ABSTRACT
The anti-inflammatory activity of auraptene (AUR), a citrus coumarin, in peripheral tissues is well-known, and we previously demonstrated that AUR exerts anti-inflammatory effects in the ischemic brain; the treatment of mice with AUR for eight days immediately after ischemic surgery suppressed demise and neuronal cell death in the hippocampus, possibly through its anti-inflammatory effects in the brain. We suggested that these effects were at least partly mediated by the suppression of inflammatory mediators derived from astrocytes. The present study showed that (1) AUR, as a pretreatment for five days before and another three days after ischemic surgery, suppressed microglial activation, cyclooxygenase (COX)-2 expression in astrocytes, and COX-2 mRNA expression in the hippocampus; (2) AUR suppressed the lipopolysaccharide-induced expression of COX-2 mRNA and the mRNA of pro-inflammatory cytokines in cultured astrocytes; (3) AUR was still detectable in the brain 60 min after its intraperitoneal administration. These results support our previous suggestion that AUR directly exerts anti-inflammatory effects on the brain.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Brain/drug effects , Coumarins/pharmacology , Animals , Anti-Inflammatory Agents/administration & dosage , Brain/metabolism , Brain/pathology , Brain Ischemia/drug therapy , Brain Ischemia/genetics , Brain Ischemia/metabolism , Brain Ischemia/mortality , Coumarins/administration & dosage , Cyclooxygenase 2/genetics , Cyclooxygenase 2/metabolism , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Gene Expression Regulation/drug effects , Glial Fibrillary Acidic Protein/genetics , Glial Fibrillary Acidic Protein/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Inflammation Mediators/metabolism , Male , MiceABSTRACT
The present study evaluated the effects of treatment with the citrus flavonoid, 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF) on protection against memory impairment and neuronal death in a global cerebral ischemia mouse model. The results showed that HMF, administrated for three days immediately after ischemic surgery, protected against ischemia-induced memory dysfunction, rescued neuronal cell death in the CA1 cell layer, increased the production of BDNF, stimulated the autophosphorylation of CaMK II and suppressed microglial activation in the hippocampus. These results suggest that HMF has a neuroprotective effect after brain ischemia by inducing BDNF production and anti-inflammatory effects.
Subject(s)
Brain Ischemia/drug therapy , Flavonoids/pharmacology , Hippocampus/drug effects , Neuroprotective Agents/pharmacology , Animals , Brain Ischemia/metabolism , Cell Death/drug effects , Disease Models, Animal , Flavonoids/chemistry , Hippocampus/metabolism , Male , Memory Disorders/drug therapy , Memory Disorders/metabolism , Mice, Inbred C57BL , Neurons/cytology , Neurons/drug effects , Neurons/metabolism , Neuroprotective Agents/chemistryABSTRACT
In the present study using a transient global ischemia mouse model, we showed that (1) a citrus flavonoid 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF) induced the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and cAMP response element-binding protein (CREB) in the hippocampus after ischemia; (2) HMF increased the expression of brain-derived neurotrophic factor (BDNF), a representative neurotrophic factor in the central nervous system, in the hippocampal dentate gyrus, and most BDNF-positive cells were also stained with anti-glial fibrillary acidic protein (one of the major intermediate filament proteins of mature astrocytes) and (3) HMF increased doublecortin positive neuronal precursor cells in the dentate gyrus subventricular zone or subgranular zone. These results suggest that HMF has the ability to induce BDNF production in astrocytes and enhance neurogenesis after brain ischemia, which may be mediated by activation of ERK1/2 and CREB.
