Pharmacodynamics of Memantine: An Update

Memantine received marketing authorization from the European Agency for the Evaluation of Medicinal Products (EMEA) for the treatment of moderately severe to severe Alzheimer´s disease (AD) in Europe on 17th May 2002 and shortly thereafter was also approved by the FDA for use in the same indication in the USA. Memantine is a moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with strong voltage-dependency and fast kinetics. Due to this mechanism of action (MOA), there is a wealth of other possible therapeutic indications for memantine and numerous preclinical data in animal models support this assumption. This review is intended to provide an update on preclinical studies on the pharmacodynamics of memantine, with an additional focus on animal models of diseases aside from the approved indication. For most studies prior to 1999, the reader is referred to a previous review [196]

In-medium chiral SU(3) dynamics and hypernuclear structure

A previously introduced relativistic energy density functional, successfully applied to ordinary nuclei, is extended to hypernuclei. The density-dependent mean field and the spin-orbit potential are consistently calculated for a $\Lambda$ hyperon in the nucleus using the SU(3) extension of in-medium chiral perturbation theory. The leading long range $\Lambda N$ interaction arises from kaon-exchange and $2\pi$-exchange with $\Sigma$ hyperon in the intermediate state. Scalar and vector mean fields reflecting in-medium changes of the quark condensates are constrained by QCD sum rules. The model, applied to oxygen as a test case, describes spectroscopic data in good agreement with experiment. In particular, the smallness of the $\Lambda$ spin-orbit interaction finds a natural explanation in terms of an almost complete cancellation between scalar-vector background contributions and long-range terms generated by two-pion exchange.Comment: 10 pages, 2 figures, elsart class. Minor revision

Nuclei, Superheavy Nuclei and Hypermatter in a chiral SU(3)-Modell

A model based on chiral SU(3)-symmetry in nonlinear realisation is used for the investigation of nuclei, superheavy nuclei, hypernuclei and multistrange nuclear objects (so called MEMOs). The model works very well in the case of nuclei and hypernuclei with one Lambda-particle and rules out MEMOs. Basic observables which are known for nuclei and hypernuclei are reproduced satisfactorily. The model predicts Z=120 and N=172, 184 and 198 as the next shell closures in the region of superheavy nuclei. The calculations have been performed in self-consistent relativistic mean field approximation assuming spherical symmetry. The parameters were adapted to known nuclei.Comment: 19 pages, 11 figure

Warm strange hadronic matter in an effective model with a weak Y-Y interaction

An effective model is used to study the equation of state of warm strange hadronic matter with nucleons, Lambda-hyperons, Xi-hyperons, sigmastar and phi. In the calculation, a newest weak Y-Y interaction deduced from the recent observation of a He double hypernucleus is adopted. Employing this effective model, the results with strong Y-Y interaction and weak Y-Y interaction are compared.Comment: 9 pages, 9 figure

Regionally Distinct N -Methyl-D-Aspartate Receptors Distinguished by Quantitative Autoradiography of [ 3 H]MK-801 Binding in Rat Brain

Quantitative autoradiography of [ 3 H]MK-801 binding was used to characterize regional differences in N -methyl-d-aspartate (NMDA) receptor pharmacology in rat CNS. Regionally distinct populations of NMDA receptors were distinguished on the basis of regulation of [ 3 H]MK-801 binding by the NMDA antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). CPP inhibited [ 3 H]MK-801 binding in outer cortex (OC) and medial cortex (MC) with apparent K i values of 0.32-0.48 Μ M , whereas in the medial striatum (MS), lateral striatum (LS), CA1, and dentate gyrus (DG) of hippocampus, apparent K i values were 1.1-1.6 Μ M . In medial thalamus (MT) and lateral thalamus (LT) the apparent K i values were 0.78 Μ M . In the presence of added glutamate (3 Μ M ), the relative differences in apparent K i values between regions maintained a similar relationship with the exception of the OC. Inhibition of [ 3 H]MK-801 binding by the glycine site antagonist 7-chlorokynurenic acid (7-ClKyn) distinguished at least two populations of NMDA receptors that differed from populations defined by CPP displacement. 7-ClKyn inhibited [ 3 H]MK-801 binding in OC, MC, MS, and LS with apparent K i values of 6.3-8.6 Μ M , whereas in CA1, DG, LT, and MT, K i values were 11.4-13.6 Μ M . In the presence of added glycine (1 Μ M ), the relative differences in apparent K i values were maintained. Under conditions of differential receptor activation, regional differences in NMDA receptor pharmacology can be detected using [ 3 H]MK-801 binding.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65616/1/j.1471-4159.1993.tb03295.x.pd

Hyperon-hyperon interactions and properties of neutron matter

We present results from Brueckner-Hartree-Fock calculatons for beta stable neutron star matter with nucleonic and hyperonic degress degrees of freedom, employing the most recent parametrizations of the baryon-baryon interaction of the Nijmegen group. It is found that the only strange baryons emergin in beta stable matter up to total barionic densities of 1.2 fm^-3 are $\Sigma^-$ and $\Lambda$. The corresponding equations of state are then used to compute properties of neutron stars such as masses and radii.Comment: 27 pages, LateX, includes 8 PostScript figures, (submitted to PRC

Neutron Star Constraints on the H Dibaryon

We study the influence of a possible H dibaryon condensate on the equation of state and the overall properties of neutron stars whose population otherwise contains nucleons and hyperons. In particular, we are interested in the question of whether neutron stars and their masses can be used to say anything about the existence and properties of the H dibaryon. We find that the equation of state is softened by the appearance of a dibaryon condensate and can result in a mass plateau for neutron stars. If the limiting neutron star mass is about that of the Hulse-Taylor pulsar a condensate of H dibaryons of vacuum mass 2.2 GeV and a moderately attractive potential in the medium could not be ruled out. On the other hand, if the medium potential were even moderately repulsive, the H, would not likely exist in neutron stars. If neutron stars of about 1.6 solar mass were known to exist, attractive medium effects for the H could be ruled out. Certain ranges of dibaryon mass and potential can be excluded by the mass of the Hulse-Taylor pulsar which we illustrate graphically.Comment: Revised by the addition of a figure showing the region of dibaryon mass and potential excluded by the Hulse-Taylor pulsar. 18 pages, 11 figures, latex (submitted to Phys. Rev. C

Dihyperon in Chiral Colour Dielectric Model

The mass of dihyperon with spin, parity $J^{\pi}=0^{+}$ and isospin $I = 0$ is calculated in the framework of Chiral colour dielectric model. The wave function of the dihyperon is expressed as a product of two colour-singlet baryon clusters. Thus the quark wave functions within the cluster are antisymmetric. Appropriate operators are then used to antisymmetrize inter-cluster quark wave functions. The radial part of the quark wavefunctions are obtained by solving the the quark and dielectric field equations of motion obtained in the Colour dielectric model. The mass of the dihyperon is computed by including the colour magnetic energy as well as the energy due to meson interaction. The recoil correction to the dihyperon mass is incorporated by Peierls-Yoccoz technique. We find that the mass of the dihyperon is smaller than the $\Lambda-\Lambda$ threshold by over 100 MeV. The implications of our results on the present day relativistic heavy ion experiments is discussed.Comment: LaTeX, 13 page

The fraction of activated N-methyl-d-Aspartate receptors during synaptic transmission remains constant in the presence of the glutamate release inhibitor riluzole

Excessive N-methyl-d-aspartate (NMDA) receptor activation is widely accepted to mediate calcium-dependent glutamate excitotoxicity. The uncompetitive, voltage-dependent NMDA receptor antagonist memantine has been successfully used clinically in the treatment of neurodegenerative dementia and is internationally registered for the treatment of moderate to severe Alzheimer′s disease. Glutamate release inhibitors (GRIs) may also be promising for the therapy of some neurodegenerative diseases. During the clinical use of GRIs, it could be questioned whether there would still be a sufficient number of active NMDA receptors to allow any additional effects of memantine or similar NMDA receptor antagonists. To address this question, we determined the fraction of NMDA receptors contributing to postsynaptic events in the presence of therapeutically relevant concentrations of the GRI riluzole (1 μM) using an in vitro hippocampal slice preparation. We measured the charge transfer of pharmacologically isolated excitatory synaptic responses before and after the application of the selective, competitive NMDA receptor antagonist D-AP5 (100 μM). The fraction of activated NMDA receptors under control conditions did not differ from those in the presence of riluzole. It is therefore likely that NMDA receptor antagonists would be able to exert additional therapeutic effects in combination therapy with GRIs