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Psoriasis Pathogenesis

Psoriasis is a chronic, immune-inflammatory disorder that mainly affects the skin and manifests as raised, well-demarcated, erythematous plaques with adherent silvery scales. Histological features of psoriatic lesions include epidermal hyperplasia with acanthosis, caused by aberrant terminal differentiation and hyperproliferation of epidermal keratinocytes, and a marked infiltration into the dermis and epidermis of inflammatory cells, including T-cells, neutrophils, macrophages and dendritic cells.

Adapted from Nestle et al, 2009


Inflammation
Keratinocytes hyperproliferation and altered differentiation

The interplay between keratinocytes and immune cells has been found to be fundamental in the pathogenesis of psoriasis, since it generates inflammatory and immune circuits responsible for initiation, progression and persistence of the disease.

Keratinocytes themselves are a source of immune-inflammatory mediators (e.g. cytokines, chemokines) that lead to the recruitment and activation of immune cells and sustain psoriasis lesions. Immune cells infiltrate establishes a milieau which leads to keratinocytes hyperproliferation and altered differentiation.

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

NAC-GED-0507 and/or its metabolic precursor (GED-0507):
  • 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.

Acne Pathogenesis

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Potential Indications

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References

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