Edaravone was originally developed as a potent free radical scavenger, and has been widely used to treat acute ischemic stroke in Japan since 2001. Free radicals play an important role in the pathogenesis of a variety of diseases, such as cardiovascular diseases and stroke. Therefore, free radicals may be targets for therapeutic intervention in these diseases. Edaravone shows protective effects on ischemic insults and inflammation in the heart, vessel, and brain in experimental studies. As well as scavenging free radicals, edaravone has anti-apoptotic, anti-necrotic, and anti-cytokine effects in cardiovascular diseases and stroke. Edaravone has preventive effects on myocardial injury following ischemia and reperfusion in patients with acute myocardial infarction. Edaravone may represent a new therapeutic intervention for endothelial dysfunction in the setting of atherosclerosis, heart failure, diabetes, or hypertension, because these diseases result from oxidative stress and/or cytokine-induced apoptosis. This review evaluates the potential of edaravone for treatment of cardiovascular disease, and covers clinical and experimental studies conducted between 1984 and 2013. We propose that edaravone, which scavenges free radicals, may offer a novel option for treatment of cardiovascular diseases. However, additional clinical studies are necessary to verify the efficacy of edaravone.

Stroke is a major cause of mortality and disability worldwide. The main cause of stroke is atherosclerosis, and the most common risk factor for atherosclerosis is hypertension. Therefore, antihypertensive treatments are recommended for the prevention of stroke. Three angiotensin receptor blockers (ARBs), telmisartan, irbesartan and candesartan, inhibit the expression of the receptor for advanced glycation end-products (RAGE), which is one of the pleiotropic effects of these drugs. High mobility group box 1 (HMGB1) is the ligand of RAGE, and has been recently identified as a lethal mediator of severe sepsis. HMGB1 is an intracellular protein, which acts as an inflammatory cytokine when released into the extracellular milieu. Extracellular HMGB1 causes multiple organ failure and contributes to the pathogenesis of hypertension, hyperlipidemia, diabetes mellitus, atherosclerosis, thrombosis, and stroke. This is the first review of the literature evaluating the potential of three ARBs for the HMGB1-RAGE axis on stroke therapy, including prevention and acute treatment. This review covers clinical and experimental studies conducted between 1976 and 2013. We propose that ARBs, which inhibit the HMGB1/RAGE axis, may offer a novel option for prevention and acute treatment of stroke. However, additional clinical studies are necessary to verify the efficacy of ARBs.

Acute ischemic stroke (AIS) is a major cause of morbidity and mortality in the aging population worldwide. Alteplase, a recombinant tissue plasminogen activator, is the only Food and Drug Administration-approved thrombolytic agent for the treatment of AIS. Only 2-5% of patients with stroke receive thrombolytic treatment, mainly due to delay in reaching the hospital. Edaravone is a free radical scavenger marketed in Japan to treat patients with AIS, who present within 24 h of the onset of symptoms. When used in combination with alteplase, edaravone may have three useful effects: enhancement of early recanalization, inhibition of alteplase‑induced hemorrhagic transformation and extension of the therapeutic time window for alteplase. This is the first review of the literature evaluating the clinical efficacy of edaravone, aiming to clarify whether edaravone should be further evaluated for clinical use worldwide. This review covers both clinical and experimental studies conducted between 1994 and 2012. Edaravone is a potentially useful neurovascular protective agent, used in combination with thrombolytic agents to treat >15 million patients devastated by stroke worldwide annually. Additional clinical studies are necessary to verify the efficacy of edaravone when used in combination with a thrombolytic agent.

The mechanisms underlying the depression of evoked fast excitatory postsynaptic currents (EPSCs) following superfusion with medium deprived of oxygen and glucose (in vitro ischemia) for a 4-min period in hippocampal CA1 neurons were investigated in rat brain slices. The amplitude of evoked fast EPSCs decreased by 85 ± 7% of the control 4 min after the onset of in vitro ischemia. In contrast, the exogenous glutamate-induced inward currents were augmented, while the spontaneous miniature EPSCs obtained in the presence of tetrodotoxin (TTX, 1 μM) did not change in amplitude during in vitro ischemia. In a normoxic medium, a pair of fast EPSCs was elicited by paired-pulse stimulation (40-ms interval), and the amplitude of the second fast EPSC increased to 156 ± 24% of the first EPSC amplitude. The ratio of paired-pulse facilitation (PPF ratio) increased during in vitro ischemia. Pretreatment of the slices with adenosine 1 (A1) receptor antagonist, 8-cyclopenthyltheophiline (8-CPT) antagonized the depression of the fast EPSCs, in a concentration-dependent manner: in the presence of 8-CPT (1–10 μM), the amplitude of the fast EPSCs decreased by only 20% of the control during in vitro ischemia. In addition, 8-CPT antagonized the enhancement of the PPF ratio during in vitro ischemia. A pair of presynaptic volleys and excitatory postsynaptic field potentials (fEPSPs) were extracellularly recorded in a proximal part of the stratum radiatum in the CA1 region. The PPF ratio for the fEPSPs also increased during in vitro ischemia. On the other hand, the amplitudes of the first and second presynaptic volley, which were abolished by TTX (0.5 μM), did not change during in vitro ischemia. The maximal slope of the Ca²⁺-dependent action potential of the CA3 neurons, which were evoked in the presence of 8-CPT (1 μM), nifedipine (20 μM), TTX (0.5 μM), and tetraethyl ammonium chloride (20 mM), decreased by 12 ± 6% of the control 4 min after the onset of in vitro ischemia. These results suggest that in vitro ischemia depresses the evoked fast EPSCs mainly via the presynaptic A1 receptors, and the remaining 8-CPT–resistant depression of the fast EPSCs is probably due to a direct inhibition of the Ca²⁺ influx to the axon terminals.

Stroke is an enormous public health problem with an imperative need for more effective therapies. In therapies for ischemic stroke, tissue plasminogen activators, antiplatelet agents and anticoagulants are used mainly for their antithrombotic effects. However, free radical scavengers, minocycline and growth factors have shown neuroprotective effects in the treatment of stroke, while antihypertensive drugs, lipid-lowering drugs and hypoglycemic drugs have shown beneficial effects for the prevention of stroke. In the present review, we evaluate the treatment and prevention of stroke in light of clinical studies and discuss new anti-stroke effects other than the main effects of drugs, focusing on optimal pharmacotherapy.

Intracellular recordings were made from hippocampal CA1 neurons in rat slice preparations. Superfusion with oxygen- and glucose-deprived medium (in vitro ischemia) produced a rapid depolarization ∼5 min after the onset of the superfusion. Even when oxygen and glucose were reintroduced immediately after rapid depolarization, the membrane depolarized further (persistent depolarization) and reached 0 mV (irreversible depolarization) after 5 min from the reintroduction. The pretreatment of the slice preparation with a phospholipase A₂(PLA₂) inhibitor, para-bromophenacyl bromide, or a cytochrome P-450 inhibitor, 17-octadecynoic acid, significantly restored the membrane to the preexposure potential level after the reintroduction of oxygen and glucose. The administration of 14,15-epoxyeicosatrienoic acid or 20-hydroxyeicosatetraenoic acid did not change the latency of the rapid depolarization and did not allow the membrane potential to recover after the ischemic exposure. In contrast, after pretreatment with cyclooxygenase or lipoxygenase inhibitors, such as indomethacin, resveratrol, Dup-697, nordihydroguaiaretic acid, and 3,4-dihydrophenyl ethanol, a minority of neurons tested showed postischemic recovery from the persistent depolarization. Improved recovery was also seen after treatment with the free radical scavengers, edaravone and α-tocopherol. These results suggest that the activation of the arachidonic acid cascade via PLA₂and the free radicals produced by arachidonic acid metabolism contribute to the irreversible depolarization produced by in vitro ischemia.