Regulation of circadian gene activity in fibroblasts from ADHD patients through Rosiglitazone: a pilot study

Attention-deficit/hyperactivity disorder (ADHD) is a frequently observed condition, with about 70% of individuals diagnosed with ADHD experiencing irregular sleep-wake patterns. Beyond the primary symptoms of ADHD, there is a significant overlap with sleep-related issues, indicating that disrupted sleep patterns may exacerbate ADHD symptoms. ADHD-related sleep problems can be traced to a delayed circadian rhythm and a later onset of melatonin production. Therefore, normalizing circadian rhythms has been proposed as a potential therapeutic target for psychiatric disorders. Recent animal studies have provided compelling evidence linking peroxisome proliferator-activated receptor gamma (PPARγ), a key regulator of energy metabolism, to the regulation of physiological and behavioral rhythms. In this study, we hypothesized that treating fibroblasts from ADHD patients, which exhibit disturbances in circadian rhythmicity that are replicated in peripheral fibroblasts, with rosiglitazone may restore their circadian rhythmicity to that of the controls. To this end, we used cultures of fibroblasts obtained from skin biopsy explants of ADHD patients and controls and investigated the temporal patterns of clock gene expression over a period of 24 h. We report that the administration of the PPARγ agonist, rosiglitazone significantly realigns the chronobiological patterns of ADHD patient samples and control groups by inducing phase shifts in the expression of the BMAL1, PER3, and CRY1 clock genes. Nevertheless, rosiglitazone showed limited impact on the amplitude and phase of CLOCK1, NPAS2, and PER1. No notable changes were observed in PER2 and PER3 gene expression. The data from cultured human dermal fibroblasts indicate that PPARγ-agonists may help regulate circadian molecular mechanisms. Given the shared genetic pathways between ADHD and obesity, future studies could investigate the potential of RSG as a treatment for circadian rhythm disorders, particularly in obese patients with ADHD.