|
References |
(1) Nucleus and gene expression. |
|
Binding to DNA |
|
Binds to histone-DNA complex and induces conformational changes of chromatin. |
[20] |
Induces topological changes of DNA. |
[21,22] |
|
Altered gene expression. |
|
Induces decreased expression of neurofilament and tubulin. |
[23] |
Induces altered expression of genes of neurofilament, APP, and neuron specific enolase. |
[24] |
Induces decreased expression of transferrin receptor. |
[25] |
Induces altered expression of RNA polymerase I. |
[26] |
Induces downregulation of mitochondrial cytochrome c oxidase. |
[27] |
Induces altered expression of calbindin-D28k. |
[28] |
Induces decrease in the expression of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). |
[29] |
Induces expression of pro-inflammatory genes and pro-apoptotic genes. |
[30] |
Induces elevated expression of APP. |
[31,32] |
Induces altered expression of oxidative stress marker genes (SOD1, glutathione reductase, etc.). |
[33] |
Induces decreased expression of neprilysin. |
[34] |
Induces altered expression of β-APP secretase (BACE1 and BACE2). |
[35] |
|
(2) Cellular functions |
|
Energy metabolismo |
|
Inhibits the activity of hexokinase |
[36] |
Inhibits the activity of phosphofructokinase |
[37] |
Inhibits the activity of glucose-6-phosphate dehydrogenase |
[38] |
Causes mitochondrial dysfunction and depletion of ATP |
[39,40] |
Decreases in activity and expression of TCA-cycle related enzymes (succinate dehydrogenase (SDH), alpha-ketoglutarate dehydrogenase (KGDH), isocitrate dehydrogenase-NAD+ IDH), fumarase (FUM), aconitase (ACN), and cytochrome c oxidase (Cyt C Ox)). |
[41] |
|
Phosphorylation and dephosphorylation |
|
Inhibits the activity of protein phosphatase. |
[42] |
Increases the activity of protein kinase C and cytoskeleton proteins. |
[43] |
Accelerates phosphorylation and accumulation of neurofilament. |
[44] |
Enhances Ca2+/Calmodulin dependent protein kinase activity. |
[45] |
Accelerates phosphorylation of MAP 2 and neurofilament. |
[46] |
Inhibits dephosphorylation of tau. |
[47] |
Induces nonenzymatic phosphorylation of tau. |
[48] |
|
Abnormal accumulation of proteins |
|
Causes the conformational change and the accumulation of neurofilament and MAP1A, MAP1B. |
[49] |
Accelerates the phosphorylation of tau and its accumulation. |
[50] |
Causes the accumulation of tau protein in neuroblastoma cells or in primary cultured neurons. |
[51,52] |
Causes the accumulation of tau protein in experimental animals. |
[53,54] |
Causes neurofibrillary degeneration in vivo. |
[55] |
Causes the accumulation of AβP in cultured neurons or in neuroblastoma cells. |
[56,57] |
Causes the accumulation of AβP in vivo. |
[58,59] |
|
Neurotransmitter release |
|
Inhibits glutamate release. |
[60] |
Impairs synaptic transmission. |
[61,62] |
Inactivates glutamate dehydrogenase. |
[63] |
Inhibits NMDA-type glutamate receptor. |
[64] |
Inhibits choline acetyl transferase and tyrosine hydroxylase, glutamate decarboxylase. |
[65,66] |
Influences acetyl-CoA and inhibits acetylcholine release. |
[67] |
Activates monoamine oxidase. |
[68,69] |
Inhibits dopamine beta-hydroxylase. |
[70] |
Inhibits uptake of serotonin and noradrenalin in synaptosomes. |
[71] |
|
Channel inhibition |
|
Influences the activities of Na+ channels and K+ channels. |
[72] |
Enhances the voltage-activated Na+ channels. |
[73] |
Inhibits the voltage-gated calcium channel. |
[62,74] |
Inhibits the IP3-mediated Ca2+ release. |
[75] |
|
Others |
|
Influences GTP binding proteins as aluminum fluoride. |
[76] |
Inhibits GAP junction. |
[77] |
Inhibits axonal transports. |
[78] |
Binds to calmodulin and inhibition of calmodulin-binding enzymes. |
[79] |
Induces inflammatory responses. |
[80] |
|
(3) Membrane lipids |
|
|
Peroxidation |
|
Accelerates iron-induced membrane lipid peroxidation. |
[81] |
Enhances lipid peroxidation in liposomes. |
[82] |
Induces peroxidation of myelin lipids in vivo. |
[83] |
Increases peroxidation products (malondialdehyde). |
[50] |
|
Membrane properties |
|
Causes the change the lipid/phospholipids profiles of myelinin vivo. |
[84] |
Induces the change in membrane physical properties (surface potential, lipid fluidity, and lipid arrangement). |
[83] |
Induces the change of membrane fluidity. |
[85] |
|
(4) Higher functions |
|
|
Cell death |
|
Causes the apoptotic neuronal death. |
[86,87] |
Causes the apoptosis of astrocytes. |
[88] |
Causes the death of motor neuron. |
[89,90] |
|
Behavior, learning, and memory, others |
|
Inhibits long term potentiation (LTP). |
[91,92] |
Causes learning disorder or memory deficit in experimental animals. |
[93–95] |
Influences electrical activity in hippocampus and inhibits spatial learning memory deficit in aging rats. |
[96] |
Causes memory deficit in AD model mice. |
[97,98] |
Causes encephalopathy in dialysis patients. |
[99] |
Causes encephalopathy in patients with renal failure. |
[100] |