GW-0742

Anxiety disorders, with heightened female prevalence, are closely linked to neuroinflammatory dysregulation. This study elucidates the anti-anxiety mechanism of steroid receptor RNA activator (SRA), a long non-coding RNA, through its modulation of inflammatory pathways. In female SRA knockout mice, anxiety-like behaviors correlated with reduced peroxisome proliferator-activated receptor δ (PPARδ) expression in the hippocampus and amygdala, key regions for neuroinflammatory regulation. Mechanistically, SRA directly enhanced nuclear factor κB (NF-κB)-dependent PPARδ transcription, independent of estrogen or Akt/inhibitor of nuclear factor κB kinase subunit β (IKKβ) signaling. This SRA/NF-κB/PPARδ axis suppressed neuroinflammatory cascades, as PPARδ agonism (GW0742) or SRA reconstitution reversed anxiety phenotypes and restored PPARδ levels. Notably, androgens in males masked SRA deficiency's role by autonomously upregulating PPARδ, underscoring sex-specific vulnerability. Although SRA deficiency in females exacerbated inflammation-associated anxiety, ovariectomy confirmed estrogen-independent regulation by SRA. These findings highlight SRA as a critical modulator of neuroinflammatory resilience via NF-κB/PPARδ signaling, offering novel therapeutic avenues for sex-biased anxiety disorders tied to inflammatory pathophysiology.

Systemic lupus erythematosus (SLE) is a persistent autoimmune inflammatory disease associated with an elevated risk of kidney damage. The etiology of SLE remains unclear; nevertheless, current investigations increasingly indicate that increased DNA damage and deficiencies in the mechanisms of its repair might contribute to its pathogenesis, necessitating the identification and management of the disease. Therapies for SLE have improved considerably over recent decades. However, drugs that specifically address the underlying pathogenic pathways, such as potential DNA repair deficiencies, are unavailable. In this situation, drugs that ameliorate the altered DNA damage/repair might be a possible option for treating SLE. We investigated whether GW0742, an agonist of the peroxisome proliferator activator receptor β/δ, improves kidney function and ameliorates DNA damage/repair alteration in female lupus-prone mice. The results demonstrate that the repeated administration of GW0742 significantly ameliorates DNA damage/repair alteration in the bone marrow cells of lupus-prone animals, as assessed by the comet test. Furthermore, the administration of GW0742 restored the impaired DNA damage/repair pathway in lupus-prone mice by decreasing Gadd45a and p53 expression while elevating Ogg1 and Parp1 in the kidney tissues. The administration of GW0742 recovered the disturbed kidney redox balance in lupus-prone mice. It also ameliorated the altered biochemical markers related to lupus nephritis, as demonstrated by reduced levels of urinary protein and albumin, serum creatinine, and BUN. GW0742's protective outcome was verified by its ability to diminish the increased inflammatory marker MPO activity and ameliorated kidney histological characteristics of SLE. This suggests that GW0742 is a promising novel therapeutic agent for managing SLE and its associated complications.