12-week melatonin intake attenuates cardiac autonomic dysfunction and oxidative stress in multiple sclerosis patients: a randomized controlled trial

Abstract

Multiple sclerosis (MS) can induce cardiac autonomic dysfunction identified by a decreased heart rate variability (HRV) which was linked to oxidative stress, vitamin D deficiency and sleep disturbance. Previous MS studies revealed the antioxidant and anti-inflammatory effects of exogenous melatonin, as well as its benefits on sleep and vitamin D. We aimed to investigate the change in HRV, oxidative stress, systemic inflammation and sleep following melatonin supplementation in MS patients. Participants were randomly allocated to either a melatonin group (MG, n = 15) or a placebo group (PG, n = 12) (3 mg/night during 12 weeks). Pre- and post-tests included HRV analysis (Kubios software), sleep dairy and biological analysis [oxidative stress biomarkers (malondialdehyde (MDA), advanced oxidation protein products (AOPP) and reduced glutathione (GSH)); 25-hydroxyvitamin D; C-reactive protein and cholinesterase Gen.2 (CHE2)]. Based on the pre-post supplementation change (Δ _(T1₋T0)), melatonin increased the root mean square of successive differences between normal heartbeats [Δ_MG (14.17 ± 16.93) vs. Δ_PG (₋8.61 ± 12.67), p = 0.0007] and the HRV high-frequency band [Δ_MG (6.86 ± 14.85) vs. Δ_PG (₋12.58 ± 13.30), p = 0.0016] comparatively with placebo. MG showed a decrease in the HRV low-frequency band [Δ_MG (₋4.96 ± 10.08) vs. Δ_PG (10.22 ± 13.54), p = 0.003] as well as in the MDA [Δ_MG (₋2.27 ± 1.92) vs. Δ_PG (0.22 ± 2.30), p = 0.005] and AOPP levels [Δ_MG (₋113.97 ± 137.72) vs. Δ_PG (156.46 ± 230.52), p = 0.0008] compared with PG. Melatonin enhanced the GSH [Δ_MG (10.51 ± 14.93) vs. Δ_PG (₋5.05 ± 10.18), p = 0.004] and CHE2 levels [Δ_MG (407.07 ± 723.26) vs. Δ_PG (₋22.92 ± 506.52), p = 0.029] as well as sleep quality [scores: Δ_MG (1.50 ± 1.28) vs. Δ_PG (₋1.05 ± 2.05), p = 0.0006] and quantity [weighted total sleep time: Δ_MG (0.74 ± 1.14) vs. Δ_PG (₋1.04 ± 1.00), p = 0.0003] comparatively with placebo. Caregivers may recommend 12-week nocturnal melatonin intake to attenuate cardiac autonomic dysfunction, oxidative stress and sleep disorders in MS patients.Clinical registration This study was prospectively registered in the Pan African Clinical Trial Registry database (PACTR202007465309582) on 23 July 2020 ( https://pactr.samrc.ac.za/ .).

Keywords: Cardiac autonomic dysfunction; Melatonin; Multiple sclerosis; Oxidative stress; Sleep; Vitamin D.