In vitro models for neuropathic pain phenotypic screening in brain therapeutics.

The discovery of brain therapeutics faces a significant challenge due to the low translatability of preclinical results into clinical success. To address this gap, several efforts have been made to obtain more translatable neuronal models for phenotypic screening. These models allow the selection of active compounds without predetermined knowledge of drug targets. In this review, we present an overview of various existing models within the field, examining their strengths and limitations, particularly in the context of neuropathic pain research. We illustrate the usefulness of these models through a comparative review in three crucial areas: i) the development of novel phenotypic screening strategies specifically for neuropathic pain, ii) the validation of the models for both primary and secondary screening assays, and iii) the use of the models in target deconvolution processes.

Theoretical equations of state for a charged fluid.

In this article, we present a molecular thermodynamic study of a system of N particles contained within a volume V and interacting via a hard-core pair potential with an attractive interaction according to the Wolf model for charged systems. This variable-range potential is characterized by three parameters: the repulsive hard-core diameter σ, the energy-well depth ϵ, and the inverse range α; a fourth parameter of the model is a cut-off distance xc that depends on α according to the relation xc = 2/α. Two equations of state (EOSs) are presented and derived from thermodynamic perturbation theory and Monte Carlo (MC) simulation data. The first EOS is given by the standard Zwanzig's high-temperature expansion of the Helmholtz free energy, where the first three perturbation terms a1, a2, and a3 were obtained from MC simulations in the canonical ensemble (NVT) and parameterized as functions of α and the reduced density of particles ρ* = Nσ3/V. The second EOS was obtained from the discrete perturbation theory applied to a discrete representation of the Wolf potential. Results for pressures, internal energies, and isochoric heat capacities are compared to the MC computer simulation data of the Wolf system, including vapor-liquid coexistence curves, for different values of α. Overall, both EOSs give a very good representation of the thermodynamic properties of the Wolf fluid when 0.3 ≤ α ≤ 1.0 and 0.05 ≤ ρ* ≤ 0.8. Since the Yukawa fluid can reproduce information of screened ionic interactions, we discuss the equivalence between the Wolf and Yukawa fluids in the context of equivalent systems in liquid theory.

Decrease of adenylyl cyclase activity and expression by a sigma1 receptor ligand and putative atypical antipsychotic.

We examined whether changes in the adenylyl cyclase system could be induced by the administration of the sigma1 receptor ligand and putative atypical antipsychotic 4-[4-fluorophenyl]-1,2,3,6-tetrahydro-1-[4-[1,-2,4-triazol-1-il]butyl]pyridine citrate) (E-5842). Repeated (21 days) but not acute (2 h) treatment with E-5842 induced a significant decrease in adenylyl cyclase type I immunoreactivity and adenylyl cyclase activity in rat frontal cortex membranes, with less or no effect in other brain regions such as the hippocampus or the striatum. Changes in immunoreactivity were not observed in other adenylyl cyclases (type V/VI). The reported changes, observed only after a chronic treatment, could be related to the mechanism of action of sigma receptor ligands in general or to that of E-5842 in particular and should be taken into account, given the long duration of treatment in psychiatric patients.

Changes in phosphoinositide signalling activity and levels of the alpha subunit of G(q/11) protein in rat brain induced by E-5842, a sigma(1) receptor ligand and potential atypical antipsychotic.

Changes in the phosphoinositide (PPI) signal transduction system induced by E-5842, a new sigma(1) (sigma(1)) receptor ligand and potential atypical antipsychotic, were studied in the rat frontal cortex, hippocampus and striatum. Acute treatment with E-5842 increased phospholipase C (PLC) activity in the striatum and the hippocampus. Chronic treatment with E-5842 induced an increase in the activity of PLC in the frontal cortex and the striatum. Similar up-regulation of the activity of the enzyme was also observed in rat frontal cortex membranes in presence of GTPgammaS. After chronic treatment with E-5842, it was also observed a significant increase of the immunoreactivity levels of G(q/11)alpha in the frontal cortex. Our results suggest that part of the antipsychotic effects of E-5842 could be related to the regulation of the PPI signal transduction pathway, especially after a prolonged treatment.