Edaravone, a Free Radical Scavenger, Delayed Symptomatic and Pathological Progression of Motor Neuron Disease in the Wobbler Mouse

Abstract

Edaravone, a free radical scavenger is used widely in Japanese patients with acute cerebral infarction. This antioxidant could have therapeutic potentials for other neurological diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the upper and the lower motor neuron, leading to death within 3–5 years after onset. A phase III clinical trial of edaravone suggested no significant effects in ALS patients. However, recent 2nd double-blind trial has demonstrated therapeutic benefits of edaravone in definite patients diagnosed by revised El Escorial diagnostic criteria of ALS. Two previous studies showed that edaravone attenuated motor symptoms or motor neuron degeneration in mutant superoxide dismutase 1-transgenic mice or rats, animal models of familial ALS. Herein we examined whether this radical scavenger can retard progression of motor dysfunction and neuropathological changes in wobbler mice, sporadic ALS-like model. After diagnosis of the disease onset at the postnatal age of 3–4 weeks, wobbler mice received edaravone (1 or 10 mg/kg, n = 10/group) or vehicle (n = 10), daily for 4 weeks by intraperitoneal administration. Motor symptoms and neuropathological changes were compared among three groups. Higher dose (10 mg/kg) of edaravone treatment significantly attenuated muscle weakness and contracture in the forelimbs, and suppressed denervation atrophy in the biceps muscle and degeneration in the cervical motor neurons compared to vehicle. Previous and the present studies indicated neuroprotective effects of edaravone in three rodent ALS-like models. This drug seems to be worth performing the clinical trial in ALS patients in the United States of American and Europe, in addition to Japan.

Protective effects of the neurosteroid allopregnanolone in a mouse model of spontaneous motoneuron degeneration

“…An increased generation of free radicals, 4-hydroxynonenal and high activity of NOS are indicators of oxidative stress in the spinal cord of WRs [1,55]. Likewise, the attenuation of motoneuron degeneration by antioxidant agents, nitric oxide inhibitors, the antioxidant steroid U-74389F and edaravone, a free radical scavenger, also support the importance of oxidative stress in WRs motoneurons [56][57][58]. Our results showed that NOS/NADPHdactive motoneurons and glial cells were about 3-fold higher in young WRs than controls, coincided with the main period of motoneuron death.…”

Inhibition of the Platelet-activating factor receptor for the treatment of Amyotrophic Lateral Sclerosis?

“…Riluzole modulates glutamate neurotransmission by inhibiting both glutamate release and postsynaptic glutamate receptor signaling. Edaravone is a free radical scavenger (20). Riluzole increases patient survival by 3 to 6 months and relieves respiratory discomfort while the therapeutic effects of Edaravone are still controversial (21).…”

Antioxidant Alternatives in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review

“…This antioxidant has been associated with a delay in the clinical onset of the disease (Table 1) in transgenic mice that express mutant copies of the gene encoding SOD1 (an animal model of ALS) (Gurney et al, 1996). Measurements of the erythrocyte activity of the three main radical scavenging enzymes (SOD1, CAT, and GPx) indicated that vitamin E supplementation (300-3000 U/day) in 14 ALS patients did not affect the activity of the Gurney et al, 1996;Desnuelle et al, 2001;Ascherio et al, 2005;Veldink et al, 2007; Ikeda and Iwasaki, 2015;Banno et al, 2005;Yoshino and Kimura, 2006;Miyamoto et al, 2013;Abe et al, 2014;Bailly, 2019 three enzymes (Przedborski et al, 1996). One study showed an accumulation of vitamin E in the spinal cord and increased MDA levels over the lifetime of the mouse compared to non-transgenic mice (Hall et al, 1998).…”