Table 1.
Preclinical Studies Evaluating Melatonin Combined with Hypothermia for Neonatal Encephalopathy.
| Study | Model | Formulation and Dosing | Pharmacokinetics | aEEG | 1H MRS Lac/NAA | Immuno-Histochemistry | Other Outcomes |
|---|---|---|---|---|---|---|---|
| Robertson et al. (2013) [98] | Piglet model HI | Sigma-Aldrich in ethanol, 30 mg/kg over 6 h at 10 min and 24 h after HI |
Cmax 21.0 mg/L at 6 h after HI Range: 17–31 mg/L |
No difference | Reduction in Lac/NAA in thalamic voxel | Reduction in TUNEL+ cell death in Hip, IC, Caud, PTMN | Reduction in gene expression of CD86 and SOCS3 and increase in SphK1 |
| Robertson et al. (2019) [99] | Piglet model HI | Chiesi ethanol-free, 5 mg/kg over 6 h at 2 h and 26 h after HI OR 15 mg/kg over 6 h at 2 h and 26 h after HI |
5 mg/kg: Cmax 3.97 mg/L at 8 h after HI Range: 1–5mg/L 15 mg/kg: Cmax 16.8 mg/L at 8 h after HI Range: 7–19 mg/L |
No difference | No difference | No overall TUNEL+ cell death reduction but localised reduction in sCTX | N/A |
| Robertson et al. (2020) [100] | Piglet model HI | Sigma-Aldrich in ethanol, 18 mg/kg over 2 h at 1 h and 25 h after HI | Cmax 18.8 mg/L at 3 h after HI Range: 7–21 mg/L |
Improved aEEG from 19–24 h after HI | Reduction in Lac/NAA at 24 h and 48 h in WM and BGT voxels | Reduction in overall TUNEL+ cell count with regional reduction in pvWM and IC. | Ethanol associated with partial protection: aEEG recovery, reduction in TUNEL+ cell count |
| Pang et al. (2021) [101] | Piglet model HI | Chiesi ethanol-free, 20 mg/kg over 2 h at 1 h, 24 h and 48 h after HI | Cmax 27.8 mg/L at 3 h after HI Range: 10–30 mg/L |
Improved aEEG from 25–30 h after HI | Reduction in Lac/NAA at 66 h in BGT voxel | No overall TUNEL+ cell count reduction but localised reduction in sCTX | Erythropoietin did not provide added neuroprotection to HT + melatonin after 72 h |
| Carloni et al. (2017) [102] | In vitro, Hip slice cultures | Sigma-Aldrich dissolved in 0.05% DMSO | 100 μM (~25 mg/L) | N/A | N/A | Dose-dependent reduction in cell death in synergy with HT | N/A |
aEEG: amplitude integrated electroencephalogram, Caud = caudate, Hip = Hippocampus, HI = Hypoxia-ischaemia, HT = therapeutic hypothermia, IC = internal capsule, Lac/NAA = lactate to N-acetylaspartate peak ratio, PTMN = putamen, pvWM = periventricular white matter, sCTX, sensorimotor cortex, TUNEL = Terminal deoxynucleotidyl transferase dUTP nick end labelling, SOCS3 = Suppressor of Cytokine Signaling 3, SphK1 = Sphingosine kinase 1.