Edaravone and cyclosporine A as neuroprotective agents for acute ischemic stroke

Abstract

It is well known that acute ischemic stroke (AIS) and subsequent reperfusion produce lethal levels of reactive oxygen species (ROS) in neuronal cells, which are generated in mitochondria. Mitochondrial ROS production is a self-amplifying process, termed "ROS-induced ROS release". Furthermore, the mitochondrial permeability transition pore (MPTP) is deeply involved in this process, and its opening could cause cell death. Edaravone, a free radical scavenger, is the only neuroprotective agent for AIS used in Japan. It captures and reduces excessive ROS, preventing brain damage. Cyclosporine A (CsA), an immunosuppressive agent, is a potential neuroprotective agent for AIS. It has been investigated that CsA prevents cellular death by suppressing MPTP opening. In this report, we will outline the actions of edaravone and CsA as neuroprotective agents in AIS, focusing on their relationship with ROS and MPTP.

Keywords: Acute ischemic stroke; cyclosporine A; edaravone; mitochondrial permeability transition pore; reactive oxygen species.

Figure 1

Definition of reactive oxygen species (ROS) and free radicals. Typical molecules are expressed by common name, Lewis structure, and chemical formula. A red dot on the Lewis structure means unpaired electrons. Reactive oxygen species are species that contain one or more oxygen atom and are much more reactive than molecular oxygen. The ROS that contain nitrogen are called reactive nitrogen species. A free radical is each molecule or its fragment that can exist independently and contains one or two unpaired electrons (adapted from reference 58).

Figure 2

Oxidative phosphorylation and reactive oxygen species production in mitochondria. The diagrams of the mitochondrial inner membrane show key components of the electron transport chain (ETC). Reducing equivalents of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH₂) produced from the tricarboxylic acid cycle feed electrons to the ETC along the mitochondrial inner membrane. The electrons flow through the ETC with the following sequence: complex I and II→coenzyme Q (Q)→complex III→cytochrome C (Cyt C)→complex IV→O₂, during which coupled redox reactions drive H⁺ across the inner membrane, forming the proton gradient and the negative mitochondrial membrane potential (ΔΨ_m = −150 to −180 mV). The free energy is stored in the proton gradient, and ΔΨ_m then drives H⁺ through the mitochondrial ATP synthase (complex V), converting adenosine diphosphate to ATP. An estimated 0.1–1% of the electrons leak prematurely to O₂ at complexes I, or III, resulting in the formation of superoxide (${\mathrm{O}}_2^{·-}$).59

Figure 3

Reactive oxygen species (ROS) generation and oxidative damage by brain ischemia. Brain ischemia induces ROS generation (upstream) and neurons are damaged by ROS (downstream), resulting in dysfunction or cell death. The mitochondria electron transport chain (ETC), together with the mitochondrial permeability transition pore (MPTP), produce cyclical ROS bursts, a process termed “ROS‐induced ROS release”. Edaravone scavenges upstream ROS, whereas cyclosporine A inhibits downstream MPTP opening (adapted from reference 13).

Figure 4

Model of mitochondrial permeability transition pore (MPTP) structure. The MPTP is formed at the interface between two F₁F_O ATP synthase (electron transport chain complex V) dimers. Phosphorylation and acetylation of cyclophilin‐D (CyP‐D) favor its interaction with ATP synthase and pore opening following increases in Ca²⁺ and reactive oxygen species induced by ischemia and reperfusion. After the MPTP opens, molecules <1.5 kDa and water freely pass between the mitochondrial intermembrane. ΔΨ_m turns to 0 mV, and subsequently, the mitochondrial matrix swells and membrane rupture occurs. Finally, pro‐apoptotic factors are released to the cytosol. As a result, MPTP induces cell death (adapted from reference 60). CsA, cyclosporine A.