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Abstract: 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPhtCho) (1μM) enhanced long-term depression (LTD), a synaptic plasticity relevant to learning and memory, in the CA1 region of rat hippocampal slices, where expression of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit GluR1 on the plasma membrane was decreased. In the water maze test, oral administration with POPhtCho (5mg/kg) significantly shortened the prolonged retention latency for rats intraperitoneally injected with scopolamine (1mg/kg), while the acquisition latency was not affected. For humans with mild cognitive impairment and dementia (average of Mini Mental State Examination score, 18), oral intake with POPhtCho (300mg/day, once after breakfast) everyday raised the score to over 20, corresponding to normal cognitive functions, throughout 6 months after intake. The results of the present study, thus, indicate that POPhtCho could ameliorate cognitive disorders, possibly by enhancing LTD. [Copyright &y& Elsevier]

The linoleic acid derivative 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) activated Ca2+/calmodulin-dependent protein kinase II (CaMKII) by inhibiting protein phosphatase-1 (PP-1). DCP-LA induced a transient huge facilitation of synaptic transmission monitored from the CA1 region of rat hippocampal slices, which was largely inhibited by the CaMKII inhibitor KN-93. DCP-LA potentiated kainate-evoked whole-cell membrane currents for Xenopus oocytes expressing α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors composed of the GluR1, GluR3, GluR1/GluR2, GluR1/GluR3, and GluR1/GluR2/GluR3 subunits, and the potentiation was significantly inhibited by KN-93. A similar potentiation was still found with mutant GluR1 (S831A) receptor lacking CaMKII phosphorylation site. The GluR1 and GluR2 subunits formed AMPA receptors in the rat hippocampus, and DCP-LA increased expression of both the subunits on the plasma membrane. The DCP-LA action was blocked by KN-93 and the exocytosis inhibitor botulinum toxin type A, but not by the endocytosis inhibitor phenylarsine oxide. DCP-LA, thus, appears to activate CaMKII through PP-1 inhibition, that stimulates AMPA receptor exocytosis to increase expression of the receptors on the plasma membrane, responsible for potentiate AMPA receptor responses and facilitation of hippocampal synaptic transmission. J. Cell. Physiol. 221: 183–188, 2009. © 2009 Wiley-Liss, Inc [ABSTRACT FROM AUTHOR]

Abstract: Aims: The present study was conducted to understand the role of 1,2-dilynoleoyl-sn-glycero-3-phosphocholine (DLPhtCho) in cognitive functions. Main methods: Two-electrode voltage-clamp was made to Xenopus oocytes expressing rat α7 acetylcholine (ACh) receptors. Field excitatory postsynaptic potentials (fEPSPs) were monitored from the CA1 region of rat hippocampal slices. Water maze test was carried out to assess spatial learning and memory for rats. Key findings: In the oocyte expression system, DLPhtCho at a concentration of 10 µM potentiated ACh-evoked currents to approximately 190% of basal amplitudes 70 min after 10-min treatment. In contrast, 1-stearoyl-2-lynoleoyl-sn-glycero-3-phosphocholine (SLPhtCho), 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine (PLPhtCho), and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPhtCho) had no effect on the currents. DLPhtCho (10 µM) enhanced slope of fEPSPs to about 150% of basal levels at 70-min treatment, that is inhibited by α-bungarotoxin, an inhibitor of α7 ACh receptors, while no enhancement was obtained with SLPhtCho, PLPhtCho, or POPhtCho. In the water maze test, oral administration with DLPhtCho (5 mg/kg) significantly shortened the prolonged acquisition latency for rats intraperitoneally injected with scopolamine (1 mg/kg). Significance: The results of the present study show that DLPhtCho improves scopolamine-induced learning and memory deficits, possibly by facilitating hippocampal synaptic transmission under the control of α7 ACh receptors. DLPhtCho, therefore, could be developed as a beneficial anti-dementia drug. [Copyright &y& Elsevier]

Nicotinic acetylcholine (ACh) receptors, such as α7, α3β4 and α4β2 receptors in the hippocampus, are suggested to modulate neurotransmitter release. 8-[2-(2-Pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) (100 n m), a linoleic acid derivative, potentiated responses of α7, α3β4 and α4β2 ACh receptors expressed in Xenopus oocytes that are blocked by 3-(1-[dimethylaminopropyl] indol-3-yl)-4-[indol-3-yl] maleimide (GF109203X), a selective inhibitor of protein kinase C (PKC), except for α3β4 ACh receptors. DCP-LA enhanced the nicotine-triggered release of GABA from rat hippocampal slices in the presence of tetrodotoxin in a bell-shaped dose-dependent manner at concentrations ranging from 10 n m to 10 µ m, although DCP-LA by itself had no effect on GABA release. The DCP-LA action was inhibited by GF109203X or α-bungarotoxin, an inhibitor of α7 ACh receptors, but not by mecamylamine or dihydro-β-erithroidine, an inhibitor of α3β4 and α4β2 ACh receptors. A similar effect on GABA release was obtained with 12- O-tetradecanoylphorbol 13-acetate, a PKC activator. DCP-LA (100 n m) also enhanced GABA release triggered by choline, an agonist of α7 ACh receptors, but not 3-[2(s)-azetidinylmethoxy] pyridine, an agonist of α4β2 ACh receptors. In addition, DCP-LA (100 n m) increased the rate of nicotine-triggered GABAA receptor-mediated miniature inhibitory post-synaptic currents, monitored from CA1 pyramidal neurons of rat hippocampal slices, and the effect was also inhibited by GF109203X or α-bungarotoxin but not by mecamylamine. Thus, the results of the present study indicate that DCP-LA stimulates GABA release by enhancing activity of pre-synaptic α7 ACh receptors present on the GABAergic terminals of interneurons that transmit to CA1 pyramidal neurons via a PKC pathway. [ABSTRACT FROM AUTHOR]

The present study examined the effects of the proinflammatory cytokine interleukin-18 (IL-18) on mouse hippocampal synaptic transmission. IL-18 (100 ng/ml) significantly increased amplitude and frequency of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated miniature excitatory postsynaptic currents (AMPA–mEPSCs), that are monitored from CA1 pyramidal neurons of mouse hippocampal slices. IL-18 (100 ng/ml) enhanced slope of basal field excitatory postsynaptic potentials (fEPSPs) that are recorded from the CA1 region of mouse hippocampal slices. There was no significant difference in the expression of Schaffer collateral/CA1 long-term potentiation (LTP) between in the presence and absence of IL-18, although IL-18 tended to inhibit saturation levels of the potentiation induced by tetanic stimulation in a dose-dependent manner at concentrations ranged from 10 ng/ml to 1 μg/ml. Paired-pulse facilitation in the presence of IL-18 (100 ng/ml) was not influenced after tetanic stimulation, while that in the absence of IL-18 was depressed. The results of the present study, thus, suggest that IL-18 stimulates synaptically released glutamate and enhances postsynaptic AMPA receptor responses in CA1 pyramidal neurons of mouse hippocampal slices, thereby facilitating basal hippocampal synaptic transmission without affecting the LTP. [Copyright &y& Elsevier]

In a whole-cell patch-clamp configuration, currents through N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor channels were monitored in cultured rat hippocampal neurons, and those currents were depressed to 25 and 28% of basal levels, respectively, by 3-min treatment with tunicamycin (10 μM), an inhibitor of protein N-glycosylation. Tunicamycin (10 μM) reduced amplitude of population spikes elicited in the dentate gyrus of rat hippocampal slices, reaching 78% of basal levels 60 min after the beginning of treatment, and long-term potentiation (LTP) of the perforant path was never induced in the presence of tunicamycin. Tunicamycin, thus, appears to serve as a modulator for NMDA and AMPA receptors, regardless of N-glycosylation, thereby inhibiting neurotransmission and LTP in the dentate gyrus. [Copyright &y& Elsevier]

Abstract: Olprinone, an inhibitor of cyclic nucleotide phosphodiesterase III, inhibited an increase in intracellular Ca2+ concentrations for acutely dissociated rat hippocampal pyramidal neurons induced by extracellular high K+ (35mM) depolarization. Olprinone (100μM) significantly reduced spontaneous glutamate release from rat hippocampal slices. Furthermore, olprinone significantly decreased the rate of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated miniature excitatory postsynaptic currents (AMPA-mEPSCs) monitored from CA1 pyramidal neurons of rat hippocampal slices, and the effect was blocked by KT5823, an inhibitor of protein kinase G (PKG), but not by H-89, an inhibitor of protein kinase A (PKA). In the PKA assay using PC-12 cells, olprinone did not activate PKA. Taken together, the results of the present study show that olprinone attenuates intracellular Ca2+ rise through voltage-sensitive Ca2+ channels and inhibits presynaptic glutamate release via a cGMP/PKG pathway. [Copyright &y& Elsevier]

2-Pyrrolidinone, a metabolite of aniracetam, potentiated currents through α7 receptors expressed in Xenopus oocytes, in a bell-shaped dose-dependent manner at concentrations ranged from 1 nM to 10 μM, with a maximum at 100 nM (189% of original levels 60 min after 20-min treatment). The potentiation was inhibited by GF109203X, a selective inhibitor of protein kinase C (PKC), but not by KN-93, a selective inhibitor of CaMKII, or H-89, a selective inhibitor of protein kinase A (PKA). In the PKC assay using reversed-phase high-performance liquid chromatography, 2-pyrrolidinone enhanced activity of PKC-ϵ activated by linoleic acid to about 1.8-times greater than that in the absence of 2-pyrrolidinone, although it did not directly activate PKC-ϵ. In the Western immunoblot analysis, rat hippocampal slices treated with 2-pyrrolidinone (100 nM) was more reactive to an antibody against phosphorylated myristoylated alanine-rich C kinase substrate (MARCKS) than untreated slices. 2-Pyrrolidinone (100 nM) induced a long-lasting facilitation of hippocampal synaptic transmission in the CA1 region of rat hippocampal slices, and the facilitation was inhibited by GF109203X or α-bungarotoxin, an inhibitor of α7 receptors. The results of the present study suggest that 2-pyrrolidinone enhances activity of activated PKC, thereby potentiating α7 receptor responses, and then leading to a facilitation of hippocampal synaptic transmission. [Copyright &y& Elsevier]

The present study investigated the effects of (−)-epigallocatechin gallate (EGCG), which is the major component of polyphenol in green tea, on nitric oxide (NO) stress-induced neuronal damage, by monitoring NO mobilizations in the intact rat hippocampus and assaying the viability of cultured rat hippocampal neurons. A 10-min ischemia increased NO (NO3−/NO2−) concentrations in the intact rat hippocampus, while EGCG (50 mg/kg i.p.) inhibited the increase by 77% without affecting hippocampal blood flow. The NO donor, sodium nitroprusside (SNP; 50 μM), produced NO (NO3−/NO2−), while EGCG inhibited it in a dose-dependent manner at concentrations ranging from 50 to 200 μM. Treatment with SNP (100 μM) reduced the viability of cultured rat hippocampal neurons to 22% of control levels, while EGCG caused it to recover to 51% for 10 μM, 73% for 20 μM, and 70% for 50 μM. Taken together, it appears that EGCG could protect against ischemic neuronal damage by deoxidizing peroxynitrate/peroxynitrite, which is converted to NO radical or hydroxy radical. [Copyright &y& Elsevier]