Evidence questioning cromolyn's effectiveness and selectivity as a ‘mast cell stabilizer' in mice

Abstract

Cromolyn, widely characterized as a “mast cell stabilizer”, has been used in mice to investigate the biological roles of mast cells in vivo. However, it is not clear to what extent cromolyn can either limit the function of mouse mast cells or influence biological processes in mice independently of effects on mast cells. We confirmed that cromolyn (at 10 mg/kg in vivo or 10 – 100 μM in vitro) can inhibit IgE-dependent mast cell activation in rats in vivo (measuring Evans blue extravasation in passive cutaneous anaphylaxis and increases in plasma histamine in passive systemic anaphylaxis) and in vitro (measuring peritoneal mast cell β-hexosaminidase release and prostaglandin D2 synthesis). However, under the conditions tested, cromolyn did not inhibit those mast cell-dependent responses in mice. In mice, cromolyn also failed to inhibit the ear swelling or leukocyte infiltration at sites of passive cutaneous anaphylaxis. Nor did cromolyn inhibit IgE-independent degranulation of mouse peritoneal mast cells induced by various stimulators in vitro. At 100 mg/kg, a concentration ten times higher than that which inhibited passive systemic anaphylaxis in rats, cromolyn significantly inhibited the increases in plasma concentrations of mouse mast cell protease-1 (but not of histamine) during passive systemic anaphylaxis, but had no effect on the reduction in body temperature in this setting. Moreover, this concentration of cromolyn (100 mg/kg) also inhibited LPS-induced TNF production in genetically mast cell-deficient C57BL/6-KitW-sh/W-sh mice in vivo. These results question cromolyn’s effectiveness and selectivity as an inhibitor of mast cell activation and mediator release in the mouse.

Type 1 Diabetes in NOD Mice Unaffected by Mast Cell Deficiency

“…In most cases, these studies have been performed using nonspecific mast cell "stabilizers" (48) or Kit mutant mice that, although mast cell-deficient, have other immune (18) and relevant nonimmune abnormalities, which include, notably, the recent discovery of the role of Kit in pancreatic b-cell function (49). Taking into account the pleiotropic abnormalities in Kit mutant mice, it is conceivable that several roles that have been attributed to mast cells are not mast cell-specific, but instead caused by the Kit mutations.…”

“…In fact, although highly speculated (14,15,36), the effect of mast cell deficiency on T1D had never been directly assessed genetically in vivo, with the exception of an abstract suggesting that NOD.Kit W/Wv mice failed to develop T1D (52). Indirectly, one study tested the effect of mast cell inhibition using the mast cell stabilizer disodium cromoglycate and found that this significantly delayed the onset of T1D (10); however, the specificity and function of this drug is controversial (48). In contrast, a second study activated mast cells and basophils via antiFc´RI antibody treatment and reported that this treatment delayed the onset of T1D (11).…”

Mast cells: Versatile gatekeepers of pain

“…Pre-administration of histamine receptor antagonists as well as sodium cromoglycate (SCG) – a compound widely used as a mast cell granule stabilizer – also reduced later phases of formalin pain [35]. It is important to remember that SCG can have direct effects on nerves [36] and can also have differential effects on mast cell degranulation depending on the experimental system [37]. Therefore, all experimental evidence that uses SCG as a mast cell-tropic reagent should be interpreted with caution unless accompanied by suitable controls or follow-up experiments conducted in mast cell-deficient conditions.…”

Mast Cell Stabilization Ameliorates Autoimmune Anti-Myeloperoxidase Glomerulonephritis

“…There is some controversy as to whether DSCG can effectively attenuate MC degranulation in mice. 39 However, there are a number of reports showing that this drug successfully stabilizes MCs by attenuating MC degranulation in a number of murine models. [40][41][42] We also demonstrated that DSCG could significantly attenuate MC degranulation in a model of passive cutaneous anaphylaxis in C57BL/6 mice (Supplemental Figure 1).…”