ABSTRACT
Donepezil is a potent acetylcholinesterase inhibitor used for the treatment of Alzheimer's disease (AD). Additional therapeutically relevant target for donepezil is sigma1 receptor (Sig1-R). Beta-amyloid peptide (Aß) is believed to contribute to the pathogenesis of AD. In our previous work (Kapai et al., 2012), we have shown that donepezil antagonizes the suppressive action of Aß(1-42) on long-term potentiation (LTP) in rat hippocampal slices. The purpose of the present study was to determine whether Sig1-R is involved into the mechanisms of donepezil action. For this purpose, we have tested whether agonist of Sig1-R PRE-084 mimics, and antagonist of Sig1-R haloperidol abolishes the effect of donepezil. Population spikes (PSs) were recorded from the pyramidal layer of the CA1 region of rat hippocampal slices. Drugs were applied by addition to the perfusate starting 15 min before and ending 5 min after the tetanus. In the control group, the amplitude of PS 30 min post-tetanus reached 153±10%. Aß (200 nM) markedly suppressed the LTP magnitude or even caused the suppression of baseline PS (82±8%, P<0.001). This suppression of LTP could be markedly prevented when 1 µM donepezil was co-administered with Aß (136±11%, P<0.05). Further, we co-administered three substances: Aß, donepezil and 0.5 µM haloperidol and have found that haloperidol antagonized the stimulating effect of donepezil on LTP (92±6%, P<0.05). Agonist of Sig1-R PRE-084 (0.1-10 µM) enhanced control LTP and abolished the inhibitory effect of Aß on LTP in a concentration-dependent manner. The amplitude of PS 30 min post-tetanus reached 183±7% (P<0.01) for 10 µM PRE-084. The results suggest that activation of Sig1-R is involved into the mechanisms of donepezil-induced rescue of hippocampal LTP impaired by Aß.
Subject(s)
Amyloid beta-Peptides/toxicity , CA1 Region, Hippocampal/drug effects , CA1 Region, Hippocampal/physiology , Cholinesterase Inhibitors/pharmacology , Indans/pharmacology , Long-Term Potentiation/drug effects , Peptide Fragments/toxicity , Piperidines/pharmacology , Receptors, sigma/metabolism , Animals , Donepezil , Haloperidol/pharmacology , Male , Morpholines/pharmacology , Rats , Rats, Wistar , Receptors, sigma/agonists , Receptors, sigma/antagonists & inhibitorsABSTRACT
Echinacea purpurea is a widely used plant immunomodulator with a selective immunomodulatory effect depending on the dilution of the initial preparation. In low doses, it causes selective induction of pro- and anti-inflammatory cytokines. The results recommend this preparation in a wide range of concentrations for adequate correction of the immune system work aimed at restoring the Th1/Th2 balance in various diseases.
Subject(s)
Cytokines/drug effects , Cytokines/metabolism , Echinacea , Plant Extracts/pharmacology , Biological Products , Cells, Cultured , Humans , Immunologic Factors/pharmacology , Interleukin-10/metabolism , Interleukin-1beta/metabolism , Interleukin-4/metabolism , Interleukin-6/metabolism , Interleukin-8/metabolism , Leukocytes, Mononuclear/drug effects , Th1-Th2 Balance/drug effects , Tumor Necrosis Factor-alpha/metabolismABSTRACT
ß-Amyloid peptide 1-42 in a concentration of 200 nM impairs induction of long-term posttetanic potentiation of population spike in CA1 pyramidal neurons in rat hippocampal slices. Application of donepezil, a drug used for the treatment of Alzheimer disease, in a concentration of 1 µM eliminates the suppressive effect of ß-amyloid peptide 1-42 on long-term posttenanic potentiation in the hippocampus.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Hippocampus/physiology , Indans/pharmacology , Long-Term Potentiation/physiology , Neuroprotective Agents/pharmacology , Peptide Fragments/metabolism , Piperidines/pharmacology , Animals , Donepezil , Hippocampus/drug effects , Indans/therapeutic use , Long-Term Potentiation/drug effects , Male , Piperidines/therapeutic use , Rats , Rats, Wistar , Statistics, NonparametricABSTRACT
Preapplication of peptide piracetam analogue pyroglutamyl-asparagine amide to rat hippocampal slices facilitates long-term potentiation of focal responses in the CA1 field after weak tetanization of the synaptic input (30 pulses, 100 Hz). This treatment normalized the development of long-term potentiation after standard tetanization (100 pulses, 100 Hz) impaired by ethanol.
Subject(s)
Dipeptides/pharmacology , Hippocampus/drug effects , Long-Term Potentiation/drug effects , Pyrrolidonecarboxylic Acid/analogs & derivatives , Pyrrolidonecarboxylic Acid/pharmacology , Animals , Arginine Vasopressin/pharmacology , Electric Stimulation , Hippocampus/physiology , In Vitro Techniques , Male , Nootropic Agents/pharmacology , Peptide Fragments/pharmacology , Rats , Rats, WistarABSTRACT
Preincubation of rat hippocampal slices with 0.05-0.5 microM pyroglutamylasparagine amide improved characteristics of long-term potentiation of focal responses in the synaptic system of Schaffer collaterals-CA1 field pyramids facilitating LTP development and increasing its amplitude and duration. Presumably, the positive modulation of plastic characteristics of synaptic transmission in the hippocampusis is responsible for facilitation of learning and memory induced by pyroglutamylasparagine.
Subject(s)
Amides/pharmacology , Dipeptides/pharmacology , Hippocampus/drug effects , Synaptic Transmission , Animals , Hippocampus/metabolism , Long-Term Potentiation , Male , Pyrrolidonecarboxylic Acid/analogs & derivatives , Rats , Rats, Wistar , Synapses/drug effects , Time FactorsABSTRACT
Long-term potentiation of CA1 field potentials was induced by weak tetanic orthodromic stimulation of the Schaffer collateral/commissural fibers in isolated hippocampal slices perfused with a medium containing arginine vasopressin fragment AVP(4-9)in micromolar concentrations. It is hypothesized that AVP(4-9)affects induction of long-term potentiation at the intracellular level.
