Biomedical subjects

Pierre Le Grevès

Publications and source records attributed to Pierre Le Grevès.

8 recordsLinked to original sources

PubMed2006

Growth hormone replacement in hypophysectomized rats affects spatial performance and hippocampal levels of NMDA receptor subunit and PSD-95 gene transcript levels.

Clinical studies have demonstrated that growth hormone (GH) promotes learning and memory processes in GH-deficient (GHD) patients. In animal studies, GH also influences the N-methyl-D-aspartate (NMDA) receptor system in the hippocampus, an essential component of long-term potentiation (LTP), which is highly involved in memory acquisition. This study was designed to examine the beneficial effects of recombinant human GH (rhGH) on cognitive function in male rats with multiple hormone deficiencies resulting from hypophysectomy (Hx). The performance of an rhGH-treated group and an untreated control group was appraised in the Morris water maze (MWM). The rhGH-treated group performed significantly better in the spatial memory task than the control animals on the second and third trial days. Further training eliminated this difference between the groups. Hippocampal mRNA expression of the NMDA subunits NR1, NR2A and NR2B, insulin-like growth factor type 1 receptor (IGF-1R), and postsynaptic density protein-95 (PSD-95) was then measured in the animals by Northern blot analysis. The results suggest that there may be a relationship between the NMDA receptor subunit mRNA expression levels and learning ability, and that learning is improved by rhGH in Hx rats. Furthermore, a link between MWM performance and PSD-95 was also suggested by this study.

Animals↗

PubMed2005

Endomorphin-1 and endomorphin-2 differentially interact with specific binding sites for substance P (SP) aminoterminal SP1-7 in the rat spinal cord.

Endomorphin-1 (EM-1) and endomorphin-2 (EM-2) represent two opioid active tetrapeptides with high affinity and selectivity for the mu-opioid (MOP) receptor. Both EM-1 and EM-2 exhibit strong inhibition of pain signals in the central nervous system (CNS). In contrast to these compounds, the undecapeptide substance P (SP) facilitates pain influx in the CNS. SP has been implicated in a number of functions in the central nervous system, including pain processing and reward. Its aminoterminal fragment SP1-7 has been shown to modulate several actions of SP in the CNS, the nociceptive effect included. Although the actions of SP1-7 have been known for long no specific receptor for the SP fragment has yet been cloned. In this study, we demonstrate the presence of specific binding sites for the heptapeptide in the rat spinal cord. The binding affinity for unlabeled SP1-7 to the specific sites for the labeled heptapeptide highly exceeded those of SP and other C- or N-terminal fragments thereof. The NK-1, NK-2 and NK-3 receptor ligands [Sar9, Met(O2)11]SP, R396 and senktide, respectively, showed no or negligible binding. Moreover, both EM-1 and EM-2 were found to interact with SP1-7 binding. However, a significant difference in binding affinity between the two opioid active tetrapeptides was observed. As recorded from replacement curves the affinity of EM-2 was 10 times weaker than that for SP1-7 but about 100 times higher than that of EM-1. Among other Tyr-Pro-containing peptides Tyr-MIF-1 but not Tyr-W-MIF-1 exhibited affinity of similar potency as EM-2. These results strengthen the previously observed differences between EM-1 and EM-2 in various functional studies. Moreover, using a cell line (C6) expressing the MOP receptor it was shown that the labeled SP1-7 did not interact with binding to this receptor and no functional response was seen for the SP heptapeptide on the MOP receptor by means of stimulation in the GTPgammaS assay. This suggests that the identified SP1-7 binding sites, with high affinity also for EM-2, are not identical to the MOP receptor and apparently not to any of the known tachykinin receptors.

Animals↗

PubMed2005

Age-related effects of IGF-1 on the NMDA-, GH- and IGF-1-receptor mRNA transcripts in the rat hippocampus.

Insulin-like growth factor-1 (IGF-1) and growth hormone (GH) have been suggested to promote memory and cognitive capabilities. In a recent publication we observed that GH increase the proportion of the NR2B subunit mRNA transcript of the NMDA receptor in rat hippocampus. NR2B has been suggested to be essential for spatial learning and long-term potentiation (LTP). This effect of GH might be IGF-1-mediated or a result of a co-ordination with IGF-1. To test this hypothesis further, we examined the effects of 10 daily s.c. injections of IGF-1 on NMDA receptor subunits (NR1, NR2A, and NR2B), GH receptor (GHR), GH binding protein (GHBP) and type 1 IGF receptor (IGF-1R) gene transcripts in the hippocampus. The NR2B subunit mRNA increased in young (11 weeks) but not in older (14-16 months) rats and the expression of the NR2A mRNA was decreased in both groups. The ratio of NR2B to NR2A is suggested to mirror the potential for synaptic plasticity. In both age groups, IGF-1 treatment resulted in a significant increase of this ratio at transcription level. The GHR mRNA increased in young rats, mimicking the effect of GH, while the IGF-1R mRNA was decreased in the older group of rats after IGF-1 treatment. These results suggest that IGF-1 in many aspects may mediate the actions earlier shown for GH.

Age Factors↗

PubMed2005

Pleiotrophin gene transcription in the rat nucleus accumbens is stimulated by an acute dose of amphetamine.

Pleiotrophin (PTN) is a heparin-binding protein with diverse functions. For example, it stimulates neurite outgrowth, mitogenesis, repair and differentiation, effects that are similar to those of the neurotrophins. The neurotrophins have, in recent years, been implicated as mediators of structural plasticity, suggested to underlie the development of behavioural sensitisation to many drugs of abuse. Since NMDA receptor antagonists inhibit the underlying morphological changes, the mechanisms are thought to be highly dependent on the activation of the NMDA subtype of glutamate receptors. To investigate if PTN has a possible role in structural plasticity, its responsiveness to an acute dose of amphetamine was studied. Amphetamine is a well-characterised inducer of sensitisation. A group of rats was systemically treated with amphetamine (10 mg/kg) and the effect on the PTN gene transcription was studied 4 h later. A separate group of rats was pretreated with the NMDA receptor antagonist MK-801 (0.25 mg/kg) 30 min prior to the administration of amphetamine. Northern blot analysis revealed a significant increase of the PTN transcript after the administration of amphetamine. However, MK-801 pretreatment did not block this effect; in contrast, it further increased PTN mRNA levels. As the response to the two drugs resembles the one earlier reported on the gene expression of brain-derived neurotrophic factor (BDNF), the present results suggest that PTN may be an attractive protein to study further in the field of synaptic plasticity.

Amphetamine↗

PubMed2005

The effect of dehydroepiandrosterone sulfate and allopregnanolone sulfate on the binding of [(3)H]ifenprodil to the N-methyl-d-aspartate receptor in rat frontal cortex membrane.

Neurosteroids have been shown to modulate the N-methyl-d-aspartate (NMDA) receptor function. Dehydroepiandrosterone sulfate (DHEAS) is shown to participate in memory and learning processes as well as preventing glutamate neurotoxicity in hippocampus. In this study we have focused on the modulatory effect of neurosteroids on ifenprodil binding to the NR2B subunit of the NMDA receptor. We show that DHEAS and allopregnanolone sulfate (ALLOPREGS) exert different effects on the [(3)H]ifenprodil binding at 10, 30 or 100 nM, corresponding to physiological concentrations. The effects include changes in the ifenprodil displacement curve, changing it from a one-site fit into a two-site fit leaving B(max), K(d) and K(off) unaffected. Our results indicate that DHEAS and ALLOPREGS induce an allosteric modulation of the NMDA receptor, an observation that might contribute to the understanding of the effects of these neurosteroids.

Animals↗

PubMed2005

Low concentrations of neuroactive steroids alter kinetics of [3H]ifenprodil binding to the NMDA receptor in rat frontal cortex.

The modulatory effects of the two neurosteroids pregnenolone sulphate (PS) and pregnanolone sulphate (3alpha5betaS) on [3H]ifenprodil binding to the N-methyl-D-aspartate (NMDA) receptor in rat frontal cortex were studied. The binding for [3H]ifenprodil itself displayed monophasic kinetics in all experiments. None of the neurosteroids displaced the radioligand from its binding site on the NR2B subunit of the NMDA receptor. However, their continual presence at nanomolar concentrations had significant effects on ligand binding kinetics, interacting through distinct sites in saturation, competition and dissociation experiments. PS at 30 nM enhanced the specific binding to about 150% of that in its absence and enhanced the dissociation rate three-fold indicating a positive modulation of [3H]ifenprodil binding to the NMDA receptor. Furthermore, PS increased Bmax and decreased Kd suggesting that the neurosteroid exposes new [3H]ifenprodil binding sites with altered properties. In contrast, 3alpha5betaS (30 nM) decreased specific [3H]ifenprodil binding to approximately 40% of that determined for the radioligand alone. The presence of 3alpha5betaS at nanomolar concentrations induced biphasic curve fits in saturation, competition as well as dissociation experiments. In conclusion, the present study show that the allosteric modulators PS or 3alpha5betaS change [3H]ifenprodil binding kinetics in a way indicating conformational alteration of its binding site on the NR2B subunit.

Animals↗

PubMed2003

Substance P(1-7) affects the expression of dopamine D2 receptor mRNA in male rat brain during morphine withdrawal.

Previous studies have confirmed an important role of the undecapeptide substance P (SP) in opioid reward and dependence. It is further shown that the SP N-terminal metabolite SP(1-7) may attenuate the intensity of opioid withdrawal in mice. In this study we have investigated the effect of the heptapeptide fragment on the expression of the brain dopamine D2 receptor mRNA and on the withdrawal reaction, as well, in morphine-dependent rats. Male Sprague-Dawley rats were randomly distributed into two groups. Guide cannula was implanted and aimed at the lateral ventricle and animals were subsequently made opioid dependent by two daily injections of morphine (10 mg/kg) for 7 days. Half an hour before naloxone challenge (2 mg/kg) one group of rats received an injection of SP(1-7) (28 nmol per rat) and the other, serving as control, was injected with saline through the cannula. Animals were decapitated 4 h following SP(1-7) or saline injections. The results indicated that the level of the dopamine D2 receptor transcript was significantly reduced by SP(1-7) in nucleus accumbens and frontal cortex but not altered in the striatum. In behavioral tests it was found that the heptapeptide attenuated several somatic withdrawal symptoms. The observed reduction in the receptor transcript in nucleus accumbens and frontal cortex is suggested to reflect an increased dopamine activity in these areas, which in turn may counteract the withdrawal reaction.

Animals↗

PubMed2002

Growth hormone induces age-dependent alteration in the expression of hippocampal growth hormone receptor and N-methyl-D-aspartate receptor subunits gene transcripts in male rats.

Studies were conducted to evaluate the effects of s.c. injected recombinant human growth hormone (GH) on the expression of the gene transcript of N-methyl-D-aspartate receptor subunits type 1 (NR1), type 2A (NR2A), and type 2B (NR2B) in the male rat hippocampus. The GH-induced effects on the expression of hippocampal gene transcripts of GH receptor (GHR) and GH-binding protein were also examined. Male Sprague-Dawley rats, kept in four groups of two different ages, was treated with the hormone or saline during 10 days before decapitation and tissue dissection. Brain tissues collected were analyzed for mRNA content by using the Northern blot technique. The results indicated that in adult young rats (11 weeks of age) the hormone elicited a decrease in the mRNA expression of NR1 but an increase in that of the NR2B subunit. In elderly adult rats (57-67 weeks of age) GH induced an increase in the expression of the hippocampal message for NR1 and NR2A. Meanwhile, the hormone induced a significant up-regulation of the GHR transcript in hippocampus of adult young rats but not in elderly adult rats. It was further found that a significant positive correlation exists between the level of GHR mRNA and the expression of the NR2B subunit transcript in adult young rats. The GH-induced increase in the expression of hippocampal mRNA for the NR2B subunit is compatible with a previously observed memory promoting effect seen for the hormone, because overexpression of this N-methyl-D-aspartate receptor subunit is shown to enhance cognitive capabilities.

Aging↗