NAC-GED-0507 anti-inflammatory effects and normalisation of altered proliferation and differentiation in normal human keratinocytes
NAC-GED-0507 EFFECTS ON TNFα-INDUCED MRNA OF IL-6
NAC-GED-0507 EFFECTS ON TNFα-INDUCED IL-6 SECRETION
NAC-GED-0507 effects on NF-kB
nuclear translocation
NAC-GED-0507 EFFECTS ON TNFα-INDUCED KERATINOCYTES PROLIFERATION
NAC-GED-0507 and GED-0507 (its metabolic precursor), significantly decrease NF-κB nuclear translocation, and inhibit TNFα-induced IL-6 gene expression and protein secretion in NHKs. Moreover they significantly counteract the TNF-α-induced altered keratinocytes proliferation (as demonstrated by the reduction of ki67), and altered differentiation (data not shown).
In vivo study in the mouse model of IL-21-induced epidermal hyperplasia
Model of psoriasis-like skin pathology, induced by intradermal injection of IL-21, a cytokine highly expressed in psoriatic plaques and known to play a key role in the pathological process of psoriasis.
Topical application of 1% GED-0507 (metabolic precursor of NAC-GED-0507) for 6 days significantly reduced epidermal hyperplasia and lymphocytes infiltrate. Moreover, the treatment significantly decreased IL-21, TNF-α and K6, mRNA expression. GED-0507 cream significantly improved the IL-21 induced epithelial hyperplasia, differentiation and inflammation.
Summary
- In in vitro studies performed in normal human keratinocytes (NHKs), upregulates PPARγ mRNA levels in a dose dependent manner, inhibits the activation of NF-kB, inhibit expression and secretion of pro-inflammatory cytokines stimulated with different biological inflammatory stimuli. Moreover NAC-GED-0507 normalizes NHKs TNF-α-induced proliferation and altered differentiation. The anti-inflammatory effects are mediated by PPARγ since they were abrogated in PPARγ silenced NHKs
- Inhibits the secretion of IL-2, a cytokine relevant in the pathogenesis of psoriasis, in skin biopsies collected from plaque type psoriatic subjects
- Inhibits the LPS-induced expression of IL-12, IL-21, IL-23 and TNF-alpha in PBMCs from control subjects and patients with psoriasis
- Decreases cellular infiltrate and epidermal hyperplasia upon topical application in the mouse model of psoriasis-like skin lesions elicited by IL-21
- Inhibited insulin-induced Akt/mTOR signaling (known to mediate insulin-induced cellular growth, proliferation, lipid synthesis)
- NAC-GED-0507 effects on SZ95 cells are counteracted by the co-administration of the PPARγ antagonist GW9662 or abolished in SZ95 PPARγ silenced cells
Conclusion
NAC-GED-0507 represents a promising compound for therapeutic interventions in an immune-inflammatory skin disease associated with aberrant differentiation and proliferation of keratinocytes like psoriasis.