Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of alpha 6 GABA(A) receptors

gamma-Aminobutyric acid type A (GABA(A)) receptors containing the alpha 6 subunit are located in trigeminal ganglia, and their reduction by small interfering RNA increases inflammatory temporomandibular and myofascial pain in rats. We thus hypothesized that enhancing their activity may help in neuropathic syndromes originating from the trigeminal system. Here, we performed a detailed electrophysiological and pharmacokinetic analysis of two recently developed deuterated structurally similar pyrazoloquinolinone compounds. DK-I-56-1 at concentrations below 1 mu M enhanced gamma-aminobutyric acid (GABA) currents at recombinant rat alpha 6 beta 3 gamma 2, alpha 6 beta 3 delta and alpha 6 beta 3 receptors, whereas it was inactive at most GABA(A) receptor subtypes containing other alpha subunits. DK-I-87-1 at concentrations below 1 mu M was inactive at alpha 6-containing receptors and only weakly modulated other GABA(A) receptors investigated. Both plasma and brain tissue kinetics of DK-I-56-1 were relatively slow, with half-lives of 6 and 13 hr, respectively, enabling the persistence of estimated free brain concentrations in the range 10-300 nM throughout a 24-hr period. Results obtained in two protocols of chronic constriction injury of the infraorbital nerve in rats dosed intraperitoneally with DK-I-56-1 during 14 days after surgery or with DK-I-56-1 or DK-I-87-1 during 14 days after trigeminal neuropathy were already established, demonstrated that DK-I-56-1 but not DK-I-87-1 significantly reduced the hypersensitivity response to von Frey filaments. Significance Neuropathic pain induced by trigeminal nerve damage is poorly controlled by current treatments. DK-I-56-1 that positively modulates alpha 6 GABA(A) receptors is appropriate for repeated administration and thus may represent a novel treatment option against the development and maintenance of trigeminal neuropathic pain

Diversity regained: Precautionary approaches to COVID-19 as a phenomenon of the total environment

As COVID-19 emerged as a phenomenon of the total environment, and despite the intertwined and complex relationships that make humanity an organic part of the Bio- and Geospheres, the majority of our responses to it have been corrective in character, with few or no consideration for unintended consequences which bring about further vulnerability to unanticipated global events. Tackling COVID-19 entails a systemic and precautionary approach to human-nature relations, which we frame as regaining diversity in the Geo-, Bio-, and Anthropospheres. Its implementation requires nothing short of an overhaul in the way we interact with and build knowledge from natural and social environments. Hence, we discuss the urgency of shifting from current to precautionary approaches to COVID-19 and look, through the lens of diversity, at the anticipated benefits in four systems crucially affecting and affected by the pandemic: health, land, knowledge and innovation. Our reflections offer a glimpse of the sort of changes needed, from pursuing planetary health and creating more harmonious forms of land use to providing a multi-level platform for other ways of knowing/understanding and turning innovation into a source of global public goods. These exemplary initiatives introduce and solidify systemic thinking in policymaking and move priorities from reaction-based strategies to precautionary framework

Extrasynaptic GABAA [GABA tief A] receptors in neurological disease

[gamma]-aminobuttersäure (GABA) gehört zu den komplexesten Neurotransmittern im Gehirn. Dieser Umstand wird deutlich, wenn man die Diversität der Rezeptoren, deren Verteilung in verschiedenen Hirnregionen, deren Bedeutung in zahlreichen neurologischen Erkrankungen und die vielfältige Pharmakologie betrachtet. GABA wirkt zumeist hemmend durch Aktivierung von GABA(A) Rezeptoren, welche ligandengesteuerte Chloridkanäle sind, und GABA(B) Rezeptoren, welche G-Protein-gekoppelte Rezeptoren sind. Phasische und tonische Übertragung stellen die beiden hauptsächlichen Funktonsweisen von GABA(A) Rezeptoren dar. Letztere erhielt zunehmende Beachtung seit der ersten Beschreibung vor etwa 20 Jahren. Tonische GABAerge Übertragung wird durch eine spezifische Untergruppe von GABA(A) Rezeptoren mediiert, welche typischer Weise [delta] oder [alpha]5 Untereinheiten im Rezeptor-Pentamer tragen, und an der extrasynaptischen Zelloberfläche positioniert sind.^ Sie übt einen starken hemmenden Einfluss auf die Erregbarkeit von Nervenzellen aus, und moduliert deren Input-Output-Funktion. Viele Substanzen sind in der Lage, die Funktion extrasynaptischer GABA(A) Rezeptoren zu modulieren, darunter Neurosteroide, Barbiturate, Anästhetika und Ethanol. Zu den [delta]-spezifischen Substanzen gehören etwa der Agonist Gaboxadol und der positive allosterische Modulator DS2. Die vorliegende Arbeit zeigt, dass der Kv7 K+-Kanal Aktivator Retigabin ebenfalls ein subtyp-spezifischer Modulator von GABA(A) Rezeptoren ist. In einer Konzentration von 10 [mu]M verstärkt Retigabin maximale GABA-Ströme in GABA(A) Rezeptoren, welche eine [delta]-Untereinheit beinhalten, während [gamma]-GABA(A) Rezeptoren unbeeinflusst bleiben. Die Verstärkung von [delta]-GABA(A) Rezeptoren findet bereits bei therapeutisch erreichbaren Retigabin-Konzentrationen statt.^ DarÜberhinaus konnte in kultivierten Hippokampus-Neuronen gezeigt werden, dass Retigabin in der Lage ist, eine gesteigerte neuronale Aktivität im Sinne eines epileptischen Anfalles zu reduzieren, selbst unter Anwesenheit des Kv7 K+-Kanal Blockers XE991. Dieser Umstand legt nahe, dass die Aktivität an [delta]-GABA(A) Rezeptoren einen Beitrag zur anti-epileptischen Wirkung von Retigabin leistet. Seit Kurzem gibt es Hinweise darauf, dass tonische GABAerge Übertragung auch eine Rolle in Chorea Huntington spielt, einer autosomal-dominanten, monogenetischen, neurodegenerativen Erkrankung geprägt von einer typischen Trias bestehend aus motorischen, kognitiven und psychiatrischen Symptomen. Insbesondere die GABAergen Projektionsneurone des Striatum sind bei dieser Erkrankung von der Neurodegeneration betroffen.^ In zwei gängigen Mausmodellen von Chorea Huntington hat sich bei deutlich symptomatischen Tieren gezeigt, dass diese bestimmte Nervenzell-Population unter verringerter tonischer GABAerger Hemmung steht. Darauf aufbauend wird in der vorliegenden Arbeit gezeigt, dass auch ein weiteres Modell - das BACHD Mausmodell, welches das komplette humane mutierte Huntingtin-Gen als transgenes Konstrukt exprimiert - verringerte tonische GABA-Ströme an striatalen Projektionsneuronen aufweist. Dies ist außerdem bereits bei jungen, relativ asymptomatischen Tieren der Fall, welche noch keinen Zellverlust im Striatum erkennen lassen. Dadurch liegt der Schluss nahe, dass die verringerte tonische GABAerge Hemmung einen prädisponierenden Faktor fÜr nachfolgende Neurodegeneration aufgrund von Exzitotoxizität darstellt.^ Es ist daher denkbar, und kann in weiterer Folge Überprüft werden, dass spezifische positive Modulatoren jener [delta]-GABA(A) Rezeptoren, die auf den striatalen Projektionsneuronen vorkommen, einen therapeutischen Nutzen in Chorea Huntington haben könnten.[gamma]-aminobutyric acid (GABA) is one of the most complex transmitters in the brain, in terms of receptor diversity and distribution, disease relevance and pharmacology. GABA is usually inhibitory via its action on GABA(A) receptors, which are ligand-gated Cl--channels, and GABA(B) receptors, which are G-protein-coupled receptors. Among the two modes of operation of GABA(A)Rs, phasic and tonic transmission, the latter has gained increasing interest since its first description some 20 years ago. Tonic GABAergic transmission is mediated by a specific subset of extrasynaptic GABA(A)Rs, usually containing [delta] or [alpha]5 subunits within the receptor pentamer, and exerts powerful control over excitability and the input-output relation of neuronal activity. The list of substances that are able to modulate the function of extrasynaptic GABA(A)Rs includes neurosteroids, barbiturates, anaesthetics and ethanol.^ Compounds that are selective for [delta]-GABA(A)Rs include the agonist gaboxadol and the positive allosteric modulator DS2. Here, it is shown that the Kv7 K+ channel activator retigabine is also a subtype selective modulator of GABA(A)Rs with a unique profile. Most strikingly, at 10 [mu]M, it enhances maximum currents through all [delta]-containing GABA(A)Rs, while it is a null-modulator at [gamma]-containing ones. Retigabine enhances [delta]-GABA(A)Rs already at therapeutic concentrations. Moreover, in cultures of primary hippocampal neurons, retigabine is effective at reducing seizure-like activity even in the presence of the Kv7 K+ channel blocker XE991, suggesting that the [delta]-enhancing properties of retigabine contribute to the antiepileptic activity of the drug.^ Recent evidence has also pointed towards alterations of tonic GABAergic transmission in Huntington's Disease (HD), an autosomal dominant monogenetic neurodegenerative disorder characterised by a typical triad of motor, cognitive and psychiatric symptoms. Specifically, striatal medium spiny neurons (MSNs) are the most vulnerable neuronal cell type in HD, and these cells were shown to be under reduced tonic GABAergic inhibition in two common HD models at symptomatic age. To expand on this finding, it is demonstrated here that also the transgenic, full-length human mutant huntingtin BACHD mouse model exhibits reduced tonic GABA currents on MSNs. Importantly, this alteration is already evident at early, mildly symptomatic stages and throughout the course of the disease, possibly predisposing these cells to excitotoxic damage and degeneration. Therefore, specific positive modulators of [delta]-GABA(A)Rs present on striatal MSNs could possibly be of therapeutic value in HD.submitted by Marco TrevenZsfassung in dt. SpracheWien, Med. Univ., Diss., 2014OeBB(VLID)271253

Epilepsia / The anticonvulsant retigabine is a subtype selective modulator of GABAA receptors

Objective Within its range of therapeutic plasma concentrations, the anticonvulsant retigabine (ezogabine) is believed to selectively act on Kv7 channels. Here, the contribution of specific aminobutyric acid (GABA)A receptor subtypes to the antiseizure effects of retigabine was investigated. Methods Using patchclamp recordings, seizurelike activity, tonic currents, and GABAinduced currents in hippocampal neurons were tested for their sensitivity toward retigabine, as were recombinant GABAA receptors expressed in tsA 201 cells. Results Retigabine reduced seizurelike activity elicited by low Mg2+ in a concentrationdependent manner with half maximal inhibition at 1 m. Seizurelike activity triggered by blocking either Kv7 channels or GABAA receptors was equally reduced by retigabine, but when these channels/receptors were blocked simultaneously, the inhibition was lost. Retigabine (10 m) enhanced bicucullinesensitive tonic currents in hippocampal neurons, but failed to affect GABAevoked currents. However, when receptors involved in phasic GABAergic inhibition were blocked by penicillin, retigabine did enhance GABAevoked currents. In tsA 201 cells expressing various combinations of GABAA receptor subunits, 10 m retigabine enhanced currents through 12, 42, 43, and 62 receptors, but left currents through 122S, 432S, 532S, and 622S receptors unaltered. With receptors, retigabine diminished currents through 12 and 43, but increased currents through 62 receptors. The enhancement of currents through 12 receptors by retigabine was concentration dependent and became significant at 1 m. Significance These results demonstrate that retigabine is a subtype selective modulator of GABAA receptors with preference for extrasynaptic containing receptors; this property may contribute to its broad antiepileptic effectiveness and explain its lack of effect on absence seizures.(VLID)484740

Repeating patterns : Predictive processing suggests an aesthetic learning role of the basal ganglia in repetitive stereotyped behaviors

Recurrent, unvarying, and seemingly purposeless patterns of action and cognition are part of normal development, but also feature prominently in several neuropsychiatric conditions. Repetitive stereotyped behaviors (RSBs) can be viewed as exaggerated forms of learned habits and frequently correlate with alterations in motor, limbic, and associative basal ganglia circuits. However, it is still unclear how altered basal ganglia feedback signals actually relate to the phenomenological variability of RSBs. Why do behaviorally overlapping phenomena sometimes require different treatment approaches−for example, sensory shielding strategies versus exposure therapy for autism and obsessive-compulsive disorder, respectively? Certain clues may be found in recent models of basal ganglia function that extend well beyond action selection and motivational control, and have implications for sensorimotor integration, prediction, learning under uncertainty, as well as aesthetic learning. In this paper, we systematically compare three exemplary conditions with basal ganglia involvement, obsessive-compulsive disorder, Parkinson’s disease, and autism spectrum conditions, to gain a new understanding of RSBs. We integrate clinical observations and neuroanatomical and neurophysiological alterations with accounts employing the predictive processing framework. Based on this review, we suggest that basal ganglia feedback plays a central role in preconditioning cortical networks to anticipate self-generated, movement-related perception. In this way, basal ganglia feedback appears ideally situated to adjust the salience of sensory signals through precision weighting of (external) new sensory information, relative to the precision of (internal) predictions based on prior generated models. Accordingly, behavioral policies may preferentially rely on new data versus existing knowledge, in a spectrum spanning between novelty and stability. RSBs may then represent compensatory or reactive responses, respectively, at the opposite ends of this spectrum. This view places an important role of aesthetic learning on basal ganglia feedback, may account for observed changes in creativity and aesthetic experience in basal ganglia disorders, is empirically testable, and may inform creative art therapies in conditions characterized by stereotyped behaviors.publishe

Childhood‐onset progressive dystonia associated with pathogenic truncating variants in CHD8

International audienceOriginally described as a risk factor for autism, CHD8 loss-of-function variants have recently been associated with a wider spectrum of neurodevelopmental abnormalities. We further expand the CHD8-related phenotype with the description of two unrelated patients who presented with childhood-onset progressive dystonia. Whole-exome sequencing conducted in two independent laboratories revealed a CHD8 nonsense variant in one patient and a frameshift variant in the second. The patients had strongly overlapping phenotypes characterized by generalized dystonia with mild-to-moderate neurodevelopmental comorbidity. Deep brain stimulation led to clinical improvement in both cases. We suggest that CHD8 should be added to the growing list of neurodevelopmental disorder-associated genes whose mutations can also result in dystoniadominant phenotypes

Scientific Reports / Molecular tools for GABAA receptors : High affinity ligands for 1-containing subtypes

-Aminobutyric acid type A (GABAA) receptors are pentameric GABA-gated chloride channels that are, in mammalians, drawn from a repertoire of 19 different genes, namely 1-6, 1-3, 1-3, , , , and 1-3. The existence of this wide variety of subunits as well as their diverse assembly into different subunit compositions result in miscellaneous receptor subtypes. In combination with the large number of known and putative allosteric binding sites, this leads to a highly complex pharmacology. Recently, a novel binding site at extracellular +/ interfaces was described as the site of modulatory action of several pyrazoloquinolinones. In this study we report a highly potent ligand from this class of compounds with pronounced 1-selectivity that mainly lacks -subunit selectivity. It constitutes the most potent 1-selective positive allosteric modulatory ligand with known binding site. In addition, a proof of concept pyrazoloquinolinone ligand lacking the additional high affinity interaction with the benzodiazepine binding site is presented. Ultimately, such ligands can be used as invaluable molecular tools for the detection of 1-containing receptor subtypes and the investigation of their abundance and distribution.(VLID)460736

A randomised controlled trial on effectiveness and feasibility of sport climbing in Parkinson’s disease

Abstract Physical activity is of prime importance in non-pharmacological Parkinson’s disease (PD) treatment. The current study examines the effectiveness and feasibility of sport climbing in PD patients in a single-centre, randomised controlled, semi-blind trial. A total of 48 PD patients without experience in climbing (average age 64 ± 8 years, Hoehn & Yahr stage 2–3) were assigned either to participate in a 12-week sport climbing course (SC) or to attend an unsupervised physical training group (UT). The primary outcome was the improvement of symptoms on the Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale part III (MDS-UPDRS-III). Sport climbing was associated with a significant reduction of the MDS-UPDRS-III (−12.9 points; 95% CI −15.9 to −9.8), while no significant improvement was to be found in the UT (−3.0 points; 95% CI −6.0 to 0.1). Bradykinesia, rigidity and tremor subscales significantly improved in SC, but not in the unsupervised control group. In terms of feasibility, the study showed a 99% adherence of participants to climbing sessions and a drop-out rate of only 8%. No adverse events occurred. This trial provides class III evidence that sport climbing is highly effective and feasible in mildly to moderately affected PD patients

Towards functional selectivity for 632 GABAA receptors: a series of novel pyrazoloquinolinones

Background and Purpose The GABAA receptors are ligandgated ion channels, which play an important role in neurotransmission. Their variety of binding sites serves as an appealing target for many clinically relevant drugs. Here, we explored the functional selectivity of modulatory effects at specific extracellular +/ interfaces, using a systematically varied series of pyrazoloquinolinones. Experimental Approach Recombinant GABAA receptors were expressed in Xenopus laevis oocytes and modulatory effects on GABAelicited currents by the newly synthesized and reference compounds were investigated by the twoelectrode voltage clamp method. Key Results We identified a new compound which, to the best of our knowledge, shows the highest functional selectivity for positive modulation at 632 GABAA receptors with nearly no residual activity at the other x32 (x = 15) subtypes. This modulation was independent of affinity for +/ interfaces. Furthermore, we demonstrated for the first time a compound that elicits a negative modulation at specific extracellular +/ interfaces. Conclusion and Implications These results constitute a major step towards a potential selective positive modulation of certain 6containing GABAA receptors, which might be useful to elicit their physiological role. Furthermore, these studies pave the way towards insights into molecular principles that drive positive versus negative allosteric modulation of specific GABAA receptor isoforms.(VLID)480595