erinacine-a and Brain-Ischemia

Maintaining glutamate homeostasis through astrocyte-enriched glutamate transporter 1 (GLT-1) is critical for neuronal survival, but it is often disrupted after brain injury. Hericium erinaceus (HE), an edible mushroom, was reported to be anti-inflammatory and neuroprotective against brain ischemia, but its effect on glutamate homeostasis was unknown. Here we investigated the neuroprotective effect of erinacine A (EA), an active component of HE, with special focus on the GLT-1 function in the in vitro and in vivo cerebral ischemia mouse models. By using oxygen-glucose deprivation (OGD) to challenge mouse glia-neuron (GN) mixed culture as the in vitro model, we found that EA treatment significantly improved neuronal/astroglial survival and attenuated OGD-induced proinflammatory NFκB and AKT signaling activations. Notably, EA attenuated OGD-induced GLT-1 downregulation, and a selective GLT-1 inhibitor WAY-213613 reversed these EA-mediated neuroprotection. EA also ameliorated glutamate excitotoxicity effectively. In a transient hypoxia-ischemia (tHI) brain injury mouse model, we examined an EA treatment strategy by performing a pre-tHI daily oral gavage of EA (oEA) for 7 days followed by a post-tHI intranasal injection of EA (nEA) for 3 days, and found that this treatment significantly protected sensorimotor cortex and improved the post-tHI forepaw grip strength. Western blotting results further revealed that EA treatment also preserved astrocyte-enriched glutamate and aspartate transporter (GLAST) as well as a GLT-1 function-associated potassium channel Kir4.1 in the cerebral cortex and striatum after tHI. These results suggest that EA is effective for preserving GLT-1 and glutamate clearance machinery to protect against excitotoxicity after ischemic brain injury.

Topics: Animals; Astrocytes; Brain Injuries; Brain Ischemia; Diterpenes; Down-Regulation; Excitatory Amino Acid Transporter 2; Glucose; Glutamic Acid; Mice

Hericium erinaceus, an edible mushroom, has been demonstrated to potentiate the effects of numerous biological activities. The aim of this study was to investigate whether H. erinaceus mycelium could act as an anti-inflammatory agent to bring about neuroprotection using a model of global ischemic stroke and the mechanisms involved. Rats were treated with H. erinaceus mycelium and its isolated diterpenoid derivative, erinacine A, after ischemia reperfusion brain injuries caused by the occlusion of the two common carotid arteries. The production of inflammatory cytokines in serum and the infracted volume of the brain were measured. The proteins from the stroke animal model (SAM) were evaluated to determine the effect of H. erinaceus mycelium. H. erinaceus mycelium reduced the total infarcted volumes by 22% and 44% at a concentration of 50 and 300 mg/kg, respectively, compared to the SAM group. The levels of acute inflammatory cytokines, including interleukin-1β, interleukin-6 and tumor necrosis factor á, were all reduced by erinacine A. Levels of nitrotyrosine-containing proteins, phosphorylation of p38 MAPK and CCAAT enhancer-binding protein (C/EBP) and homologous protein (CHOP) expression were attenuated by erinacine A. Moreover, the modulation of ischemia injury factors present in the SAM model by erinacine A seemed to result in the suppression of reactive nitrogen species and the downregulation of inducible NO synthase (iNOS), p38 MAPK and CHOP. These findings confirm the nerve-growth properties of Hericium erinaceus mycelium, which include the prevention of ischemic injury to neurons; this protective effect seems to be involved in the in vivo activity of iNOS, p38 MAPK and CHOP.

Topics: Animals; Basidiomycota; Brain Ischemia; CCAAT-Enhancer-Binding Proteins; Cell Death; Cytokines; Diterpenes; Male; Mycelium; Neurons; Neuroprotective Agents; Nitric Oxide Synthase Type II; p38 Mitogen-Activated Protein Kinases; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Transcription Factor CHOP; Tyrosine