Mechanisms of action of Manuka honey as a potential therapeutic agent for bladder pain syndrome/interstitial cystitis: clinical and laboratory studies

Abstract

Introduction: Bladder Pain Syndrome/Interstitial cystitis (BPS/IC) is a debilitating chronic inflammatory condition. It significantly reduces patients’ quality of life, work productivity and represents a huge burden on health reserves. Current treatments are failing patients. Neurogenic inflammation through the interaction between mast cells and the bladder nociceptive sensory nerve endings is thought to be implicated. Mast cells response to the neuropeptide substance P (SP) is dependent on the expression of MRGPRX2, a recently identified receptor for SP. However, its expression by resident bladder mast cells has not been elucidated. Manuka honey has anti-inflammatory and antibacterial properties. Thus, it might be a useful adjuvant therapy for BPS/IC. The aims of this study were to investigate the link between neurogenic inflammation in the pathophysiology of BPS/IC and explore the potential anti-inflammatory effects of Medihoney and Manuka honey extract on inhibiting mast cell degranulation. Materials and Method: Using immunohistochemistry, mast cell numbers and MRGPRX2 expression were evaluated in formalin-fixed paraffin embedded bladder biopsies obtained from BPS/IC patients. Sections free of inflammation were used as controls. Human LAD2 cells were stimulated by SP. Subsequently, degranulation and pro-inflammatory cytokine release, with or without pre-incubation with Medihoney or Manuka honey extract, were assessed using β-hexosaminidase assay and electrochemoluminescent assay. In addition, phospho MAPK array was used to assess the associated intracellular signalling events. Results: Upon both tryptase and chymase staining, mast cell numbers were significantly higher in the BPS/IC biopsies vs controls (166.1 ± 21.02 vs 72.64 ± 9.150 cells/mm2 ) and (155.7 ± 23.86 vs 59.83 ± 9.153 cells/mm2), respectively. Nevertheless, the percentage MRGPRX2 expression on the mast cells was significantly higher in the BPS/IC biopsies compared to controls (68% VS 28% co-expression, respectively). These findings strongly support a positive role for neurogenic inflammation in the pathophysiology of BPS/IC. Interestingly, Medihoney and Manuka honey extract strongly and dose dependently inhibited LAD2 cell degranulation with a maximum of 96% inhibition at 4% concentration. This was accompanied by strong inhibition of the intracellular signalling events well known to underly mast cell degranulation, including the phosphorylation of Akt, ERK1/2 and STAT3. Interestingly, the substance P-induced mast cell activation was accompanied by the activation of the kinases WNK1, GSK3α/β and PRAS40, which was inhibited upon pre-incubation with Medihoney or the Manuka extract. To our knowledge, the activation of the later 3 kinases is a novel finding and the exact roles of these kinases in mast cell activation is yet to be explored. Conclusion: Medihoney and the Manuka honey extract inhibited SP-induced mast cell degranulation. This strongly supports an anti-inflammatory role of these natural agents against the mast cell driven neurogenic inflammation, which is believed to be highly involved in the pathophysiology of BPS/IC. Our findings suggest that Medihoney and Manuka honey extract could potentially be an effective adjuvant intravesical therapy for BPS/IC.

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ORCID for Omar Kamal Abdelhalim Abdelwahab: orcid.org/0000-0002-5126-7616

ORCID for Bashir Lwaleed: orcid.org/0000-0001-5748-4892

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