Oleuropein Improves Long Term Potentiation at Perforant Path-dentate Gyrus Synapses in vivo / 中草药·英文版

Objective: To investigate the effect of oleuropein (OE) on long term potentiation (LTP) at hippocampal perforant path-dentate gyrus synapses in vivo. Methods: An outer guide cannula, a monopolar recording electrode, and a bipolar stimulating electrode were implanted in the skull and extracellular recording technique was used to record the population spike in the dentate gyrus of anesthetized rats. Results: Oleuropein significantly increased the basal synaptic transmission and the amplitude of population spike was increased from (117.6 ± 2.3)% to (134.9 ± 3.7)% after administration with OE. OE also accelerated LTP induction and maintenance, the population spike amplitude after high frequency stimulation was increased from (167.2 ± 12.8)% to (225.5 ± 15.5)% and the maintenance phase of LTP was from (182.1 ± 15.1)% to (210.5 ± 9.0)% respectively after administration with OE. Conclusion: Present study showed that OE significantly improved different stages of LTP, which could be the molecular mechanism of its efficacy on attenuating AD-like pathology and delaying cognitive decline. OE can be a promising drug for AD and dementia.

Sex Differences in Hippocampal Neuronal Sensitization by Nicotine in M. gerbils

We studied the sex different nicotine effect on evoked population spike amplitudes (ePSA) and connexin (Cx) expression in the hippocampus CA1 area of gerbils. Acute doses of nicotine bitartrate (0.5 mg/kg: NT-0.5) slightly reduced ePSA in males but markedly augmented that in females. Acute NT (5.0 mg/kg) markedly increased the ePSA in all gerbils. Unlike acute NT-0.5, repeated NT-0.5 injection (twice a day for 7 days) significantly increased the ePSA in males and slightly affected the NT-0.5 effect in females. The Cx36 and Cx43 expression levels as well as Cx expressing neuronal populations were significantly increased by repeated NT-0.5 in in both male and female gerbils, and particularly, Cx43 expression was somewhat prominent in females. These results demonstrated a sex difference with respect to the nicotine effect on hippocampal bisynaptic excitability, irrelevant to connexin expression.

NMDA Receptor-dependent Inhibition of Synaptic Transmission by Acute Ethanol Treatment in Rat Corticostriatal Slices

The effects of ethanol on corticostriatal synaptic transmission were examined, using extracellular recording and analysis of population spike amplitudes in rat brain slices, to study how acute ethanol intoxication impairs striatal function. Ethanol caused a decrease in population spike amplitudes in a dose dependent manner (50~200 mM). Pretreatment with picrotoxin, a gamma-amino butyric acid (GABA)A receptor antagonist, increased the population spikes but ethanol (100 mM) was still effective in decreasing the population spikes under this condition. In the presence of (DL)-2-amino-5-phosphonovaleric acid (APV), N-methyl-D-aspartate (NMDA) receptor antagonist, the inhibitory action of ethanol on population spikes was not shown. These results suggest that ethanol inhibits the glutamatergic corticostriatal synaptic transmission through blockade of NMDA receptors.

Dopamine Modulates Corticostriatal Synaptic Transmission through Both D1 and D2 Receptor Subtypes in Rat Brain

Striatum has important roles in motor control, habitual learning and memory. It receives glutamatergic inputs from neocortex and thalamus, and dopaminergic inputs from substantia nigra. We examined effects of dopamine (DA) on the corticostriatal synaptic transmission using in vitro extracellular recording technique in rat brain corticostriatal slices. Synaptic responses were elicited by stimulation of cortical glutamatergic inputs on the corpus callosum and recorded in the dorsal striatum. Corticostriatal population spike (PS) amplitudes were decreased (39.4+/-7.9%) by the application of 100microM DA. We applied receptor subtype specific agonists and antagonists and characterized the modulation of corticostriatal synaptic transmission by different DA receptor subtypes. D2 receptor agonist (quinpirole), antagonist (sulpiride), and D1 receptor antagonist (SKF 83566), but not D1 receptor agonist (SKF 38393), induced significantly the reduction of striatal PS. Pretreatment neither with SKF 83566 nor sulpiride significantly affected corticostriatal synaptic inhibition by DA. However, the inhibition of DA was completely blocked by pretreatment with mixed solution of both SKF 83566 and sulpiride. These results suggest that DA inhibits corticostriatal synaptic transmission through both D1 and D2 receptors in concert with each other.

Inhibitory Modulation of 5-Hydroxytryptamine on Corticostriatal Synaptic Transmission in Rat Brain Slice

Striatum plays a crucial role in the movement control and habitual learning. It receives an information from wide area of cerebral cortex as well as an extensive serotonergic (5-hydroxytryptamine, 5-HT) input from raphe nuclei. In the present study, the effects of 5-HT to modulate synaptic transmission were studied in the rat corticostriatal brain slice using in vitro extracellular recording technique. Synaptic responses were evoked by stimulation of cortical glutamatergic inputs on the corpus callosum and recorded in the dorsal striatum. 5-HT reversibly inhibited coticostriatal glutamatergic synaptic transmission in a dose-dependent fashion (5, 10, 50, and 100 microM), maximally reducing in the corticostriatal population spike (PS) amplitude to 40.1+/-5.0% at a concentration of 50 microM 5-HT. PSs mediated by non-NMDA glutamate receptors, which were isolated by bath application of the NMDA receptor antagonist, d, l-2-amino-5-phospohonovaleric acid (AP-V), were decreased by application of 50 microM 5-HT. However, PSs mediated by NMDA receptors, that were activated by application of zero Mg2+ aCSF, were not significantly affected by 50 microM 5-HT. To test whether the corticostriatal synaptic inhibitions by 5-HT might involve a change in the probability of neurotransmitter release from presynaptic nerve terminals, we measured the paired-pulse ratio (PPR) evoked by 2 identical pulses (50 ms interpulse interval), and found that PPR was increased (33.4+/-5.2%) by 5-HT, reflecting decreased neurotransmitter releasing probability. These results suggest that 5-HT may decrease neurotransmitter release probability of glutamatergic corticostriatal synapse and may be able to selectively decrease non-NMDA glutamate receptor-mediated synaptic transmission.

Effects of K+ channel modulators on extracellular K+ accumulation during ischemia in the rat hippocampal slice

Loss of synaptic transmission and accumulation of extracellular K+((K+)o) are the key features in ischemic brain damage. Here, we examined the effects of several K+ channel modulators on the early ischemic changes in population spike (PS) and (K+)o in the CA1 pyramidal layer of the rat hippocampal slice using electrophysiological techniques. After onset of anoxic aglycemia (AA), orthodromic field potentials decreased and disappeared in 3.3 +/- 0.22 min (mean +/- SEM, n = 40). The hypoxic injury potential (HIP), a transient recovery of PS appeared at 6.0 +/- 0.25 min (n = 40) in most slices during AA and lasted for 3.3 +/- 0.43 min. (K+)o increased initially at a rate of 0.43 mM/min (Phase 1) and later at a much faster rate (12.45 mM/min, Phase 2). The beginning of Phase 2 was invariably coincided with the disappearance of HIP. Among K+ channel modulators tested such as 4-aminopyridine (0.03, 0.3 mM), tetraethylammonium (0.1 mM), NS1619 (0.3 ~ 10 muM), niflumic acid (0.1 mM), glibenclamide (40 muM), tolbutamide (300 muM) and pinacidil (100 muM), only 4-aminopyridine (0.3 mM) induced slight increase of (K+)o during Phase 1. However, none of the above agents modulated the pattern of Phase 2 in (K+)o in response to AA. Taken together, the experimental data suggest that 4-aminopyridine-sensitive K+ channels, large conductance Ca2+/-activated K+ channels and ATP-sensitive K+ channels may not be the major contributors to the sudden increase of (K+)o during the early stage of brain ischemia, suggesting the presence of other routes of K+ efflux during brain ischemia.

Neuroprotective Effects of BAPTA-AM: A Dose-response Study and Estimation of Therapeutic Window

In central neurons, an excessive or sustained rise in the concentration of free cytoplasmic Ca2+ ions([Ca2+]i) after hypoxia may promote rapid neurodegeneration both in vitro and in vivo. Treating cells with Ca2+ chelating agents may prevent or delay a loss of cellular Ca2+ homeostasis after hypoxic injury and thus constitute an effective strategy for minimizing neuronal damage. Cell-permeant Ca2+ chelators such as 1,2-bis-(2-aminophenoxy) ethrane -N,N,N',N' -tetraacetic acid acetoxymethyl ester(BAPTA-AM) have shown evidence of neuroprotective effect against hypoxic neuronal injury. This study was designed to examine dose response and to estimate therapeutic window of BAPTA-AM for the recovery from hypoxia in vitro. Electrophysiological studies were made in CA1 neurons in rat hippocampal slices which were superfused with artificial cerebrospinal fluid(ASCF) in tissue chamber. Hypoxia was induced by replacement of 95% N2+5% CO2 from 95% O2+5% CO2 for 20min. Recovery from hypoxic injury was evaluated by using a percentage recovery of population spike. BAPTA-AM in concentration of 1, 10 and 50micrometer were administered to the artificial cerebrospinal fluid(ASCF) for 2 hours prior to hypoxia, simultaneous with hypoxia and after hypoxia. The experimental specimens were divided to seven groups and each group was compared to control ASCF group. Recovery of population spike after hypoxia was about 70% in control ASCF group, which was mild type hypoxic injury. BAPTA-AM in 10 micrometer concentration, when given just prior to hypoxia, enhanced recovery of poppulation spikes at 15 and 30min following reoxygenation(p<0.05), in comparison with control ASCF. BAPTA-AM had no neuroprotective acitvity when given after the onset of hypoxia. Also, BAPTA-AM in 1 and 50 micrometer concentration did not accentuate recovery of population spike after hypoxia. Dose response curve was inverted U-shape and the response was maximun in 10 micrometer concentration of BAPTA-AM.