Melatonin protects against transient focal cerebral ischemia in both reproductively active and estrogen-deficient female rats: the impact of circulating estrogen on its hormetic dose-response

Abstract

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.

Magnolol Reduces Glutamate-Induced Neuronal Excitotoxicity and Protects against Permanent Focal Cerebral Ischemia Up to 4 Hours

“…Exactly by which mechanisms in the glutamate-stimulated cultured neurons the dose-responsive regimen seen with magnolol for cell swelling inhibition was inconsistent with the “U-shaped” hormetic response observed for inhibiting the rises of [Ca 2+ ](i) remains to be elucidated [18], [19]. Curiously, hormetic neuroprotective responses were also observed in the magnolol-treated stroke animals in which a low-dosing regimen was ineffective whereas high dosage (200 mg/kg) induced adverse effects along with a temperature-lowering action [12], [20], [21].…”

“…Curiously, hormetic neuroprotective responses were also observed in the magnolol-treated stroke animals in which a low-dosing regimen was ineffective whereas high dosage (200 mg/kg) induced adverse effects along with a temperature-lowering action [12], [20], [21]. Thus, the in vitro dosing response might not represent the trend of dosing response observed in vivo [18]. It was very likely that magnolol actually had multiple mechanisms acted, independently or in combined, to exhibit neuroprotection observed here [12]–[17].…”

“…According the method described previously [18], cultured neurons were obtained from cerebral cortices of 1-day-old Sprague-Dawley rats. Cytotoxicity was determined at 24 hrs after treatment by using a LDH assay kit (Promega, Madison, WI) [18], [24], [25].…”

“…Cytotoxicity was determined at 24 hrs after treatment by using a LDH assay kit (Promega, Madison, WI) [18], [24], [25]. Experiments were undertaken on cultured neurons between 10 and 14 days in vitro (DIV).…”

Therapeutical Implications of Melatonin in Alzheimer’s and Parkinson’s Diseases

“…Besides the animal models of AD and PD discussed below, melatonin has been shown to lower neural damage due to cadmium toxicity (Poliandri et al 2006 ;Jimenez-Ortega et al 2011 ), hyperbaric hyperoxia (Shaikh et al 1997 ;Pablos et al 1997 ), δ-aminolevulinic acid toxicity (Princ et al 1997 ;Carneiro and Reiter 1998 ;Onuki et al 2005 ), γ radiation (Erol et al 2004 ;Shirazi et al 2011 ;Taysi et al 2008 ), focal ischemia (Lee et al 2004 ;Tai et al 2011 ), brain trauma (Beni et al 2004 ;Tsai et al 2011 ;Kabadi and Maher 2010 ), and a number of neurotoxins (Reiter et al 2010 ).…”