ArticleNeuromolecular medicine2013
Mechanism of action for NNZ-2566 anti-inflammatory effects following PBBI involves upregulation of immunomodulator ATF3.
Article in Neuromolecular medicine, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
- Improving Treatment Trial Outcomes for Rett Syndrome: The Development of Rett-specific Anchors for the Clinical Global Impression Scale.Journal of child neurology · 2015Trial
- C/EBPβ Drives Ischemia-Induced Microglial Inflammatory Reprogramming Through Transcriptional Activation of ATF3 and Exacerbates Brain Injury.Molecular neurobiology · 2026Article
- Induction of activating transcription factor 3 (ATF3) in the cerebral cortex of a mouse model of blast-induced traumatic brain injury.Human cell · 2026Article
- Trofinetide Improves Cognitive Function in APP/PS1 Mice by Suppressing Inflammation and Apoptosis.Molecular neurobiology · 2025Article
- Article
- Beneficial Effects of Human Schwann Cell-Derived Exosomes in Mitigating Secondary Damage After Penetrating Ballistic-Like Brain Injury.Journal of neurotrauma · 2024Article
- Ependymal cells: roles in central nervous system infections and therapeutic application.Journal of neuroinflammation · 2024Review
- Profile of Trofinetide in the Treatment of Rett Syndrome: Design, Development and Potential Place in Therapy.Drug design, development and therapy · 2024Review
- Trofinetide in Rett syndrome: A brief review of safety and efficacy.Intractable & rare diseases research · 2023Article
- Trofinetide: a pioneering treatment for Rett syndrome.Trends in pharmacological sciences · 2023Article
- Trofinetide for Rett Syndrome: Highlights on the Development and Related Inventions of the First USFDA-Approved Treatment for Rare Pediatric Unmet Medical Need.Journal of clinical medicine · 2023Review
- Concise Overview of Glypromate Neuropeptide Research: From Chemistry to Pharmacological Applications in Neurosciences.ACS chemical neuroscience · 2023Review
- Current Clinical Trials in Traumatic Brain Injury.Brain sciences · 2022Review
- Transcriptional Factors and Protein Biomarkers as Target Therapeutics in Traumatic Spinal Cord and Brain Injury.Current neuropharmacology · 2020Review
- The role of microglial inflammasome activation in pyroptotic cell death following penetrating traumatic brain injury.Journal of neuroinflammation · 2019Article
- Microglial Inflammasome Activation in Penetrating Ballistic-Like Brain Injury.Journal of neurotrauma · 2018Article
- Fragile X targeted pharmacotherapy: lessons learned and future directions.Journal of neurodevelopmental disorders · 2017Review
- Review
- Treatment of traumatic brain injury with anti-inflammatory drugs.Experimental neurology · 2016Review
- Emerging pharmacologic treatment options for fragile X syndrome.The application of clinical genetics · 2015Review
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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 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.
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