ABSTRACT
Lycium barbarum polysaccharide (LBP) have a certain curative effect on hypoglycemic and neuroprotective effects, but the specific mechanism is unclear and needs to be further explored. This study aimed to clarify the mechanisms of LBP in the treatment of ICV-STZ mice model of AD from the perspectives of insulin resistance, IRS1/PI3K/AKT signaling pathway, and synaptic protein expression. We used male C57BL/6J mice injected with STZ (3 mg/kg) in the lateral ventricle as an AD model. After treatment with LBP, the learning and memory abilities of ICV-STZ mice were enhanced, and the pathological changes in brain tissue were alleviated. LBP can regulate the expression of proteins related to the IRS1/PI3K/AKT signaling pathway and thereby reducing Aß deposition and tau protein phosphorylation in the brain of ICV-STZ mice. In addition, LBP also can up-regulate the expression of synaptic proteins. The results indicated that LBP played a neuroprotective role by regulating the IRS1/PI3K/AKT pathway, inhibiting tau protein hyperphosphorylation and improving the expression levels of synapse-related proteins.
Subject(s)
Alzheimer Disease , Drugs, Chinese Herbal , Insulin Receptor Substrate Proteins , Mice, Inbred C57BL , Neuronal Plasticity , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Signal Transduction , tau Proteins , Animals , Male , Mice , Alzheimer Disease/chemically induced , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Brain/drug effects , Brain/metabolism , Brain/pathology , Cognition/drug effects , Disease Models, Animal , Drugs, Chinese Herbal/therapeutic use , Drugs, Chinese Herbal/pharmacology , Insulin Receptor Substrate Proteins/metabolism , Insulin Resistance , Neuronal Plasticity/drug effects , Neuroprotective Agents/therapeutic use , Neuroprotective Agents/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Streptozocin , Synapses/drug effects , tau Proteins/metabolismABSTRACT
Alzheimer's disease (AD) is a common neurodegenerative disease that is always accompanied by synaptic loss in the brain. Safflower yellow (SY) is the extract of safflower, a traditional Chinese medicine, which has shown neuroprotective effects in recent studies. However, the mechanism of SY in protecting synapses remains unclear. In this study, we are going to study the mechanism of how SY treats AD in terms of synaptic plasticity. We found, via behavioral experiments, that SY treatment could improve the abilities of learning and memory in APP/PS1 mice. In addition, using Golgi staining and HE staining, we found that SY treatment could reduce the loss of dendritic spines in the pathological condition and could maintain the normal physiological state of the cells in cortex and in hippocampus. In addition, the results of immunofluorescence staining and western blotting showed that SY treatment could significantly increase the expression of synapse-related proteins. Moreover, after being treated with SY, the expression of iNOS (marker of M1 microglia) declined remarkably, and the level of Arginase-1 (marker of M2 microglia) increased significantly. Finally, we found BDNF/TrkB/ERK signaling cascade was activated. These results indicate that SY enhances synaptic plasticity in APP/PS1 mice by regulating microglia activation phenotypes and BDNF/TrkB/ERK signaling pathway.
Subject(s)
Alzheimer Disease/drug therapy , Brain-Derived Neurotrophic Factor/physiology , Chalcone/analogs & derivatives , Drugs, Chinese Herbal/therapeutic use , MAP Kinase Signaling System/drug effects , Membrane Glycoproteins/physiology , Microglia/drug effects , Neuronal Plasticity/drug effects , Phytotherapy , Protein-Tyrosine Kinases/physiology , Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Animals , Arginase/biosynthesis , Arginase/genetics , Cerebral Cortex/chemistry , Cerebral Cortex/drug effects , Cerebral Cortex/pathology , Chalcone/therapeutic use , Dendritic Spines/drug effects , Dendritic Spines/ultrastructure , Disease Models, Animal , Donepezil/pharmacology , Donepezil/therapeutic use , Enzyme Induction/drug effects , Escape Reaction/drug effects , Female , Hippocampus/chemistry , Hippocampus/drug effects , Hippocampus/pathology , Male , Memory, Long-Term/drug effects , Memory, Short-Term/drug effects , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microglia/physiology , Morris Water Maze Test/drug effects , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/genetics , Neuronal Plasticity/physiology , Nitric Oxide Synthase Type II/biosynthesis , Nitric Oxide Synthase Type II/genetics , Presenilin-1/genetics , Random AllocationABSTRACT
Prokineticin 2 (PK2), a new chemokine, causes mechanical hypersensitivity in the rat hind paw, but little is known about the molecular mechanism. Here, we have found that ionotropic P2X receptor is essential to mechanical allodynia induced by PK2. First, intraplantar injection of high dose (3 or 10 pmol) of PK2 significantly increased paw withdrawal response frequency (%) to innocuous mechanical stimuli (mechanical allodynia). And the mechanical allodynia induced by PK2 was prevented by co-administration of TNP-ATP, a selective P2X receptor antagonist. Second, although low dose (0.3 or 1 pmol) of PK2 itself did not produce an allodynic response, it significantly facilitated the mechanical allodynia evoked by intraplantar injection of α,ß-methylene ATP (α,ß-meATP). Third, PK2 concentration-dependently potentiated α,ß-meATP-activated currents in rat dorsal root ganglion (DRG) neurons. Finally, PK2 receptors and intracellular signal transduction were involved in PK2 potentiation of α,ß-meATP-induced mechanical allodynia and α,ß-meATP-activated currents, since the potentiation were blocked by PK2 receptor antagonist PKRA and selective PKC inhibitor GF 109203X. These results suggested that PK2 facilitated mechanical allodynia induced by α,ß-meATP through a mechanism involved in sensitization of cutaneous P2X receptors expressed by nociceptive nerve endings.
Subject(s)
Adenosine Triphosphate/analogs & derivatives , Gastrointestinal Hormones/pharmacology , Hyperalgesia/chemically induced , Neuropeptides/pharmacology , Adenosine Triphosphate/adverse effects , Adenosine Triphosphate/pharmacology , Animals , Drug Synergism , Ganglia, Spinal/drug effects , Ganglia, Spinal/physiology , Gastrointestinal Hormones/antagonists & inhibitors , Hyperalgesia/physiopathology , Indoles/pharmacology , Male , Maleimides/pharmacology , Membrane Potentials/drug effects , Membrane Potentials/physiology , Neuropeptides/antagonists & inhibitors , Protein Kinase C/antagonists & inhibitors , Purinergic P2X Receptor Antagonists/pharmacology , Rats , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, Peptide/antagonists & inhibitors , Receptors, Purinergic P2X3/drug effects , Receptors, Purinergic P2X3/physiologyABSTRACT
Levo-tetrahydropalmatine (l-THP), a main bioactive Chinese herbal constituent from the genera Stephania and Corydalis, has been in use in clinical practice for years in China as a traditional analgesic agent. However, the mechanism underlying the analgesic action of l-THP is poorly understood. This study shows that l-THP can exert an inhibitory effect on the functional activity of native acid-sensing ion channels (ASICs), which are believed to mediate pain caused by extracellular acidification. l-THP dose dependently decreased the amplitude of proton-gated currents mediated by ASICs in rat dorsal root ganglion (DRG) neurons. l-THP shifted the proton concentration-response curve downward, with a decrease of 40.93% ± 8.45% in the maximum current response to protons, with no significant change in the pH0.5 value. Moreover, l-THP can alter the membrane excitability of rat DRG neurons to acid stimuli. It significantly decreased the number of action potentials and the amplitude of the depolarization induced by an extracellular pH drop. Finally, peripherally administered l-THP inhibited the nociceptive response to intraplantar injection of acetic acid in rats. These results indicate that l-THP can inhibit the functional activity of ASICs in dissociated primary sensory neurons and relieve acidosis-evoked pain in vivo, which for the first time provides a novel peripheral mechanism underlying the analgesic action of l-THP.