Pharmacological Modulations of Nrf2 and Therapeutic Implications in Aneurysmal Subarachnoid Hemorrhage

Abstract

An aneurysmal subarachnoid hemorrhage (aSAH) is a subtype of stroke with high morbidity and mortality. The main causes of a poor prognosis include early brain injury (EBI) and delayed vasospasm, both of which play a significant role in the pathophysiological process. As an important mechanism of EBI and delayed vasospasm, oxidative stress plays an important role in the pathogenesis of aSAH by producing reactive oxygen species (ROS) through the mitochondria, hemoglobin, or enzymatic pathways in the early stages of aSAH. As a result, antioxidant therapy, which primarily targets the Nrf2-related pathway, can be employed as a potential strategy for treating aSAH. In the early stages of aSAH development, increasing the expression of antioxidant enzymes and detoxifying enzymes can relieve oxidative stress, reduce brain damage, and improve prognosis. Herein, the regulatory mechanisms of Nrf2 and related pharmacological compounds are reviewed, and Nrf2-targeted drugs are proposed as potential treatments for aSAH.

Keywords: Keap1-Nrf2 pathway; antioxidant therapy; brain injury; oxidative stress; subarachnoid hemorrhage.

Figure 1

Mechanisms of Keap1-dependent and Keap1-independent pharmacological modulation of Nrf2 in aSAH. Created by Figdraw. (Sal B: salvianolic acid B; ISL: isoliquiritigenin; ALO: aloperine; Andro: adrographolide; ATX: astaxanthin; MF: mangiferin; EPO: erythropoietin; SAL A: salvianolic acid A; MDF: dimethyl fumarate; tBHQ: tert-butyl hydroquinone; LUT: luteolin; AS-IV: astragaloside; SAH: subarachnoid hemorrhage; ROS: reactive oxygen species; Nrf2: nuclear factor erythroid 2-related factor 2; Keap 1: kelchlike ech-associated protein 1; PHB2: prohibitin2; OPA1: optic atrophy 1; SIRT1: sirtuin 1; HO-1: heme oxygenase-1; NQO-1: quinine oxidoreductase-1; SOD: superoxide dismutase).