Restless legs syndrome, also known as Willis-Ekbom disease, is a common neurological condition whose manifestation is affected by complex environmental and genetic interactions Restless legs syndrome can occur on its own, mostly at a young age, or with comorbidities such as cardiovascular disease, diabetes, and arterial hypertension, making it a difficult condition to properly diagnose However, the concept of restless legs syndrome as being two entities, primary or secondary to another condition, has been challenged with genetic data providing further insight into the pathophysiology of the condition Although dopaminergic treatment was formerly the first-line therapy, prolonged use can result in a serious worsening of symptoms known as augmentation Clinical studies on pregabalin, gabapentin enacarbil, oxycodone-naloxone, and iron preparations have provided new treatment options, but most patients still report inadequate long-term management of symptoms Studies of the hypoxic pathway activation and iron deficiency have provided valuable information about the pathophysiology of restless legs syndrome that should now be translated into new, more effective treatments for restless legs syndrome

Comorbidities, treatment, and pathophysiology in restless legs syndrome.

The endocannabinoid system has been placed in the anti-cancer spotlight in the last decade. The immense data load published on its dual role in both tumourigenesis and inhibition of tumour growth and metastatic spread has transformed the cannabinoid receptors CB1 (CB1R) and CB2 (CB2R), as well as other members of the endocannabinoid-like system, into attractive new targets for the treatment of various cancer subtypes. Although the clinical use of cannabinoids has been extensively documented in the palliative setting, clinical trials on their application as anti-cancer drugs are still ongoing. As drug repurposing is significantly faster and more economical than de novo introduction of a new drug into the clinic, there is hope that the existing pharmacokinetic and safety data on the endocannabinoid system ligands will contribute to their successful translation into oncological healthcare. CB1R and CB2R belong to the G protein-coupled receptor (GPCR) superfamily of membrane proteins. GPCRs have been found to form homodimers, heterodimers and higher order oligomers with other GPCRs or non-GPCRs. Currently, several CB1R and CB2R-containing heteromers have been reported and, in cancer cells, CB2R form heteromers with the G protein-coupled receptor 55 (GPR55) and the tyrosine kinase receptor (TKR) human V-Erb-B2 Avian Erythroblastic Leukaemia Viral Oncogene Homolog 2 (HER2). These protein complexes possess unique pharmacological and signalling properties, and their modulation might affect the antitumoural activity of the endocannabinoid system. This review will explore the potential of the endocannabinoid network in the anti-cancer setting as well as the clinical and ethical pitfalls behind it, and will develop on the value of cannabinoid receptor heteromers as potential new targets for anti-cancer therapies and as prognostic biomarkers.

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The Endocannabinoid System as a Target in Cancer Diseases: Are We There Yet?

Multimodal treatment for spinal cord injury: a sword of neuroregeneration upon neuromodulation.

Central pattern generators (CPGs) are generally defined as networks of neurons capable of enabling the production of central commands, specifically controlling stereotyped, rhythmic motor behaviors. Several CPGs localized in brainstem and spinal cord areas have been shown to underlie the expression of complex behaviors such as deglutition, mastication, respiration, defecation, micturition, ejaculation, and locomotion. Their pivotal roles have clearly been demonstrated although their organization and cellular properties remain incompletely characterized. In recent years, insightful findings about CPGs have been made mainly because (1) several complementary animal models were developed; (2) these models enabled a wide variety of techniques to be used and, hence, a plethora of characteristics to be discovered; and (3) organizations, functions, and cell properties across all models and species studied thus far were generally found to be well-preserved phylogenetically. This article aims at providing an overview for non-experts of the most important findings made on CPGs in in vivo animal models, in vitro preparations from invertebrate and vertebrate species as well as in primates. Data about CPG functions, adaptation, organization, and cellular properties will be summarized with a special attention paid to the network for locomotion given its advanced level of characterization compared with some of the other CPGs. Similarities and differences between these networks will also be highlighted.

Central pattern generators in the brainstem and spinal cord: an overview of basic principles, similarities and differences.

Purpose of reviewThis review discusses recent advances in the rehabilitation of motor deficits after traumatic brain injury (TBI) and spinal cord injury (SCI) using neuromodulatory techniques.Recent findingsNeurorehabilitation is currently the only treatment option for long-term improvement of motor

https://www.zora.uzh.ch/id/eprint/177014/1/application-pdf-1.pdf

Enhancing rehabilitation and functional recovery after brain and spinal cord trauma with electrical neuromodulation.

While the role of the ascending dopaminergic system in brain function and dysfunction has been a subject of extensive research, the role of the descending dopaminergic system in spinal cord function and dysfunction is just beginning to be understood. Adenosine plays a key role in the inhibitory control of the ascending dopaminergic system, largely dependent on functional complexes of specific subtypes of adenosine and dopamine receptors. Combining a selective destabilizing peptide strategy with a proximity ligation assay and patch-clamp electrophysiology in slices from male mouse lumbar spinal cord, the present study demonstrates the existence of adenosine A1-dopamine D1 receptor heteromers in the spinal motoneuron by which adenosine tonically inhibits D1 receptor-mediated signaling. A1-D1 receptor heteromers play a significant control of the motoneuron excitability, represent main targets for the excitatory effects of caffeine in the spinal cord and can constitute new targets for the pharmacological therapy after spinal cord injury, motor aging-associated disorders and restless legs syndrome.

Adenosine A 1 -Dopamine D 1 Receptor Heteromers Control the Excitability of the Spinal Motoneuron

Background: The basic motor patterns driving rhythmic limb movements during walking are generatedby networks of neurons called central pattern generators (CPGs). Within motor control systems, neuromodulatorsare necessary for proper and efficient CPG function because they induce or regulate essential componentsof spinal network activity, including firing parameters of CPG neurons and network synaptic strength, allowingthe network to change/adapt and sometimes to even become functional.Methods: The goal of this work is to focus on classical and recent findings addressing the role of neuromodulatorssuch as glutamate, dopamine, acetylcholine and adenosine in eliciting, changing and sometimes terminatingspinal CPG network function in rodents.Results: Neuromodulatory inputs onto CPG locomotor networks have been additionally related to inducing statechanges such as locomotor timing, phasing and speed, and to the induction/maintenance of actual network function.These inputs originate from supraspinal centers such as the brainstem and from intraspinal neurotransmission.The isolated in vitro rodent spinal cord preparation is a powerful model for studies on locomotor networkorganization because of its physiological and anatomical accessibility, as well as the incorporation of varioustransgenic approaches to identify specific neuronal populations. Both roles are accomplished through the actionof neuromodulators on ionotropic and metabotropic receptors mediating synaptic neurotransmission, which canbe used by neurons that are intrinsic or extrinsic components of a CPG network itself.Conclusion: This article has hopefully provided a comprehensive overview of some of the main spinal mechanismsinvolved in the modulatory control of locomotor activity.

Marla Rivera-Oliver

Papers

Adenosine A 1 -Dopamine D 1 Receptor Heteromers Control the Excitability of the Spinal Motoneuron

Neuromodulation of Spinal Locomotor Networks in Rodents