The gamma-aminobutyric acid(B) (GABA(B)) receptor was first demonstrated on presynaptic terminals where it serves as an autoreceptor and also as a heteroreceptor to influence transmitter release by suppressing neuronal Ca(2+) conductance. Subsequent studies showed the presence of the receptor on postsynaptic neurones where activation produces an increase in membrane K(+) conductance and associated neuronal hyperpolarization. (-)-Baclofen is a highly selective agonist for GABA(B) receptors, whereas the established GABA(A) receptor antagonists, bicuculline and picrotoxin, do not block GABA(B) receptors. The receptor is G(i)/G(o) protein-coupled with mixed effects on adenylate cyclase activity. The receptor comprises a heterodimer with similar subunits currently designated 1 and 2. These subunits are coupled via coiled-coil domains at their C termini. The evidence for splice variants is critically reviewed. Thus far, no unique pharmacological or functional properties have been assigned to either subunit or the variants. The emergence of high-affinity antagonists for GABA(B) receptors has enabled a synaptic role to be established. However, the antagonists have generally failed to establish the existence of pharmacologically distinct receptor types within the GABA(B) receptor class. The advent of GABA(B1) knockout mice has also failed to provide support for multiple receptor types.

https://pharmrev.aspetjournals.org/content/pharmrev/54/2/247.full.pdf

International Union of Pharmacology. XXXIII. Mammalian γ-Aminobutyric AcidB Receptors: Structure and Function

A physiological role for GABAB receptors and the effects of baclofen in the mammalian central nervous system.

Cognitive impairment in Down syndrome (DS) is characterized by deficient learning and memory. Mouse genetic models of DS exhibit impaired cognition in hippocampally mediated behavioral tasks and reduced synaptic plasticity of hippocampal pathways. Enhanced efficiency of GABAergic neurotransmission was implicated in those changes. We have recently shown that signaling through postsynaptic GABA(B) receptors is significantly increased in the dentate gyrus of Ts65Dn mice, a genetic model of DS. Here we examined a role for GABA(B) receptors in cognitive deficits in DS by defining the effect of selective GABA(B) receptor antagonists on behavior and synaptic plasticity of adult Ts65Dn mice. Treatment with the GABA(B) receptor antagonist CGP55845 restored memory of Ts65Dn mice in the novel place recognition, novel object recognition, and contextual fear conditioning tasks, but did not affect locomotion and performance in T-maze. The treatment increased hippocampal levels of brain-derived neurotrophic factor, equally in 2N and Ts65Dn mice. In hippocampal slices, treatment with the GABA(B) receptor antagonists CGP55845 or CGP52432 enhanced long-term potentiation (LTP) in the Ts65Dn DG. The enhancement of LTP was accompanied by an increase in the NMDA receptor-mediated component of the tetanus-evoked responses. These findings are evidence for a contribution of GABA(B) receptors to changes in hippocampal-based cognition in the Ts65Dn mouse. The ability to rescue cognitive performance through treatment with selective GABA(B) receptor antagonists motivates studies to further explore the therapeutic potential of these compounds in people with DS.

https://www.jneurosci.org/content/jneuro/32/27/9217.full.pdf

Deficits in Cognition and Synaptic Plasticity in a Mouse Model of Down Syndrome Ameliorated by GABAB Receptor Antagonists

Despite a strong preclinical rationale for targeting the insulin-like growth factor (IGF) axis in cancer, clinical studies of IGF-1 receptor (IGF-1R)-targeted monotherapies have been largely disappointing, and any potential success has been limited by the lack of validated predictive biomarkers for patient enrichment. A large body of preclinical evidence suggests that the key role of the IGF axis in cancer is in driving treatment resistance, via general proliferative/survival mechanisms, interactions with other mitogenic signaling networks, and class-specific mechanisms such as DNA damage repair. Consequently, combining IGF-targeted agents with standard cytotoxic agents, other targeted agents, endocrine therapies, or immunotherapies represents an attractive therapeutic approach. Anti-IGF-1R monoclonal antibodies (mAbs) do not inhibit IGF ligand 2 (IGF-2) activation of the insulin receptor isoform-A (INSR-A), which may limit their anti-proliferative activity. In addition, due to their lack of specificity, IGF-1R tyrosine kinase inhibitors are associated with hyperglycemia as a result of interference with signaling through the classical metabolic INSR-B isoform; this may preclude their use at clinically effective doses. Conversely, IGF-1/IGF-2 ligand-neutralizing mAbs inhibit proliferative/anti-apoptotic signaling via IGF-1R and INSR-A, without compromising the metabolic function of INSR-B. Therefore, combination regimens that include these agents may be more efficacious and tolerable versus IGF-1R-targeted combinations. Herein, we review the preclinical and clinical experience with IGF-targeted therapies to-date, and discuss the rationale for future combination approaches as a means to overcome treatment resistance.

/pdf/insulin-like-growth-factor-igf-pathway-targeting-in-cancer-yq9ro9z9b2.pdf

Insulin-Like Growth Factor (IGF) Pathway Targeting in Cancer: Role of the IGF Axis and Opportunities for Future Combination Studies.

Opposite effects of GABAB receptor antagonists on absences and convulsive seizures.

The actions of orally active GABAB receptor antagonists on GABAergic transmission in vivo and in vitro.

Increased acetylcholine and quisqualate responsiveness after blockade of GABAB receptors.

The introduction of MAPK pathway inhibitors paved the road for significant advancements in the treatment of BRAF-mutant (BRAF(MUT)) melanoma. However, even BRAF/MEK inhibitor combination therapy has failed to offer a curative treatment option, most likely because these pathways constitute a codependent signaling network. Concomitant PTEN loss of function (PTEN(LOF)) occurs in approximately 40% of BRAF(MUT) melanomas. In this study, we sought to identify the nodes of the PTEN/PI3K pathway that would be amenable to combined therapy with MAPK pathway inhibitors for the treatment of PTEN(LOF)/BRAF(MUT) melanoma. Large-scale compound sensitivity profiling revealed that PTEN(LOF) melanoma cell lines were sensitive to PI3Kβ inhibitors, albeit only partially. An unbiased shRNA screen (7,500 genes and 20 shRNAs/genes) across 11 cell lines in the presence of a PI3Kβ inhibitor identified an adaptive response involving the IGF1R-PI3Kα axis. Combined inhibition of the MAPK pathway, PI3Kβ, and PI3Kα or insulin-like growth factor receptor 1 (IGF1R) synergistically sustained pathway blockade, induced apoptosis, and inhibited tumor growth in PTEN(LOF)/BRAF(MUT) melanoma models. Notably, combined treatment with the IGF1R inhibitor, but not the PI3Kα inhibitor, failed to elevate glucose or insulin signaling. Taken together, our findings provide a strong rationale for testing combinations of panPI3K, PI3Kβ + IGF1R, and MAPK pathway inhibitors in PTEN(LOF)/BRAF(MUT) melanoma patients to achieve maximal response.

/pdf/maximizing-the-efficacy-of-mapk-targeted-treatment-in-3cm1wb2vf4.pdf

Maximizing the Efficacy of MAPK-Targeted Treatment in PTENLOF/BRAFMUT Melanoma through PI3K and IGF1R Inhibition.

Abstract P137: SGLT2 inhibition improves BYL719-induced hyperglycemia and hyperinsulinemia in rat pre-clinical models

Neben ihrer klassischen Verwendung als Antiepileptika werden Carbamazepin und Valproat seit einigen Jahren auch erfolgreich zur Behandlung affektiver Krankheiten eingesetzt; vor allem sind akut-antimanische und langzeit-prophylaktische Wirkungen bei bipolar-affektiven Storungen beschrieben worden [2, 7]. Obwohl beide Praparate seit Jahren untersucht werden, ist ihr Wirkmechanismus ungeklart. Wir beabsichtigen hier lediglich einen kurzen Abris des aktuellen Wissensstandes wiederzugeben, wo¬bei wir zahlreiche Befunde aus Platzgrunden nicht berucksichtigen. Drei wichtige, potentielle Wirkungsorte werden diskutiert. Es sind dies: 1. Interaktionen mit Ionenkanalen, 2. die Affinitat zu bestimmten Rezeptortypen und 3. die Beeinflussung von Neurotransmittern.

Neuronale Wirkungsmechanismen von Carbamazepin und Valproat

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