u-0126 and Memory-Disorders

Sevoflurane has been shown to stimulate or depress memory in adult rats; however, the cellular mechanism of this bidirectional effect has not been fully investigated.. We used an intra-hippocampal microinfusion of U0126 to suppress ERK activation. Male SD rats were randomly assigned to four groups: Sham, 0.11%SEV, 0.3%SEV and 0.3%+U0126. They received bilateral injections of U0126 or saline. Rats were anesthetized, and Inhibitory Avoidance (IA) training was performed immediately after anesthesia. The memory retention latency was observed 24 h later. In another experiment, the hippocampus was removed 45 min after IA training to assess ARC expression, the synapsin 1 protein levels and the phosphorylation level of ERK.. Treatment with 0.11%SEV led to rapid phosphorylation of ERK, while 0.3%SEV inhibited phosphorylation; the latter change was reversed by the microinfusion of U0126 in the hippocampus. The memory latency result had similar tendencies. The local infusion of U0126 abolished the 0.3%SEV-induced memory impairment and ERK inhibition. Selective upregulations of ARC and synapsin 1 proteins were observed in the 0.3%SEV group compared with the 0.11%SEV group.. The results indicate that different doses of sevoflurane trigger synaptic plasticity-related cytoskeleton proteins through the ERK signaling pathway. This novel modulation by inhalational agents may help to reduce their side-effects on memory function.

Topics: AIDS-Related Complex; Anesthetics, Inhalation; Animals; Butadienes; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Escape Reaction; Hippocampus; Learning Disabilities; Male; MAP Kinase Signaling System; Memory Disorders; Methyl Ethers; Nitriles; Rats; Rats, Sprague-Dawley; Sevoflurane; Synapsins

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Butadienes; Caspase 3; Cells, Cultured; Cerebral Cortex; Extracellular Signal-Regulated MAP Kinases; Male; Memory Disorders; Mitochondria; Nerve Degeneration; Neurons; Nitriles; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Saponins; Synapses; tau Proteins

The C/EBP β is a basic leucine zipper transcription factor that regulates a variety of biological processes, including metabolism, cell proliferation and differentiation, and immune response. Recent findings show that C/EBP β-induced inflammatory responses mediate kainic acid-triggered excitotoxic brain injury. In this article, we show that protein kinase C ζ enhances K-ras expression and subsequently activates the Raf/MEK/ERK1/2 pathway in the hippocampus of domoic acid (DA)-treated mice, which promotes C/EBP β expression and induces inflammatory responses. Elevated production of TNF-α impairs mitochondrial function and increases the levels of reactive oxygen species by IκB kinase β/NF-κB signaling. The aforementioned inflammation and oxidative stress lead to memory deficits in DA-treated mice. However, troxerutin inhibits cyclin-dependent kinase 1 expression, enhances type 1 protein phosphatase α dephosphorylation, and abolishes MEK/ERK1/2/C/EBP β activation, which subsequently reverses the memory impairment observed in the DA-treated mice. Thus, troxerutin is recommended as a potential candidate for the prevention and therapeutic treatment of cognitive deficits resulting from excitotoxic brain damage and other brain disorders.

Topics: Animals; Butadienes; CCAAT-Enhancer-Binding Protein-beta; CDC2 Protein Kinase; Gene Knockdown Techniques; Genes, ras; Hippocampus; Hydroxyethylrutoside; Inflammation; Inflammation Mediators; Kainic Acid; Male; Memory Disorders; Mice; Mitochondria; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NADPH Oxidases; Nitriles; Oxidative Stress; Phosphoprotein Phosphatases; Phosphorylation; Protein Kinase C; Reactive Oxygen Species; Signal Transduction

In this study, we investigated the effect of intracerebroventricular administration of ERK and p38 specific inhibitors, U0126 and PD169316, respectively, on learning and memory deficits induced by amyloid beta (Aβ) in rats. To investigate the effects of these compounds on learning and memory, we performed Morris water maze (MWM) test. U0126 and/or PD169316 improved spatial learning in MWM in Aβ-injected rats, 20 days after Aβ-injection. To determine the mechanisms of action of U0126 and PD169316, we studies their effect on some intracellular signaling pathways such as Ca(+)/cAMP-response element binding protein (CREB), c-fos, and transcription factors that regulate mitochondrial biogenesis. Based on our data, CREB and c-fos levels decreased 7 days after Aβ-injection, while U0126 and/or PD169316 pretreatments significantly increased these levels. Moreover, U0126 and PD169316 activated peroxisome proliferator-activated receptor gamma coactivator-1a, nuclear respiratory factor 1, and mitochondrial transcription factor A, 7 days after Aβ-injection. Surprisingly, these factors were returned to vehicle level, 20 days after Aβ-injection. Our findings reinforce the potential neuroprotective effect of these inhibitors against the Aβ toxicity.

Topics: Amyloid beta-Peptides; Animals; Blotting, Western; Butadienes; CA1 Region, Hippocampal; Cyclic AMP Response Element-Binding Protein; Enzyme Inhibitors; Imidazoles; Male; MAP Kinase Signaling System; Maze Learning; Memory Disorders; Microinjections; Mitochondria; NF-E2-Related Factor 1; Nitriles; p38 Mitogen-Activated Protein Kinases; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphorylation; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; RNA-Binding Proteins; Stereotaxic Techniques; Transcription Factors

1. Deposition of β-amyloid (Aβ) peptide is a defining pathological hallmark of Alzheimer's disease (AD) and is involved in memory impairment. Evidence suggests that activation of an extracellular signal-regulated kinase (ERK) pathway is related to Aβ accumulation. Thus, the aim of the present study was to investigate the effects of an ERK inhibitor (U0126) on amyloidogenesis and cognitive function in Tg2576 mice. 2. Tg2576 mice were injected with U0126 (20 mg/kg, i.p.) or vehicle (1% dimethyl sulphoxide in sterile saline) once a day for 7 days and then cognitive function was assessed by the Morris water maze test and passive avoidance test. In addition, immunostaining, western blot analysis, ELISA and enzyme activity assays were used to examine the degree of Aβ deposition in the brains of Tg2576 mice. 3. Our results showed that U0126 attenuated memory impairment and inhibited Aβ deposition in the brains of Tg2576 mice. Further experiments revealed that the inhibition of Aβ deposition by U0126 was due to a reduction in β-secretase and amyloid precursor protein expression in the brains of U0126-treated Tg2576 mice. 4. These results suggest that the ERK pathway is associated with Aβ accumulation and consequent memory dysfunction in Tg2576 mice and that inhibition of the ERK pathway may be an appropriate intervention in the treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Brain; Butadienes; Cognition Disorders; Extracellular Signal-Regulated MAP Kinases; Female; Memory Disorders; Mice; Mice, Transgenic; Nitriles

Nociceptin binds to nociceptin opioid peptide (NOP) receptors. We reported that although high doses of nociceptin impaired memory function and that these effects were mediated via NOP receptors, low doses of nociceptin attenuated the memory impairment, and these attenuating effects were not mediated via NOP receptors. Even very low doses of nociceptin were biologically active and suggested a certain binding site for this peptide, but the mechanism underlying this attenuating effect has not yet been elucidated. In the present study, we investigated the effect of an intrahippocampal injection (i.h.) of nociceptin on memory impairment induced by U0126, a MEK inhibitor, and Rp-cAMPS, a PKA inhibitor in a step-down type passive avoidance test. U0126 (2.63 nmol/mouse, i.h.) impaired memory formation and training-dependent phosphorylation of ERK2 in the hippocampus. Co-administration of nociceptin (10 fmol/mouse) significantly attenuated memory impairment, while it did not attenuate the inhibition of training-dependent phosphorylation of ERK2 induced by U0126. On the other hand, nociceptin did not attenuate memory impairment induced by Rp-cAMPS (0.448 nmol/mouse, i.h.). Nociceptin (1 fmol/mouse) also attenuated U0126 (5.26 nmol/mouse)-induced memory impairment in NOP receptor knockout mice. Nociceptin was reported to metabolize into fragments (1-13) and (14-17) in vivo, which showed pharmacological activities without affecting NOP receptors. Our findings showed that nociceptin (14-17) (1 fmol/mouse) also attenuated U0126-induced memory impairment, while nociceptin (1-13) (0.1-10 fmol/mouse) did not attenuate memory impairment. These results suggest a novel action site or mechanism for the attenuating effects of nociceptin and its metabolite, and the sequence of nociceptin (14-17) is a critical structure.

Topics: Animals; Butadienes; Enzyme Inhibitors; Humans; Male; Memory Disorders; Mice; Nitriles; Nociceptin; Opioid Peptides; Phosphorylation; Protein Serine-Threonine Kinases; Receptors, Opioid; Vasodilator Agents

Amyloid β (Aβ) peptide plays a central role in neuronal apoptosis, promoting oxidative stress, lipid peroxidation, caspase pathway activation and neuronal loss. Our previous study has shown that bone marrow-derived mesenchymal stem cells (BM-MSCs) reduce Aβ deposition when transplanted into acutely-induced Alzheimer's disease (AD) mice brain. However, the impact of reduced Aβ deposition on memory impairment and apoptosis by BM-MSCs has not yet been investigated. Therefore, the aim of the present study was to investigate the neuroprotective mechanism of BM-MSCs in vitro and in vivo. We found that BM-MSCs attenuated Aβ-induced apoptotic cell death in primary cultured hippocampal neurons by activation of the cell survival signaling pathway. These anti-apoptotic effects of BM-MSCs were also observed in an acutely-induced AD mice model produced by injecting Aβ intrahippocampally. In addition, BM-MSCs diminished Aβ -induced oxidative stress and spatial memory impairment in the in vivo model. These findings lead us to hypothesize that BM-MSCs ameliorate Aβ -induced neurotoxicity and cognitive decline by inhibiting apoptotic cell death and oxidative stress in the hippocampus. These findings provide support for a potentially beneficial role for BM-MSCs in the treatment of AD.

Topics: Amyloid beta-Peptides; Animals; Apoptosis; Bone Marrow Transplantation; Butadienes; Cells, Cultured; CREB-Binding Protein; Disease Models, Animal; Embryo, Mammalian; Enzyme Inhibitors; Ethidium; Extracellular Signal-Regulated MAP Kinases; Hippocampus; In Situ Nick-End Labeling; Maze Learning; Memory Disorders; Mesenchymal Stem Cell Transplantation; Mice; Mice, Inbred C57BL; Neurons; Nitriles; Oxidative Stress; Phosphorylation; Reaction Time; Statistics, Nonparametric; Superoxides

Cyclic AMP-specific phosphodiesterase 4 (PDE4), which is an integral component of NMDA receptor-mediated cAMP signaling, is involved in the mediation of memory processes. Given that NMDA receptors also mediate MEK/mitogen-activated protein kinase (MAPK, ERK) signaling, which is involved in synaptic plasticity, and that some PDE4 subtypes are phosphorylated and regulated by ERK, it was of interest to determine if PDE4 is involved in MEK/ERK signaling-mediated memory. It was found that rolipram, a PDE4-selective inhibitor, reversed the amnesic effect in the radial-arm maze test of the MEK inhibitor U0126 administered into the CA1 subregion of the rat hippocampus. Consistent with this, rolipram, either by peripheral administration or direct intra-CA1 infusion, enhanced the retrieval of long-term memory impaired by intra-CA1 infusion of U0126 using the step-through inhibitory avoidance test. The same dose of rolipram did not affect U0126-induced reduction of phospho-ERK1/2 levels in the CA1 subregion. However, in primary cultures of rat cerebral cortical neurons, pretreatment with U0126 increased PDE4 activity; this was correlated with the U0126-induced reduction of phospho-ERK1/2 levels. These results suggest that MEK/ERK signaling plays an inhibitory role in regulating PDE4 activity in the brain; this may be a novel mechanism by which MEK/ERK signaling mediates memory. PDE4 is likely to be an important link between the cAMP/PKA and MEK/ERK signaling pathways in the mediation of memory.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Avoidance Learning; Blotting, Western; Butadienes; Cells, Cultured; Cerebral Cortex; Cyclic Nucleotide Phosphodiesterases, Type 4; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hippocampus; Male; Maze Learning; Memory Disorders; Microinjections; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Neurons; Nitriles; Phosphodiesterase Inhibitors; Rats; Rats, Sprague-Dawley; Rolipram; Signal Transduction