Rafael Franco

• PhD
• Molecular Neurobiology laboratory at University of Barcelona

The process of obtaining the position of _Gestor Procesal_ in the Spanish judicial system, a crucial step for career advancement within the civil service, consists of two multiple-choice tests and a written exam. While the selection process aims to ensure merit-based recruitment, our analysis reveals deep structural inconsistencies. Using public ex...

Objectives Human tear analysis holds promise for biomarker discovery, but its clinical utility is hindered by the lack of standardized reference values, limiting interindividual comparisons. This study aimed at developing a protocol for normalizing metabolomic data from human tears, enhancing its potential for biomarker identification. Methods Tea...

The process of obtaining the position of _Gestor Procesal_ in the Spanish judicial system, a crucial step for career advancement within the civil service, consists of two multiple-choice tests and a written exam. While the selection process is designed to ensure merit-based hiring, this study reveals systemic inconsistencies that undermine fairness...

Aim: This study investigates the association between ApoE genotype, plasma cholesteryl ester (CE) levels, and Alzheimer’s disease (AD) status, with a focus on CE(20:4) and CE(22:5) levels as potential indicators of lipid metabolism alterations in AD patients. Methods: Publicly available metabolomics data (DOI: 10.3233/JAD-215448) from 94 AD patient...

Calcium ion (Ca²⁺) homeostasis is crucial for neuron function and neurotransmission. This study focused on the actions mediated by the CB1 receptor (CB1R), the most abundant G protein-coupled receptor (GPCR) in central nervous system (CNS) neurons, over by the AT1R, which is one of the few G protein-coupled CNS receptors able to regulate cytoplasmi...

Class A G protein‐coupled receptors (GPCRs) continue to garner interest for their essential roles in cell signalling and their importance as drug targets. Although numerous drugs in the clinic target these receptors, over 60% GPCRs remain unexploited. Moreover, the adverse effects triggered by the available unbiased GPCR modulators, limit their use...

Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell, influencing behaviors from food choices to emotional memories. These receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental monitoring. The ability of the olfactory system to regene...

The first objective is to highlight the lack of tools to measure whether a given intervention affords neuroprotection in patients with Alzheimer’s or Parkinson’s diseases. A second aim is to present the primary outcome measures used in clinical trials in cohorts of patients with neurodegenerative diseases. The final aim is to discuss whether metabo...

Background and Purpose Allosterism is a regulatory mechanism for GPCRs that can be attained by ligand‐binding or protein–protein interactions with another GPCR. We have studied the influence of the dimer interface on the allosteric properties of the A2A receptor and CB2 receptor heteromer. Experimental Approach We have evaluated cAMP production, p...

A novel concept has been recently put forward in the mind/body interface (https://doi.org/10.37349/ent.2024.00074). The new concept has led to a new word: vitaction. Vitactions offer benefits to the brain and mind comparable to the advantages vitamins provide for the body’s overall health. The field of vitactions is as it was the vitamin field one...

G protein-coupled receptors (GPCRs) exist within a landscape of interconvertible conformational states and in dynamic equilibrium between monomers and higher-order oligomers, both influenced by ligand binding. Here, we have shown that a homobivalent ligand formed by equal chromenopyrazole moieties as pharmacophores, connected by 14 methylene units,...

Bioluminescence and fluorescence resonance energy transfer (BRET and FRET) together with the proximity ligation method revealed the existence of G-protein-coupled receptors, Ionotropic and Receptor tyrosine kinase heterocomplexes, e.g., A2AR–D2R, GABAA–D5R, and FGFR1–5-HT1AR heterocomplexes. Molecular integration takes place through allosteric rece...

Multiple sclerosis (MS) is an autoimmune, inflammatory, and neurodegenerative disease of the central nervous system for which there is no cure, making it necessary to search for new treatments. The endocannabinoid system (ECS) plays a very important neuromodulatory role in the CNS. In recent years, the formation of heteromers containing cannabinoid...

Alterations in olfactory functions are proposed as possible early biomarkers of neurodegenerative diseases. Parkinson’s and Alzheimer’s diseases manifest olfactory dysfunction as a symptom, which is worth mentioning. The alterations do not occur in all patients, but they can serve to rule out neurodegenerative pathologies that are not associated wi...

The medial prefrontal cortex (mPFC) is involved in cognitive functions such as working memory. Astrocytic cannabinoid type 1 receptor (CB1R) induces cytosolic calcium (Ca ²⁺ ) concentration changes with an impact on neuronal function. mPFC astrocytes also express adenosine A 1 and A 2A receptors (A 1 R, A 2A R), being unknown the crosstalk between...

This paper aimed at devising an intelligence-based method to select compounds that can distinguish between open-angle glaucoma patients, type 2 diabetes patients, and healthy controls. Taking the concentration of 188 compounds measured in the aqueous humour (AH) of patients and controls, linear discriminant analysis (LDA) was used to identify the r...

Cannabidiol (CBD) is a phytocannabinoid with potential as a therapy for a variety of diseases. CBD may act via cannabinoid receptors but also via other G-protein-coupled receptors (GPCRs), including the adenosine A2A receptor. Homogenous binding and signaling assays in Chinese hamster ovary (CHO) cells expressing the human version of the A2A recept...

Background The lack of accessible and informative biomarkers results in a delayed diagnosis of Parkinson’s disease (PD), whose symptoms appear when a significant number of dopaminergic neurons have already disappeared. The retina, a historically overlooked part of the central nervous system (CNS), has gained recent attention. It has been discovered...

The family of dopamine D2‐like receptors represents an interesting target for a variety of neurological diseases, e. g. Parkinson's disease (PD), addiction, or schizophrenia. In this study we describe the synthesis of a new set of fluorescent ligands as tools for visualization of dopamine D2‐like receptors. Pharmacological characterization in radio...

Dopamine D1‐like receptors are the most abundant type of dopamine receptors in the central nervous system and, even after decades of discovery, still highly interesting for the study of neurological diseases. We herein describe the synthesis of a new set of fluorescent ligands, structurally derived from D1R antagonist SCH‐23390 and labeled with two...

The renin angiotensin system (RAS) has several components including signaling peptides, enzymes, and membrane receptors. The effort in characterizing this system in the periphery has led to the approval of a class of antihypertensives. Much less is known about RAS in the central nervous system. The production of RAS peptides and the expression of s...

Dopamine D1-like receptors are the most abundant type of dopamine receptors in the central nervous system and, even after decades of discovery, still highly interesting for the study of neurological diseases. We herein describe the synthesis of a new set of fluorescent ligands, structurally derived from D1R antagonist SCH-23390 and labeled with two...

The family of dopamine D2-like receptors represent an interesting target for a variety of neurological diseases, e.g. Parkinson's disease (PD), addiction or schizophrenia. In this study we describe the synthesis of a new set of fluorescent ligands as tools for visualization of dopamine D2-like receptors. Pharmacological characterization in radiolig...

Microglial activation often accompanies the plastic changes occurring in the brain of patients with neurodegenerative diseases. A2A and A3 adenosine receptors have been proposed as therapeutic targets to combat neurodegeneration. RNAseq was performed using samples isolated from lipopolysaccharide/interferon-γ activated microglia treated with SCH 58...

(-)-Δ9-trans-tetrahydrocannabinol (THC), which is the principal psychoactive constituent of Cannabis, mediates its action by binding to two members of the G-protein-coupled receptor (GPCR) family: the cannabinoid CB1 (CB1R) and CB2 (CB2R) receptors. Molecular dynamics simulations showed that the pentyl chain of THC could adopts an I-shape conformat...

Adenosine is a nucleoside with key functions in cell metabolism and in the regulation of several physiological processes in mammals. Its actions are mediated by cell surface adenosine receptors, which belong to class A rhodopsin-like G protein-coupled receptors (GPCRs). Four have been so far identified: A1, A2A, A2B, and A3. The potential of these...

G protein-coupled receptors (GPCRs) are the target of hundreds of approved drugs. Although these drugs were designed to target individual receptors, it is becoming increasingly apparent that GPCRs interact with each other to form heteromers. Approved drug targets are often part of a GPCR heteromer, and therefore new drugs can be developed with hete...

Theobromine is an abundant methylxanthine in cocoa/chocolate. A recent article in BMC Psychiatry concludes that theobromine consumption increases the risk of depression. In our opinion, it is difficult to make a correlation between dietary habits and the risk of depression, the diagnosis of which is not simple to make. Also, it is not easy to asses...

Heteromer formation is unknown for the olfactory family of G protein-coupled receptors (GPCRs). We here identified, in a heterologous system, heteromers formed by the adenosine A2A receptor (A2AR), which is a target for neuroprotection, and an olfactory receptor. A2AR interacts with the receptor family 51, subfamily E, member 2 (OR51E2), the human...

Adenosine is a neuroregulatory nucleoside that acts through four G protein-coupled receptors (GPCRs), A1, A2A, A2B and A3, which are widely expressed in cells of the nervous system. The A2A receptor (A2AR), the GPCR with the highest expression in the striatum, has a similar role to that of receptors for dopamine, one of the main neurotransmitters....

There is no approved drug capable of halting the progression of the most prevalent neurodegenerative disorders, namely Alzheimer’s disease (AD) and Parkinson’s disease (PD). Current therapeutic strategies focus mainly on the inhibition of the formation of protein aggregates and their deposition in the central nervous system. However, after almost a...

Increased adenosine A2A receptor (A2AR) expression and activation underlies a higher incidence of spontaneous calcium release in atrial fibrillation (AF). Adenosine A3 receptors (A3R) could counteract excessive A2AR activation, but their functional role in the atrium remains elusive, and we therefore aimed to address the impact of A3Rs on intracell...

Most neurodegenerative disorders, including the two most common, Alzheimer’s disease (AD) and Parkinson’s disease (AD), course with activation of microglia, the resident innate immune cells of the central nervous system. A3 adenosine receptor (A3R) agonists have been proposed to be neuroprotective by regulating the phenotype of activated microglia....

Background: The N-methyl-D-aspartate receptor (NMDAR) is a target in current treatments for Alzheimer’s disease (AD). The human prion protein (PrPC) has an important role in the pathophysiology of AD. We hypothesized that PrPC modulates NMDA signaling, thus being a process associated with Alzheimer’s disease. Methods: NMDAR signaling was characteri...

A critical aspect of drug development in the therapy of neuropsychiatric diseases is the “Target Problem”, that is, the selection of a proper target after not simply the etiopathological classification but rather the detection of the supposed structural and/or functional alterations in the brain networks. There are novel ways of approaching the dev...

It is of particular interest the potential of cannabinoid and angiotensin receptors as targets in the therapy of Parkinson's disease (PD). While endocannabinoids are neuromodulators that act through the CB1 and CB2 cannabinoid receptors, the renin angiotensin-system is relevant for regulation of the correct functioning of several brain circuits. Re...

The NMDA receptor plays a central role in the CNS excitatory neurotransmission, being also a therapeutic target to combat AD. Receptor function deregulation is, at least in part, responsible for the progression of the disease. In this regard it would be interesting to discover membrane proteins capable of interacting with NMDA receptors, and being...

The tricarboxylic acid (TCA) or Krebs cycle, which takes place in prokaryotic cells and in the mitochondria of eukaryotic cells, is central to life on Earth and participates in key events such as energy production and anabolic processes. Despite its relevance, it is not perceived as tightly regulated compared to other key metabolisms such as glycol...

Molecular dynamic (MD) simulations have become a common tool to study the pathway of ligand entry to the orthosteric binding site of G protein-coupled receptors. Here, we have combined MD simulations and site-directed mutagenesis to study the binding process of the potent JWH-133 agonist to the cannabinoid CB2 receptor (CB2R). In CB2R, the N-termin...

Introduction: Following approval of antagonists in Parkinson's disease therapy, the A2A adenosine receptor (A2AR) is gaining interest as a target to combat a variety of diseases. Areas covered: This review focuses on the therapeutic potential of targeting A2AR inside but also outside the central nervous system, more precisely to combat cardiac a...

Microdialysis assays demonstrated a possible role of orexin in the regulation of amyloid beta peptide (Aß) levels in the hippocampal interstitial fluid in the APP transgenic model. CB2R is overexpressed in activated microglia, showing a neuroprotective effect. These two receptors may interact, forming CB2-OX1-Hets and becoming a new target to comba...

The composition of the aqueous humor of patients with type 2 diabetes is relevant to understanding the underlying causes of eye-related comorbidities. Information on the composition of aqueous humor in healthy subjects is limited due to the lack of adequate controls. To carry out a metabolomics study, 31 samples of aqueous humor from healthy subjec...

Background: Cannabidiol (CBD) is a phytocannabinoid with potential in one of the most prevalent syndromes occurring at birth, the hypoxia of the neonate. CBD targets a variety of proteins, cannabinoid CB2 and serotonin 5HT1A receptors included. These two receptors may interact to form heteromers (CB2–5HT1A-Hets) that are also a target of CBD. Aims:...

The composition of the aqueous humor of patients with glaucoma is relevant to understand the underlying causes of the pathology. Information on the concentration of metabolites and small molecules in the aqueous humor of healthy subjects is limited. Among the causes of the limitations is the lack of healthy controls since, until recently, they were...

The Krebs cycle in cells that contain mitochondria is necessary for both energy production and anabolic processes. In given cell/condition, the Krebs cycle is dynamic but remains at a steady state. In this article, we first aimed at comparing the properties of a closed cycle versus the same metabolism in a linear array. The main finding is that, un...

The free fatty acid FFA3 receptor (FFA3R) belongs to the superfamily of G-protein-coupled receptors (GPCRs). In the intestine and adipose tissue, it is involved in the regulation of energy metabolism, but its function in the brain is unknown. We aimed, first, to investigate the expression of the receptor in the hippocampus of Alzheimer disease (AD)...

There is great interest in identifying natural products that can be approved as nutraceuticals. A good option is to induce transcription of vitagenes, which would lead to increased expression of proteins that provide the means to maintain homeostasis. In fact, the induction of vitagenes is considered relevant during aging, especially if aging is ac...

The classical terms agonists and antagonists for G protein coupled receptors (GPCRs) have often become misleading. Even the biased agonism concept does not describe all the possibilities already demonstrated for GPCRs. The cannabinoid CB2 receptor (CB2R) emerged as a promising target for a variety of diseases. Reasons for such huge potential are ce...

Adenosine (Ado) receptors have been instrumental in the detection of heteromers and other higher-order receptor structures, mainly via interactions with other cell surface G-protein-coupled receptors. Apart from the first report of the A1 Ado receptor interacting with the A2A Ado receptor, there has been more recent data on the possibility that eve...

There is evidence of ghrelinergic-cannabinoidergic interactions in the central nervous system (CNS) that may impact on the plasticity of reward circuits. The aim of this article was to look for molecular and/or functional interactions between cannabinoid CB1 and ghrelin GHS-R1a receptors. In a heterologous system and using the bioluminescence reson...

Background: Etiology of Alzheimer's disease (AD) remain unclear. Different pathological processes have been described, such as phosphorylation of tau protein, amyloid plaques, oxidative stress or neuroinflammation. It has been described that over-activation of the NMDA receptor due to an increase in glutamate levels induces excitotoxicity in neuro...

The free fatty acid FFA3 receptor (FFA3R) belongs to the superfamily of G-protein-coupled receptors (GPCRs). In the intestine and adipose tissue, it is involved in the regulation of energy metabolism but its function in the brain is unknown. We aimed, first, to investigate the expression of the receptor in the hippocampus of Alzheimer disease (AD)...

Background The cannabinoid CB 2 receptor (CB 2 R), which is a target to afford neuroprotection, and N-methyl-D-aspartate (NMDA) ionotropic glutamate receptors, which are key in mediating excitatory neurotransmission, are expressed in both neurons and glia. As NMDA receptors are the target of current medication in Alzheimer’s disease patients and wi...

We have here assessed, using D9-tetrahydrocannabinol (D9-THC) for comparison, the, effect of Δ9-tetrahydrocannabinolic acid (D9-THCA) and of Δ9- Δ9-, tetrahydrocannabivarin (D9-THCV) that is mediated by human versions of CB1, CB2, and CB1-CB2 receptor functional units, expressed in a heterologous system. Binding, to the CB1 and CB2 receptors was ad...

Extracellular adenosine accumulates in the environment of numerous tumors. For years, this fact has fueled preclinical research to determine whether adenosine receptors (ARs) could be the target to fight cancer. The four ARs discovered so far, A1, A2A, A2B and A3, belong to the class A family of G protein-coupled receptors (GPCRs) and all four have...

Countries where only RNA and adenoviral (AV)-based vaccines are available need (urgently) the approval of classic-type (e.g. inactivated) anti-SARS-CoV-2 vaccines; also, specific anti-COVID-19 medication is needed to combat the pandemic. Setting a threshold of 30% (in percentage of vaccinated population), the proportion of new cases versus total ca...

Cannabinoids have been reported as orexigenic, i.e., as promoting food intake that, among others, is controlled by the so-called “hunger” hormone, ghrelin. The aim of this paper was to look for functional and/or molecular interactions between ghrelin GHSR1a and cannabinoid CB2 receptors at the central nervous system (CNS) level. In a heterologous s...

The renin–angiotensin system (RAS) not only plays an important role in controlling blood pressure, but also participates in almost every process to maintain homeostasis in mammals. The occurrence of RAS in the basal ganglia suggests that the system may be targeted to improve the therapy of neurodegenerative diseases. We found heteromers formed by M...

Although antioxidants can act locally to react with an oxidant, oral administration of “antioxidants” is quite useless in treating oxidative stress in tissues. Furthermore, it does not make sense to consider a vitamin as an antioxidant, but vitamin B3 leads to the in vivo formation of compounds that are essential for reducing this stress. A rigorou...

ACE2 plays a pivotal role in the balance between the pro-oxidative pro-inflammatory and the anti-oxidative anti-inflammatory arms of the renin-angiotensin system. Furthermore, ACE2 is the entry receptor for SARS-CoV-2. Clarification of ACE2-related mechanisms is crucial for the understanding of COVID-19 and other oxidative stress and inflammation-r...

Cannabidiol (CBD), the second most abundant of the active compounds found in the Cannabis sativa plant, is of increasing interest because it is approved for human use and is neither euphorizing nor addictive. Here, we design and synthesize novel compounds taking into account that CBD is both a partial agonist, when it binds to the orthosteric site,...

The autism spectrum disorder (ASD) comprises a series of neurological diseases that share serious alterations of the development of the central nervous system. The degree of disability may vary so that Asperger’s may have a relatively normal life and get positions of responsibility in corporations and even in Governments, whereas other ASD sufferer...

Neuronal survival depends on the glia, that is, on the astroglial and microglial support. Neurons die and microglia are activated not only in neurodegenerative diseases but also in physiological aging. Activated microglia, once considered harmful, express two main phenotypes: the pro-inflammatory or M1, and the neuroprotective or M2. When neuroinfl...

The mechanism of nigral dopaminergic neuronal degeneration in Parkinson’s disease (PD) is unknown. One of the pathological characteristics of the disease is the deposition of α-synuclein (α-syn) that occurs in the brain from both familial and sporadic PD patients. This paper constitutes a narrative review that takes advantage of information related...

5-hydroxytryptamine (5-HT) is derived from the essential amino acid L-tryptophan. Although the compound has been studied extensively for its neuronal handling and synaptic actions, serotonin 5-HT receptors can be found extra-synaptically and not only in neurons but in many types of mammalian cells, inside and outside the central nervous system (CNS...

Background and aims: CD4+ T-cells constitute central players in inflammatory bowel diseases (IBD), driving inflammation in the gut-mucosa. Current evidence indicates that CCR9 and the integrin α4β7 are necessary and sufficient to imprint colonic homing on CD4+ T-cells upon inflammation. Interestingly, dopaminergic signalling has been previously in...

Adenosine is one of the most ancient signaling molecules and has receptors in both animals and plants. In mammals there are four specific receptors, A1, A2A, A2B, and A3, which belong to the superfamily of G-protein-coupled receptors (GPCRs). Evidence accumulated in the last 20 years indicates that GPCRs are often expressed as oligomeric complexes...

Methamphetamine is, worldwide, one of the most consumed drugs of abuse. One important side effect is neurodegeneration leading to a decrease in life expectancy. The aim of this paper was to check whether the drug affects one of the receptors involved in neurodegeneration/neuroprotection events, namely the adenosine A2A receptor (A2AR). First, we no...

Suitable in vivo and in vitro models are instrumental for the development of new drugs aimed at improving symptoms or progression of multiple sclerosis (MS). The cuprizone (CPZ)-induced murine model has gained momentum in recent decades, aiming to address the demyelination component of the disease. This work aims at assessing the differential cytot...

Background and Purpose The enzyme α/β‐hydrolase domain containing 6 (ABHD6), a new member of the endocannabinoid system, is a promising therapeutic target against neuronal‐related diseases. However, how ABHD6 activity is regulated is not known. ABHD6 coexists in protein complexes with the brain‐specific carnitine palmitoyltransferase 1C (CPT1C). CP...

Cocaine not only increases brain dopamine levels but also activates the sigma1 receptor (σ1 R) that in turn regulates orexigenic receptor function. Identification of interactions involving dopamine D1 (D1 R), ghrelin (GHS-R1a ), and σ1 receptors have been addressed by biophysical techniques and a complementation approach using interfering peptides....