Indoprofen ((±)-Indoprofe)

Indoprofen prevents muscle wasting in aged mice through activation of PDK1/AKT pathway

Background: Muscle wasting, resulting from aging or pathological conditions, leads to reduced quality of life, increased morbidity, and increased mortality. Much research effort has been focused on the development of exercise mimetics to prevent muscle atrophy and weakness. In this study, we identified indoprofen from a screen for peroxisome proliferator-activated receptor γ coactivator α (PGC-1α) inducers and report its potential as a drug for muscle wasting. Methods: The effects of indoprofen treatment on dexamethasone-induced atrophy in mice and in 3-phosphoinositide-dependent protein kinase-1 (PDK1)-deleted C2C12 myotubes were evaluated by immunoblotting to determine the expression levels of myosin heavy chain and anabolic-related and oxidative metabolism-related proteins. Young, old, and disuse-induced muscle atrophic mice were administered indoprofen (2 mg/kg body weight) by gavage. Body weight, muscle weight, grip strength, isometric force, and muscle histology were assessed. The expression levels of muscle mass-related and function-related proteins were analysed by immunoblotting or immunostaining. Results: In young (3-month-old) and aged (22-month-old) mice, indoprofen treatment activated oxidative metabolism-related enzymes and led to increased muscle mass. Mechanistic analysis using animal models and muscle cells revealed that indoprofen treatment induced the sequential activation of AKT/p70S6 kinase (S6K) and AMP-activated protein kinase (AMPK), which in turn can augment protein synthesis and PGC-1α induction, respectively. Structural prediction analysis identified PDK1 as a target of indoprofen and, indeed, short-term treatment with indoprofen activated the PDK1/AKT/S6K pathway in muscle cells. Consistent with this finding, PDK1 inhibition abrogated indoprofen-induced AKT/S6K activation and hypertrophic response. Conclusions: Our findings demonstrate the effects of indoprofen in boosting skeletal muscle mass through the sequential activation of PDK1/AKT/S6K and AMPK/PGC-1α. Taken together, our results suggest that indoprofen represents a potential drug to prevent muscle wasting and weakness related to aging or muscle diseases.

Indoprofen exerts a potent therapeutic effect against sepsis by alleviating high mobility group box 1-mediated inflammatory responses

Indoprofen is a non-steroidal anti-inflammatory drug, and has provided insights into treatment of spinal muscular atrophies; however, the treatment effect of indoprofen on sepsis and the precise underlying mechanism remain to be elucidated. This study was carried out to examine the inhibitory effect of indoprofen on high mobility group box 1 (HMGB1)-mediated inflammatory responses in vivo and in vitro. Intraperitoneal injection of indoprofen (20 or 40 mg/kg) at 8 h post-sepsis markedly improved the survival of BALB/c mice and ameliorated multiple-organ injury by blocking the inflammatory responses. In addition, indoprofen partially reduced the HMGB1 level in the serum and in the lung, as well as ameliorated pulmonary edema. Mechanistically, indoprofen potently inhibited the release of HMGB1 following stimulation by lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (poly I:C), and suppressed recombinant human HMGB1(rhHMGB1)-induced inflammatory responses. It was also found that indoprofen has both cyclooxygenase 2-dependent and -independent inhibitory effects on the proinflammatory effect of HMGB1 in THP-1 cells. Further, the drug reduced rhHMGB1-induced cell surface levels of toll-like receptor 2, toll-like receptor 4, and receptor of advanced glycation end-products in a concentration-dependent manner. Collectively, these data demonstrated that the anti-inflammatory effect of indoprofen in sepsis was associated with HMGB1-mediated inflammatory responses, thus offering a favorable mechanistic basis to support the therapeutic potential of indoprofen for the treatment of lethal sepsis or other inflammatory diseases.

Indoprofen--another NSAID

Intravenous indoprofen for prompt relief of acute gout: a regimen-finding study

The results of an open exploratory trial with different regimens of indoprofen in patients with acute gouty arthritis are described. Two main daily regimens were assessed: (a) indoprofen 200 mg as an intravenous bolus, followed by slow infusion of 100 mg/hour for about 4 hours (24 attacks treated in twenty-three patients); and (b) indoprofen 400 mg as an intravenous bolus (13 attacks treated in twelve patients). In both regimens intravenous indoprofen was supplemented with 400-600 mg daily of indoprofen by mouth. The patient's response, as judged by pain, tenderness, local heat, redness, range of motion and joint circumference, was dramatic in both series, with no significant difference between them at any time of observation. Substantial improvement was apparent for subjective variables already within 2 hours after the beginning of treatment, and a complete resolution was obtained in 35 of 37 attacks within 48 hours. A mild adverse reaction was recorded in one patient for each group (dizziness and gastric pain, respectively). Intravenous indoprofen appears to afford an extremely rapid relief of acute gout; of the two regimens assessed, the second should be preferred in that it seems to be at least equally effective but less troublesome for the patients.

Indoprofen versus ibuprofen in osteoarthrosis: a short-term, double-blind, crossover trial

A double-blind, crossover, short-term clinical trial was carried out in osteoarthrosis to compare the activity of two non-steroidal anti-inflammatory drugs. Twenty-four patients were given orally, in sequence, 600 mg indoprofen daily and 1200 mg ibuprofen daily, or vice-versa, for 1 week with no interval between treatment periods. Pain, quality of sleep, and overall effectiveness were recorded at the end of each week by inviting patients to express a score on a simple rating scale. Finally, patients were asked to express a preference for one treatment or the other. Significant improvement was observed in all parameters following treatment with both drugs. The distribution of score differences between indoprofen and ibuprofen was in favour of the former in all measurements; statistical analysis, however, demonstrated a significant superiority of indoprofen only for pain elicited by passive motion. The patients' preferences were also in favour of indoprofen, though not attaining statistical significance. Indoprofen was well tolerated, and no side-effects were observed. While on treatment with ibuprofen, 1 patient had to be withdrawn from the study because of gastric intolerance and 2 further patients had transient skin rashes.