Discipline of Pharmacology, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales 2006, Australia.
Published: May 2020
AI Article Synopsis
Article Abstract
Glycine neurotransmission in the dorsal horn of the spinal cord plays a key role in regulating nociceptive signaling, but in chronic pain states reduced glycine neurotransmission is associated with the development of allodynia and hypersensitivity to painful stimuli. This suggests that restoration of glycine neurotransmission may be therapeutic for the treatment of chronic pain. Glycine transporter 2 inhibitors have been demonstrated to enhance glycine neurotransmission and provide relief from allodynia in rodent models of chronic pain. In recent years, photoswitchable compounds have been developed to provide the possibility of controlling the activity of target proteins using light. In this study we have developed a photoswitchable noncompetitive inhibitor of glycine transporter 2 that has different affinities for the transporter at 365 nm compared to 470 nm light.
KCC2 is CNS neuron-specific chloride extruder, essential for the establishment and maintenance of the transmembrane chloride gradient, thereby enabling synaptic inhibition within the CNS. Herein, we highlight KCC2 hypofunction as a fundamental and conserved pathology contributing to neuronal circuit excitation/inhibition (E/I) imbalances that underly epilepsies, chronic pain, neuro-developmental/-traumatic/-degenerative/-psychiatric disorders. Indeed, downstream of both acquired and genetic factors, multiple pathologies (e.
Schizophrenia (SCZ) is a severe psychotic disorder characterized by a disruption in glutamatergic NMDA receptor (NMDAR)-mediated neurotransmission. Compelling evidence has revealed that NMDAR activation is not limited to L-glutamate, L-aspartate, and glycine since other free amino acids (AAs) in the atypical D-configuration, such as D-aspartate and D-serine, also modulate this class of glutamatergic receptors. Although dysregulation of AAs modulating NMDARs has been previously reported in SCZ, it remains unclear whether distinct variations of these biomolecules occur during illness progression from at-risk premorbid to clinically manifest stage.
In many neurological conditions, early-stage neural circuit adaptation preserves relatively normal behavior. In some diseases, spinal motoneurons progressively degenerate yet movement remains initially preserved. This study investigates whether these neurons and associated microcircuits adapt in a mouse model of progressive motoneuron degeneration.
Ketamine is widely used to probe cognitive functions relying on the properties of methyl-D-aspartate receptor (NMDAR) synaptic transmission. Numerous works have proved that cognitive performance and adjustments in the decision or perceptual domains are affected after ketamine injection in general circulation of primates. Here, we take advantage of that in the brain stem; horizontal saccade deceleration is controlled by glycine-NMDAR-gated current, while gamma-aminobutyric acid (GABA) current controls vertical deceleration to demonstrate that despite general circulation level manipulation of NMDAR synaptic transmission, the kinematic of the saccade appeared to be in the motor brainstem generator circuit differentially maintained.
Tranexamic acid (TXA) is an antifibrinolytic drug widely used to reduce blood loss in major surgeries and trauma patients, thus reducing morbimortality. In recent years, clinical indications for TXA have expanded, including many off-label uses. This broad use has led to an increased incidence of reported side effects and administration errors with serious neurological and cardiovascular outcomes, such as seizures, myoclonus, and arrhythmias.
