Neurodegenerative diseases and neurovascular unit damage

Abstract

Neuroprotection is essential for potential therapy not only in acute stage of stroke but also in chronic progressive neurodegenerative diseases such as ALS, Parkinson's disease (PD), and Alzheimer's disease (AD). Free radical scavenger can be such a neuroprotective candidate with inhibiting death signals and potentiating survival signals under cerebral ischemia and even neurodegenerative cellular processes. Edaravone is one such free radical scavenger, which is the first clinical drug for neuroprotection in the world and has been used from 2001 in most ischemic stroke patients in Japan.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease caused by selective death of motor neurons. Among our own 390 ALS patients, 4.1% show familial ALS (FALS), in which 50% is associated with missense mutations of SOD1, 25% were TDP43 and FUS mutations, and 6.3% is an optineurin mutation. Although the underlying mechanism of ALS has not yet been fully clarified, several reports have implicated the involvement of oxidative stress under selective death of motor neurons in both ALS patients and animal models.

A recent multicenter prospective double–blind placebo–control clinical trial with edaravone for ALS patients conducted in Japan showed a positive effect for delaying the clinical score (ALSFRS–R) during the course of examination (24 weeks). Serious or critical adverse effect was not noted in this clinical trial. Of particular was that this clinical benefit of edaravone was shown as an add–on therapy after anti–glutamatergic riluzole. These data strongly suggest a potential underlying mechanism of oxidative stress both in acute ischemic stroke and in ALS by a free radical scavenger. Edaravone is approved for ALS on 2015 in Japan, 2016 in Korea, and 2017 in USA.