Identification of novel hydrogen sulfide (H<sub>2</sub>S) donors with controlled release rates that elicit anti-inflammatory effects in RAW264.7 cells — ASN Events
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  3. Identification of novel hydrogen sulfide (H2S) donors with controlled release rates that elicit anti-inflammatory effects in RAW264.7 cells

Identification of novel hydrogen sulfide (H2S) donors with controlled release rates that elicit anti-inflammatory effects in RAW264.7 cells (#85)

Caleb Huang 1 2 , Feng Wei 3 , Brian William Dymock 3 , Philip Keith Moore 1
  1. Pharmacology, National University of Singapore, Singapore
  2. NUS Graduate School for Integrative Sciences and Engineering, Singapore
  3. Pharmacy, National University of Singapore, Singapore

Aims

Whether hydrogen sulfide (H2S) exhibits pro- or anti-inflammatory activity is not clear1. To date, 'fast-releasing H2S donors' like NaHS (release in seconds) and 'slow-releasing' H2S donors like GYY4137 (release in hours) have been examined for their effect on inflammation. We have previously shown that GYY4137 exhibited anti-inflammatory properties (c.f. NaHS2). We report here the effect of a range of novel, slow-releasing H2S donors on lipopolysaccharide (LPS) challenged macrophages in vitro.

Methods

Mouse macrophages (RAW264.7) were pretreated (30 min) with slow-releasing H2S donor compounds prior to 24 h stimulation with E. coli LPS. Supernatant was assayed for inflammatory markers. Drug toxicity was determined by MTT assay.

Results

11 novel H2S donor compounds with different H2S release rates were screened for anti-inflammatory activity in LPS-challenged macrophages. Of these, FW1256 reduced TNFα and IL-6 generation. Structural derivatives of the parent compound FW1251 & FW1259 with lower/higher H2S release rates in vitro were synthesized. These compounds not only reduced TNFα and IL-6 generation but also PGE2 and NO and were not toxic. Expression of IL-1β, COX-2 and iNOS genes were also reduced. Using a H2S specific fluorescent-detection probe, FW1251 released >50% of its H2S payload in 3 days whereas FW1256 released approximately 15% of its payload. As proof of concept that sustained H2S administration elicits an anti-inflammatory effect, repeated dosing (every 2 h for 6 h) of macrophages with NaHS significantly inhibited LPS-evoked TNFα and IL-6 generation.

Conclusion

These novel H2S donor drugs are non-toxic and show promising anti-inflammatory activity in vitro, warranting further evaluation of their effects in suitable in vivo models.

  1. Whiteman M. et al., (2011). Expert Rev Clin Pharmacol 2011, 4(1): 13-32.
  2. Whiteman M. et al., (2010). Antioxidants & Redox Signaling 2010, 12, 1147-1154.