treatment further increased these levels an additional 33 %. Since increased ATF3 may be an innate protective mechanism to limit inflammation following injury, these results demonstrating that the anti-inflammatory and neuroprotective drug NNZ-2566 increase both mRNA and protein levels of ATF3 in multiple cell types provide a cellular mechanism for NNZ-2566 modulation of neuroinflammation following PBBI.", 
  "title": "Mechanism of Action for NNZ-2566 Anti-inflammatory Effects Following PBBI Involves Upregulation of Immunomodulator ATF3", 
  "type": "article-journal", 
  "id": "1232878"
}