Natural Isoprenoids are Able to Reduce Inflammation in a Mouse Model of Mevalonate Kinase Deficiency

Abstract

Mevalonate kinase deficiency (MKD) is a rare disorder characterized by recurrent inflammatory episodes and, in most severe cases, by psychomotor delay. Defective synthesis of isoprenoids has been associated with the inflammatory phenotype in these patients, but the molecular mechanisms involved are still poorly understood, and, so far, no specific therapy is available for this disorder. Drugs like aminobisphosphonates, which inhibit the mevalonate pathway causing a relative defect in isoprenoids synthesis, have been also associated to an inflammatory phenotype. Recent data asserted that cell inflammation could be reversed by the addition of some isoprenoids, such as geranylgeraniol and farnesyl pyrophosphate. In this study, a mouse model for typical MKD inflammatory episode was obtained treating BALB/c mice with aminobisphosphonate alendronate and bacterial muramyldipeptide. The effect of exogenous isoprenoids-geraniol, farnesol, and geranylgeraniol-was therefore evaluated in this model. All these compounds were effective in preventing the inflammation induced by alendronate-muramyldipeptide, suggesting a possible role for these compounds in the treatment of MKD in humans. (Pediatr Res 64: 177-182, 2008)

Mouse model of mevalonate kinase deficiency: comparison of cytokine and chemokine profile with that of human patients

“…62/2000-B, 6 October 2000, and approved by the University of Trieste Ethical Committee. The experimental design has been previously described (9). Briefly, mice were randomly divided into groups of six animals each: group 1, untreated controls; group 2, Ald (6.5 or 13 mg/ kg) on day 0 and MDP 100 μg/kg on day 3; group 3, Ald and MDP as in group 2 plus GOH 250 mg/kg on day 2.…”

“…For this reason, we developed a mouse model of MKD (9), showing that the chemical inhibition of the mevalonate pathway through the use of an aminobisphosphonate (alendronate (Ald) or pamidronate) and statins (lovastatin) leads to a moderate inflammatory phenotype that could be amplified by bacterial compounds such as muramyl dipeptide (MDP) or lipopolysaccharide (LPS) (10,11). Ald inhibits the mevalonate pathway and should regenerate the physiologic activation of a dose-dependent inflammatory process.…”

“…Owing to their isoprenoid structure, these compounds are supposed to enter the mevalonate pathway and bypass the biochemical block, thus reconstructing the pathway and limiting the shortage of geranyl-geranyl pyrophosphate (4,5,9). Moreover, the isoprenoids can rescue inflammation in the MKD mouse model (9) as well as in the Ald/lovastatin-LPS-treated Raw 264.7 cell lines (10), and in human monocytes (13). Based on the previous partial success of biological drugs, we decided to evaluate the modulation of cytokines and chemokines in our MKD animal model in the presence or in the absence of GOH.…”

The inhibition of mevalonate pathway induces upregulation of NALP3 expression: new insight in the pathogenesis of mevalonate kinase deficiency

“…Human peripheral blood mononuclear cells (HPBMCs) were isolated by density gradient centrifugation using Ficoll-Paque (GE Healthcare, Uppsala, Sweden) and cultured in RPMI-1640 (Euroclone, Italy) containing 2 mM glutamine, 100 U/ml penicillin-streptomycin and 10% fetal calf serum (FCS, Euroclone, Milano, Italy). 2Â10 6 HPBMCs from healthy donors or MKD patients were incubated with or -in the case of patientswithout alendronate 100 mM for 24 h and with LPS 1 mg/ml for 4 h. Alendronate (Sigma Aldrich) and LPS (Sigma Aldrich, Milano, Italy) were dissolved in distilled water (respectively at 10 mM and 1 mg/ml).…”

“…3 Recently, we described a mouse model of MKD obtained through the inhibition of mevalonate pathway with alendronate combined with the induction of acute inflammation with a bacterial compound. 6 Similarly, we treated human monocytes with alendronate and bacterial lipopolysaccharide (LPS) to simulate a cellular model for a MKD typical episode.…”