Melatonin (5-15 mg/kg) protects male animals against
ischemic stroke. We explored the potential interactions and synergistic neuroprotection of
melatonin and
estrogen using a panel of lipid peroxidation and radical-scavenging assays, primary neuronal cultures subjected to
oxygen-
glucose deprivation (OGD), and
lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Neuroprotective efficacy of
melatonin was also evaluated in both reproductively active and ovariectomized female rats subjected to transient focal
cerebral ischemia. Relative to
melatonin or
estradiol (E2) alone, a combination of the two agents exhibited robust, synergistic
antioxidant and radical-scavenging actions (P<0.05, respectively). Additionally, the two agents, when combined at large doses, showed synergistic inhibition in the production of
tumor necrosis factor alpha (TNF-α) and
interleukin-6 (IL-6) in the LPS-stimulated RAW 264.7 cells (P<0.05, respectively). Alternatively, co-treatment with
melatonin and E2 independently, but not combined, showed a U-shaped dose-responsive (hormetic) cytoprotection for neuronal cultures subjected to OGD. When combined at a dosage either positively or negatively skewed from each optimal dosage, however, co-treatment caused synergistic neuroprotection. Relative to vehicle-injected controls,
melatonin given intravenously at 1-5 mg/kg, but not 0.1 or 15 mg/kg, significantly reduced
brain infarction and improved neurobehavioral outcomes (P<0.05, respectively) in reproductively active female rats. In ovariectomized
stroke rats,
melatonin was only effective at a large dosage (15-50 mg/kg). These results demonstrate complex interactions and synergistic
antioxidant, radical-scavenging, and anti-inflammatory actions between
estradiol and
melatonin, and highlight the potential need to rectify the
melatonin's hormetic dose-response by the level of circulating
estradiol in the treatment of female
stroke patients.