Increased oxidative stress in patients with amyotrophic lateral sclerosis and the effect of edaravone administration

Figures & data

Table 1 Levels of plasma antioxidants and lipids in patients with ALS as compared to age-matched healthy controls (average ± SD)

	ALS	Normal control	P
n	26	55
Male/female	14/12	38/17
Age	60.9 ± 11.2	60.1 ± 9.3
VC, μM	24.9 ± 15.0	31.1 ± 21.0
UA, μM	215 ± 94	314 ± 93	<0.001
BR, μM	3.7 ± 3.3	6.9 ± 3.6	<0.001
VE, μM	33.5 ± 10.2	28.5 ± 7.3
TQ10, nM	829 ± 332	710 ± 206
%CoQ10	20.9 ± 10.3	3.9 ± 1.3	<0.001
FFA, μM	486 ± 377	457 ± 288
%PUFA	19.0 ± 4.1	23.6 ± 4.6	<0.001
%16:1	2.9 ± 1.5	3.9 ± 1.4
%18:1	33.8 ± 8.1	34.4 ± 5.1
FC, mM	1.55 ± 0.39	1.37 ± 0.25	<0.05
CE, mM	3.52 ± 0.95	3.36 ± 0.72
TC, mM	5.07 ± 1.33	4.72 ± 0.94
FC/CE	0.44 ± 0.04	0.41 ± 0.05	<0.01

P values were determined using the Student's t-test. VC, ascorbic acid; UA, uric acid; BR, unconjugated bilirubin; VE, vitamin E; TQ10, total coenzyme Q10; %CoQ10, ratio of oxidized form of coenzyme Q10 to TQ10; FFA, free fatty acids; %PUFA, ratio of PUFA to total FFA; %16:1, ratio of palmitoleic acid to total FFA; %18:1, ratio of oleic acid to total FFA; FC, free cholesterol; CE, cholesterol esters; TC, total cholesterol.

Figure 1 Time course of changes of ALSFRS-R at 6 months with and without edaravone treatment (mean ± SE). Repeated-measures ANOVA shows a significant difference in ΔALSFRS-R between the two groups (P < 0.008). Inset table provides the raw ALSFRS-R values.

Table 2 Classification of patients according to the value of ΔALSFRS-R (Δ) at 6 months in edaravone-treated and -untreated groups of ALS patients

Group	Δ	Untreated	Treated
Satisfactory progress group	≥0	0	6 (7) ↑
Middle group	−1 to −4	7	4 (6)→
Ingravescent group	≤ −5	12	3 (4) ↓
	Total	19	13 (17)

ΔALSFRS-R at 6 months was missing for four patients in the treated group, and classifications were estimated on the assumption that ΔALSFRS-R at 6 months was twice the ΔALSFRS-R determination at 3 months, as indicated in parentheses.

Figure 2 The increase or decrease of plasma urate levels, calculated from values at week 0 (before edaravone administration), during the course of edaravone treatment in ALS patients. Patients were divided into a satisfactory progress group, an ingravescent group, and a middle group according to their values of ΔALSFRS-R determined at 6 months of treatment. W0B/A and W1B/A are data for week 0 and week 1 before (B) and after (A) edaravone treatment, respectively; M1–6B/A are data for months 1–6 before (B) and after (A) edaravone treatment. Data for patients for whom the month 6 observation was missing are indicated by solid symbols.

Figure 3 Time course of changes in plasma ascorbate (VC) during edaravone treatment in ALS patients. Patients were divided into three groups according to the value of ΔALSFRS-R at 6 months of treatment. The average VC level in age-matched healthy controls was 31.1 ± 21.0 µM (±SD, n = 55); this range is shaded in green. W0B/A and W1B/A are data for week 0 and week 1 before (B) and after (A) edaravone treatment, respectively; M1–6B/A are data for months 1–6 before (B) and after (A) edaravone treatment. Data for patients for whom the month 6 observation was missing are indicated by solid symbols.

Figure 4 Time course of changes in the ratio of ubiquinone-10 to TQ10 (%CoQ10) during edaravone treatment in ALS patients. Patients were divided into three groups according to their values of ΔALSFRS-R determined at 6 months of treatment. Average %CoQ10 in age-matched healthy controls was 3.9 ± 1.3 (±SD, n = 55); this range is shaded in green. W0B/A and W1B/A are data for week 0 and week 1 before (B) and after (A) edaravone treatment, respectively; M1–6B/A are data for months 1–6 before (B) and after (A) edaravone treatment. Data for patients for whom the month 6 observation was missing are indicated by solid symbols.

Figure 5 Time course of changes in plasma FFA during edaravone treatment in ALS patients. Patients were divided into three groups according to their values of ΔALSFRS-R determined at 6 months of treatment. FFA level in age-matched healthy controls was 457 ± 288 µM (average ± SD, n = 55); the region above this range is shaded in red. W0B/A and W1B/A are data for week 0 and week 1 before (B) and after (A) edaravone treatment, respectively; M1–6B/A are data for months 1–6 before (B) and after (A) edaravone treatment. Data for patients for whom the month 6 observation was missing are indicated by solid symbols. Inset table shows the incidence of FFA levels greater than 745 µM (=average + SD) and the P value (Fisher's exact probability test) versus data for the ingravescent group.

Figure 6 Time course of changes in plasma ratio of PUFA to total FFA (%PUFA) in ALS patients. Patients were divided into three groups according to their values of ΔALSFRS-R determined at 6 months of treatment. %PUFA in age-matched healthy controls was 23.6 ± 4.6% (average ± SD, n = 55); the region below this range is shaded in red. W0B/A and W1B/A are data for week 0 and week 1 before (B) and after (A) edaravone treatment, respectively; M1–6B/A are data for months 1–6 before (B) and after (A) edaravone treatment. Data for patients for whom the month 6 observation was missing are indicated by solid symbols. Inset table shows the incidence of %PUFA smaller than 19.0% (= average − SD) and the P value (Fisher's exact probability test) versus data for the ingravescent group.

Figure 7 Time course of changes in plasma ratio of palmitoleic acid to total FFA (%16:1) during edaravone treatment in ALS patients. Patients were divided into three groups according to their values of ΔALSFRS-R determined at 6 months of treatment. %16:1 in age-matched healthy control was 3.9 ± 1.4% (average ± SD, n = 55); the region above this range is shaded in red. W0B/A and W1B/A are data for week 0 and week 1 before (B) and after (A) edaravone treatment, respectively; M1–6B/A are data for months 1–6 before (B) and after (A) edaravone treatment. Data for patients for whom the month 6 observation was missing are indicated by solid symbols. Inset table shows the incidence of %16:1 greater than 5.3% (=average + SD) and the P value (Fisher's exact probability test) versus data for the ingravescent group.

Figure 8 Time course of changes in plasma ratio of oleic acid to total FFA (%18:1) during edaravone treatment in ALS patients. Patients were divided into three groups according to their values of ΔALSFRS-R determined at 6 months of treatment. %18:1 in age-matched healthy controls was 34.4 ± 5.1% (average ± SD, n = 55); the region above this range is shaded in red. W0B/A and W1B/A are data for week 0 and week 1 before (B) and after (A) edaravone treatment, respectively; M1–6B/A are data for months 1–6 before (B) and after (A) edaravone treatment. Data for patients for whom the month 6 observation was missing are indicated by solid symbols. Inset table shows the incidence of %16:1 greater than 39.5% (=average + SD) and the P value (Fisher's exact probability test) versus data for the ingravescent group.