Systematic review and meta‐analysis of the efficacy of melatonin in experimental stroke

Abstract

Melatonin is a candidate neuroprotective drug for ischaemic stroke. Any decision to proceed to clinical trial for such drugs should be based on an unbiased assessment of all available data. Such an assessment should include not only the efficacy of a drug but also the in vivo characteristics and limits--in terms of time window, dose, species and model of ischaemia used--to that efficacy. Here we use a systematic approach to establish the limits to and characteristics of the neuroprotective efficacy of melatonin in experimental stroke. We have used systematic review and meta-analysis to assess the evidence for a protective effect of melatonin in animal models of focal cerebral ischaemia. Fourteen studies were identified describing procedures involving 432 animals. The point estimate for the effect of melatonin was a 42.8% (95% CI 39.3-46.3%) improvement in outcome. Efficacy was greater when ketamine anaesthesia was used, and melatonin was equally effective in permanent or temporary ischaemia. Study quality was generally poor by clinical trial standards, and no evidence was found regarding the efficacy of melatonin in focal cerebral ischaemia in aged, hypertensive or diabetic animals, in species other than rats, or at time windows beyond 2 hr. These findings demonstrate a marked efficacy of melatonin in animal models of focal cerebral ischaemia, identify priority areas for future animal research, and suggest melatonin as a candidate neuroprotective drug for human stroke.

Melatonin Reduces Inflammation and Cell Death in White Matter in the Mid-Gestation Fetal Sheep Following Umbilical Cord Occlusion

“…155 ischemic stroke (11). In these studies melatonin given at doses of more than 5 mg/kg, with treatment starting either before or during ischemia, showed maximum protection.…”

“…In adult animals, melatonin has been shown to be neuroprotective in models of focal cerebral ischemia (11) and to reduce microglia activation in the hippocampus after kainateinduced inflammation in rats (12). Melatonin also attenuated ibotenate-induced white matter cysts in neonatal mice (13).…”

Preclinical Drug Evaluation for Combination Therapy in Acute Stroke Using Systematic Review, Meta-Analysis, and Subsequent Experimental Testing

“…Owing to cost, only melatonin was tested individually: melatonin was chosen as the single-drug control because we had undertaken a meta-analysis of melatonin (Macleod et al, 2005), and at the time, its efficacy was superior to magnesium and minocycline. Combination treatment failed to reduce infarct volume in aged rats subjected to a 2-hour occlusion (F(2, 36) = 0.425, P > 0.05, partial eta square = 0.051).…”

Evaluation of Combination Therapy in Animal Models of Cerebral Ischemia

“…Inclusion and removal of data outliers was also tested. Both fixed effect and random effect meta-analysis were undertaken, and due to heterogeneity, results from the conservative random effects model are presented (DerSimonian and Laird, 1986;Macleod et al, 2004Macleod et al, , 2005a. Overall estimates of effect were calculated for (1) single treatment therapy; (2) combination therapy; and (3) synergistic efficacy.…”