Therapeutically leveraging GABAA receptors in cancer

2021 ◽  
Vol 246 (19) ◽  
pp. 2128-2135
Author(s):  
Debanjan Bhattacharya ◽  
Vaibhavkumar S Gawali ◽  
Laura Kallay ◽  
Donatien K Toukam ◽  
Abigail Koehler ◽  
...  
Keyword(s):  
Gaba Receptors ◽  
Brain Function ◽  
Gaba Receptor ◽  
Krebs Cycle ◽  
Type A ◽  
Therapeutic Benefit ◽  
Disease States ◽  
The Central Nervous System ◽  
Pathological Disease ◽  
Gaba Receptor Subunits

γ-aminobutyric acid or GABA is an amino acid that functionally acts as a neurotransmitter and is critical to neurotransmission. GABA is also a metabolite in the Krebs cycle. It is therefore unsurprising that GABA and its receptors are also present outside of the central nervous system, including in immune cells. This observation suggests that GABAergic signaling impacts events beyond brain function and possibly human health beyond neurological disorders. Indeed, GABA receptor subunits are expressed in pathological disease states, including in disparate cancers. The role that GABA and its receptors may play in cancer development and progression remains unclear. If, however, those cancers have functional GABA receptors that participate in GABAergic signaling, it raises an important question whether these signaling pathways might be targetable for therapeutic benefit. Herein we summarize the effects of modulating Type-A GABA receptor signaling in various cancers and highlight how Type-A GABA receptors could emerge as a novel therapeutic target in cancer.

scholarly journals Tricyclic antipsychotics and antidepressants can inhibit α5-containing GABAA receptors by two  distinct mechanisms            

2022 ◽  
Author(s):  
Konstantina Bampali ◽  
Filip Koniuszewski ◽  
Luca Silva ◽  
Sabah Rehman ◽  
Florian Vogel ◽  
...  
Keyword(s):  
Binding Site ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Receptor Subtypes ◽  
Therapeutic Effects ◽  
Functional Studies ◽  
Tricyclic Compounds ◽  
Electrode Voltage ◽  
Functional Inhibition ◽  
Gaba Receptor Subunits

Background and Purpose: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABA receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal a5 subunit-containing GABA receptors. The purpose of this study is to investigate tricyclic compounds in a5 subunit-containing receptor subtypes. Experimental Approach: Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABA receptor subtypes by two‐electrode voltage‐clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the a5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings. Key Results: We show that the antipsychotic drugs clozapine and chlorpromazine exert functional inhibition on multiple GABA receptor subtypes, including a5-containing ones. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in a5 GABA receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands. Conclusion and Implications: Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The CPZ site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABA receptor subtypes.

scholarly journals Tricyclic antipsychotics and antidepressants can inhibit α5-containing GABAA receptors by two  distinct mechanisms            

2022 ◽  
Author(s):  
Konstantina Bampali ◽  
Filip Koniuszewski ◽  
Luca Silva ◽  
Sabah Rehman ◽  
Florian Vogel ◽  
...  
Keyword(s):  
Binding Site ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Receptor Subtypes ◽  
Therapeutic Effects ◽  
Functional Studies ◽  
Tricyclic Compounds ◽  
Electrode Voltage ◽  
Functional Inhibition ◽  
Gaba Receptor Subunits

Background and Purpose: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABA receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal a5 subunit-containing GABA receptors. The purpose of this study is to investigate tricyclic compounds in a5 subunit-containing receptor subtypes. Experimental Approach: Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABA receptor subtypes by two‐electrode voltage‐clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the a5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings. Key Results: We show that the antipsychotic drugs clozapine and chlorpromazine exert functional inhibition on multiple GABA receptor subtypes, including a5-containing ones. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in a5 GABA receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands. Conclusion and Implications: Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The C C C C C C site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABA receptor subtypes.

scholarly journals Heterogeneous expression of GABA receptor‐like subunits LCCH3 and GRD reveals functional diversity of GABA receptors in the honeybee Apis mellifera

2020 ◽  
Vol 177 (17) ◽  
pp. 3924-3940
Author(s):  
Christopher Henry ◽  
Thierry Cens ◽  
Pierre Charnet ◽  
Catherine Cohen‐Solal ◽  
Claude Collet ◽  
...  
Keyword(s):  
Apis Mellifera ◽  
Functional Diversity ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Heterogeneous Expression

scholarly journals Infectious disease-associated encephalopathies

Critical Care ◽  
2021 ◽  
Vol 25 (1) ◽  
Author(s):  
Maria C. Barbosa-Silva ◽  
Maiara N. Lima ◽  
Denise Battaglini ◽  
Chiara Robba ◽  
Paolo Pelosi ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Cognitive Deficits ◽  
Brain Function ◽  
Cell Activation ◽  
Therapeutic Strategies ◽  
Barrier Dysfunction ◽  
Glial Cell Activation ◽  
The Central Nervous System ◽  
Underlying Mechanisms

AbstractInfectious diseases may affect brain function and cause encephalopathy even when the pathogen does not directly infect the central nervous system, known as infectious disease-associated encephalopathy. The systemic inflammatory process may result in neuroinflammation, with glial cell activation and increased levels of cytokines, reduced neurotrophic factors, blood–brain barrier dysfunction, neurotransmitter metabolism imbalances, and neurotoxicity, and behavioral and cognitive impairments often occur in the late course. Even though infectious disease-associated encephalopathies may cause devastating neurologic and cognitive deficits, the concept of infectious disease-associated encephalopathies is still under-investigated; knowledge of the underlying mechanisms, which may be distinct from those of encephalopathies of non-infectious cause, is still limited. In this review, we focus on the pathophysiology of encephalopathies associated with peripheral (sepsis, malaria, influenza, and COVID-19), emerging therapeutic strategies, and the role of neuroinflammation. Graphic abstract

SURGERY IN A HEMOPHILIAC CHILD WITH INTRACRANIAL HEMORRHAGE

PEDIATRICS ◽  
1961 ◽  
Vol 28 (5) ◽  
pp. 800-804
Author(s):  
John H. Fuerth ◽  
Paul Teng ◽  
Erwin Goldenberg
Keyword(s):  
Los Angeles ◽  
Type A ◽  
Bleeding Tendency ◽  
Laboratory Findings ◽  
Excessive Bleeding ◽  
Surgical Interventions ◽  
Fatal Hemorrhage ◽  
History Of ◽  
System 2 ◽  
The Central Nervous System

THE UNUSUAL bleeding tendency in hemophiliacs has been known since biblical times, and its hazards have been recognized in even such simple surgical procedures as circumcision.1 Perhaps the most dangerous complication of hemophilia is bleeding into the central nervous system.2 It therefore seems worthwhile to report the case of a 2-year-old hemophiliac who survived several intracranial hemorrhages, with two surgical interventions, but who 4 months later had a fourth and fatal hemorrhage. CASE REPORT History D. H. was a 2-year-old hemophiliac with numerous admissions to the Kaiser Foundation Hospital, Los Angeles, for bleeding episodes. He was born at another hospital, was circumcised shortly after birth and had excessive bleeding following this. His first admission was at the age of 1 year for bleeding following a tongue bite. At that time he had an abnormal result of a prothrombin consumption test, with 55% residual prothrombin in the serum. The prothrombin consumption was corrected by fresh normal plasma and barium sulfate adsorbed plasma, but not by serum or plasma from a known hemophiliac type A. The diagnosis of hemophilia type A was thus established. He had two brothers who were investigated and found to be normal. There was no abnormal bleeding tendency on his father's side, but two uncles of his mother and two first cousins were said to be "bleeders." No further details were known. Physical and Laboratory Findings The boy was admitted to the hospital on the evening of October 13, 1957, with a history of vomiting and progressive lethargy of 2 days' duration.

scholarly journals Striatal Neurodegeneration that Mimics Huntington’s Disease Modifies GABA-induced Currents

2018 ◽  
Vol 8 (12) ◽  
pp. 217
Author(s):  
Jorge Flores-Hernández ◽  
Jeanette Garzón-Vázquez ◽  
Gustavo Hernández-Carballo ◽  
Elizabeth Nieto-Mendoza ◽  
Evelyn Ruíz-Luna ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Receptor Subtype ◽  
Medium Spiny Neurons ◽  
Nitropropionic Acid ◽  
Spiny Neurons ◽  
Excitotoxic Damage ◽  
Induced Currents

Huntington’s Disease (HD) is a degenerative disease which produces cognitive and motor disturbances. Treatment with GABAergic agonists improves the behavior and activity of mitochondrial complexes in rodents treated with 3-nitropropionic acid to mimic HD symptomatology. Apparently, GABA receptors activity may protect striatal medium spiny neurons (MSNs) from excitotoxic damage. This study evaluates whether mitochondrial inhibition with 3-NP that mimics the early stages of HD, modifies the kinetics and pharmacology of GABA receptors in patch clamp recorded dissociated MSNs cells. The results show that MSNs from mice treated with 3-NP exhibited differences in GABA-induced dose-response currents and pharmacological responses that suggests the presence of GABAC receptors in MSNs. Furthermore, there was a reduction in the effect of the GABAC antagonist that demonstrates a lessening of this GABA receptor subtype activity as a result of mitochondria inhibition.

scholarly journals Developing the Concepts of Homeostasis, Homeorhesis, Allostasis, Elasticity, Flexibility and Plasticity of Brain Function

NeuroSci ◽  
2021 ◽  
Vol 2 (4) ◽  
pp. 372-382
Author(s):  
Alfredo Pereira
Keyword(s):  
Brain Function ◽  
Complex Dynamics ◽  
Stable States ◽  
Set Point ◽  
Brain Functions ◽  
Temporal Phase ◽  
The Central Nervous System ◽  
Elastic Processes ◽  
And Control ◽  
Flexible Processes

I discuss some concepts advanced for the understanding of the complex dynamics of brain functions, and relate them to approaches in affective, cognitive and action neurosciences. These functions involve neuro-glial interactions in a dynamic system that receives sensory signals from the outside of the central nervous system, processes information in frequency, amplitude and phase-modulated electrochemical waves, and control muscles and glands to generate behavioral patterns. The astrocyte network is in charge of controlling global electrochemical homeostasis, and Hodgkin–Huxley dynamics drive the bioelectric homeostasis of single neurons. In elastic processes, perturbations cause instability, but the system returns to the basal equilibrium. In allostatic processes, perturbations elicit a response from the system, reacting to the deviation and driving the system to stable states far from the homeostatic equilibrium. When the system does not return to a fixed point or region of the state space, the process is called homeorhetic, and may present two types of evolution: (a) In flexible processes, there are previously existing “attractor” stable states that may be achieved after the perturbation, depending on context; (b) In plastic processes, the homeostatic set point(s) is(are) changed; the system is in a process of adaptation, in which the allostatic forces do not drive it back to the previous set point, but project to the new one. In the temporal phase from the deviant state to the recovery of stability, the system generates sensations that indicate if the recovery is successful (pleasure-like sensations) or if there is a failure (pain-like sensations).

scholarly journals QT Dispersion: A Predictor of Outcome Following Acute Neurologic Events

Stroke ◽  
2001 ◽  
Vol 32 (suppl_1) ◽  
pp. 343-343
Author(s):  
Elzbieta J Wirkowski ◽  
Joseph Moonjely ◽  
Todd J Cohen ◽  
Stephanie M Manzella ◽  
Richard H Smith ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Functional Outcome ◽  
Qt Dispersion ◽  
Neurological Injury ◽  
Disease States ◽  
Qt Intervals ◽  
The Central Nervous System ◽  
The Difference ◽  
Adjusted Logistic Regression

P26 BACKGROUND: QT dispersion (QTD) reflects heterogeneity of myocardial repolarization, which is modulated by the central nervous system. Pervious studies have shown increased QTD to be a predictor of adverse outcome in various cardiac disease states. However, the central nervous system effects on QTD and its relation to functional outcomes have not been previously studied in patients with acute neurological events (NE). The objective of this study was to determine whether increased QTD is related to functional outcome in patients with cerebrovascular accidents (CVA) and transient ischemic attacks (TIA). METHODS: We studied 140 consecutive pts. aged 72±10 yrs. (48% male) admitted to our institution with NE from 1/98 to 4/98. QTD was calculated from admission EKG as the difference between maximum and minimum QT intervals. 120 pts. had interpretable EKGs with measurable QT intervals in at least 11 of 12 leads. Three separate functional scales (NIHSS, Barthel, and Rankin) were obtained on admission and discharge were recorded. RESULTS: QTD was higher in pts. with intracerebral hemorrhage as compared to CVA and TIA (70±15 vs. 53±27 vs. 48±31 msecs. p=0.03). Increased QTD was associated with lower functional outcome on all 3 scales (all p<0.05) and with higher mortality (p=0.02). QTD was higher in pts. with congestive heart failure (80±43 vs. 47±24 msecs. p=0.006) and carotid disease (59±32 vs. 46±27 msecs. p=0.045) as compared to those without. QTD was not associated with atrial fibrillation or coronary disease. All patients with TIA survived. On multivariate analysis, other independent predictors of poorer outcome were QTD (OR 1.35, 95% CI 1.08–1.68) and a trend towards age (OR 1.07, 95% CI 0.99–1.16). On age-adjusted logistic regression, mortality increased by an OR 1.28, 95% (CI 1.02–1.61) for every 10 msec increase in QTD. CONCLUSION: QTD is an independent predictor of functional outcome and mortality following acute neurological events. In this setting, QTD reflects acute neurological injury as well as underlying heart disease. The mechanism of these findings merits further study.

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