Proposing Bromo-epi-androsterone (BEA) for perioperative neurocognitive disorders with Interleukin-6 as a druggable target.

Abstract

Cognitive impairment following surgery is a significant complication, affecting multiple neurocognitive domains. The term "perioperative neurocognitive disorders" (PND) is recommended to encompass this entity. Individuals who develop PND are typically older and have increases in serum and brain pro-inflammatory cytokines notwithstanding the type of surgery undergone. Surgical trauma induces production of small biomolecules, damage-associated molecular patterns (DAMP), particularly the DAMP known as high molecular group box 1 protein (HMGB1). Mechanistically, peripheral surgical trauma promotes pro-inflammatory cytokines that stimulate central nervous system (CNS) inflammation by disrupting the blood-brain barrier (BBB) causing functional neuronal disruption that leads to PND. PND is strongly linked to elevations in serum and CNS pro-inflammatory cytokines interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα); these cytokines cause further release of HMGB1 creating a positive feedback loop that amplifies the inflammatory response. The cytokine IL-6 is necessary and sufficient for PND. Dehydroepiandrosterone (DHEA) is a principal component of the steroid metabolome and is involved in immune homeostasis. DHEA has been shown to suppress expression of several pro-inflammatory cytokines by regulation of the NF-kB pathway. Bromo-epi-androsterone (BEA) is a potent synthetic analog of DHEA; unlike DHEA, it is non-androgenic, non-anabolic and is an effective modulator of immune dysregulation. In a randomized, placebo-controlled clinical trial, BEA effected significant and sustained decreases in IL-1β, TNFα and IL-6. This article presents BEA as a potential candidate for clinical trials targeting PND and further suggests the use of BEA in elective total hip arthroplasty as a well-documented surgical entity relevant to the management of PND.