Dr. Ron’s Research Review – October 7, 2015

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This week’s research review focuses on Cromolyn.

Cromolyn is a mast cell stabilizer that prevents the release of histamine and eicosanoid from mast cells. (Yazid et al., 2013; Yazid et al., 2009)
There is a role for expanded use of sodium cromolyn in asthma. Its potent anti-inflammatory effects, lack of side effects, and acceptable dosing and method of delivery, as well as its special role in exercise-induced asthma, make it a very suitable choice in the initial therapy for control of asthma. (Netzer et al., 2012)

A recent study showed that in vivo, the levels of soluble Amyloid β are decreased by over 50% after only 1 week of daily intraperitoneally administered cromolyn sodium in a transgenic model of Alzheimer disease. It also decreases the half-life of soluble Aβ in the brain. (Hori et al., 2015)

Nasal Crom is available OTC in the US (i.e. from Amazon). Canadian pharmacies have OTC Cromolyn eye drops and Rhinaris nasal mist; and prescription inhalation and oral Gastrocrom for mastocytosis.

Dr. Ron


 

Articles

A Food and Drug Administration-approved asthma therapeutic agent impacts amyloid β in the brain in a transgenic model of Alzheimer disease.
            (Hori et al., 2015) Download
Interfering with the assembly of Amyloid β (Aβ) peptides from monomer to oligomeric species and fibrils or promoting their clearance from the brain are targets of anti-Aβ-directed therapies in Alzheimer disease. Here we demonstrate that cromolyn sodium (disodium cromoglycate), a Food and Drug Administration-approved drug already in use for the treatment of asthma, efficiently inhibits the aggregation of Aβ monomers into higher-order oligomers and fibrils in vitro without affecting Aβ production. In vivo, the levels of soluble Aβ are decreased by over 50% after only 1 week of daily intraperitoneally administered cromolyn sodium. Additional in vivo microdialysis studies also show that this compound decreases the half-life of soluble Aβ in the brain. These data suggest a clear effect of a peripherally administered, Food and Drug Administration-approved medication on Aβ economy, supporting further investigation of the potential long-term efficacy of cromolyn sodium in Alzheimer disease.

The actual role of sodium cromoglycate in the treatment of asthma--a critical review.
            (Netzer et al., 2012) Download
INTRODUCTION:  Despite international consensus and clearly written guidelines urging wider use of corticosteroids or combinations of inhaled short- and long-acting β-agonists (SABA and LABA) and corticosteroids in persistent asthma, prescribing patterns and compliance rates fall far short of recommendations. OBJECTIVES:  The failure to use steroids more aggressively is due, in part, to their side effects, even with inhaled forms of the drug. There is a role for expanded use of sodium cromolyn in asthma. Its potent anti-inflammatory effects, lack of side effects, and acceptable dosing and method of delivery, as well as its special role in exercise-induced asthma, make it a very suitable choice in the initial therapy for control of asthma. CONCLUSION:  Compared to SABA and LABA, cromoglycates alone are unsuspicious of being used to enhance physical performance.


 

Cromoglycate drugs suppress eicosanoid generation in U937 cells by promoting the release of Anx-A1.
            (Yazid et al., 2009) Download
Using biochemical, epifluorescence and electron microscopic techniques in a U937 model system, we investigated the effect of anti-allergic drugs di-sodium cromoglycate and sodium nedocromil on the trafficking and release of the anti-inflammatory protein Annexin-A1 (Anx-A1) when this was triggered by glucocorticoid (GC) treatment. GCs alone produced a rapid (within 5min) concentration-dependent activation of PKCalpha/beta (Protein Kinase C; EC 2.7.11.13) and phosphorylation of Anx-A1 on Ser(27). Both phosphoproteins accumulated at the plasma membrane and Anx-A1 was subsequently externalised thereby inhibiting thromboxane (Tx) B(2) generation. When administered alone, cromoglycate or nedocromil had little effect on this pathway however, in the presence of a fixed sub-maximal concentration of GCs, increasing amounts of the cromoglycate-like drugs caused a striking concentration-dependent enhancement of Anx-A1 and PKCalpha/beta phosphorylation, membrane recruitment and Anx-A1 release from cells resulting in greatly enhanced inhibition of TxB(2) generation. GCs also stimulated phosphatase accumulation at the plasma membrane of U937 cells. Both cromoglycate and nedocromil inhibited this enzymatic activity as well as that of a highly purified PP2A phosphatase preparation. We conclude that stimulation by the cromoglycate-like drugs of intracellular Anx-A1 trafficking and release (hence inhibition of eicosanoid release) is secondary to inhibition of a phosphatase PP2A (phosphoprotein phosphatase; EC 3.1.3.16), which probably forms part of a control loop to limit Anx-A1 release. These experiments provide a basis for a novel mechanism of action for the cromolyns, a group of drugs that have long puzzled investigators.

Anti-allergic cromones inhibit histamine and eicosanoid release from activated human and murine mast cells by releasing Annexin A1.
            (Yazid et al., 2013) Download
BACKGROUND AND PURPOSE:  Although the 'cromones' (di-sodium cromoglycate and sodium nedocromil) are used to treat allergy and asthma, their 'mast cell stabilising' mechanism of pharmacological action has never been convincingly explained. Here, we investigate the hypothesis that these drugs act by stimulating the release of the anti-inflammatory protein Annexin-A1 (Anx-A1) from mast cells. EXPERIMENTAL APPROACH:  We used biochemical and immuno-neutralisation techniques to investigate the mechanism by which cromones suppress histamine and eicosanoid release from cord-derived human mast cells (CDMCs) or murine bone marrow-derived mast cells (BMDMCs) from wild type and Anx-A1 null mice. KEY RESULTS:  CDMCs activated by IgE-FcRε1 crosslinking, released histamine and prostaglandin (PG) D2, which were inhibited (30-65%) by 5 min pre-treatment with cromoglycate (10 nM) or nedocromil (10 nM), as well as dexamethasone (2 nM) and human recombinant Anx-A1 (1-10 nM). In CDMCs cromones potentiated (2-5 fold) protein kinase C (PKC) phosphorylation and Anx-A1 phosphorylation and secretion (3-5 fold). Incubation of CDMCs with a neutralising anti-Anx-A1 monoclonal antibody reversed the cromone inhibitory effect. Nedocromil (10 nM) also inhibited (40-60%) the release of mediators from murine bone marrow derived-mast cells from wild type mice activated by compound 48/80 and IgE-FcRε1 cross-linking, but were inactive in such cells when these were prepared from Anx-A1 null mice or when the neutralising anti-Anx-A1 antibody was present. CONCLUSIONS AND IMPLICATIONS:  We conclude that stimulation of phosphorylation and secretion of Anx-A1 is an important component of inhibitory cromone actions on mast cells, which could explain their acute pharmacological actions in allergy. These findings also highlight a new pathway for reducing mediator release from these cells.

 

References

Hori, Y, et al. (2015), ‘A Food and Drug Administration-approved asthma therapeutic agent impacts amyloid β in the brain in a transgenic model of Alzheimer disease.’, J Biol Chem, 290 (4), 1966-78. PubMedID: 25468905
Netzer, NC, et al. (2012), ‘The actual role of sodium cromoglycate in the treatment of asthma--a critical review.’, Sleep Breath, 16 (4), 1027-32. PubMedID: 22218743
Yazid, S, et al. (2009), ‘Cromoglycate drugs suppress eicosanoid generation in U937 cells by promoting the release of Anx-A1.’, Biochem Pharmacol, 77 (12), 1814-26. PubMedID: 19428336
Yazid, S, et al. (2013), ‘Anti-allergic cromones inhibit histamine and eicosanoid release from activated human and murine mast cells by releasing Annexin A1.’, PLoS One, 8 (3), e58963. PubMedID: 23527056