Javier Fernández-Ruiz

Javier Fernández-Ruiz
Complutense University of Madrid | UCM · Department of Biochemistry and Molecular Biology

PhD in Biochemistry and Molecular Biology

About

366
Publications
41,112
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Introduction
Javier Fernández-Ruiz is a PhD in Biochemistry (1986). He is currently Full Professor in the Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University. Together with his teaching activities in the areas of Neurochemistry and Neurobiology, he has been working during the last 37 years in different diseases of the Central Nervous System, having authored 234 research articles and 42 review articles in international journals. Also 42 chapters in national and international books and 5 international patents. He is currently the Principal Investigator of the “Cannabinoids and Neurological Disorders” research group at the Complutense University, and also at two cooperative networks of excellence research in Spain: CIBERNED and IRYCIS
Additional affiliations
January 2007 - present
July 1986 - October 1986
Southern Illinois University Carbondale
Position
  • PostDoc Position
Description
  • Postdoctoral visiting researcher
January 1981 - present
Complutense University of Madrid
Position
  • Professor (Full)

Publications

Publications (366)
Article
Full-text available
Cannabinoids act as pleiotropic compounds exerting, among others, a broad-spectrum of neuroprotective effects. These effects have been investigated in the last years in different preclinical models of neurodegeneration, with the cannabinoid type-1 (CB1) and type-2 (CB2) receptors concentrating an important part of this research. However, the issue...
Article
Dravet Syndrome (DS) is caused by mutations in the Scn1a gene encoding the α1 subunit of the sodium channel Nav1.1, which results in febrile seizures that progress to severe tonic-clonic seizures and associated comorbidities. Treatment with cannabidiol has been approved for the management of seizures in DS patients, but it appears to be also active...
Article
Full-text available
In the present study, we investigated the involvement of the chaperone protein BiP (also known as GRP78 or Hspa5), a master regulator of intracellular proteostasis, in two mouse models of neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To this end, we used mice bearing partial genetic deletion of the Bi...
Article
Full-text available
The 3-hydroxyquinone derivative of the non-psychotrophic phytocannabinoid cannabigerol, so-called VCE-003.2, and some other derivatives have been recently investigated for neuroprotective properties in experimental models of Parkinson’s disease (PD) in mice. The pharmacological effects in those models were related to the activity on the peroxisome...
Article
Full-text available
Tauopathies are a group of neurodegenerative diseases characterized by the alteration/aggregation of TAU protein, for which there is still no effective treatment. Therefore, new pharmacological targets are being sought, such as elements of the endocannabinoid system (ECS). We analysed the occurrence of changes in the ECS in tauopathies and their im...
Article
Full-text available
The activation of the cannabinoid receptor type‐2 (CB2) afforded neuroprotection in amyotrophic lateral sclerosis (ALS) models. The objective of this study was to further investigate the relevance of the CB2 receptor through investigating the consequences of its inactivation. TDP‐43(A315T) transgenic mice were crossed with CB2 receptor knock‐out mi...
Article
Natural cannabidiol ((-)-CBD) and its derivatives have increased interest for medicinal applications due to their broad biological activity spectrum, including targeting of the cannabinoid receptors type 1 (CB1R) and type 2 (CB2R). Herein, we synthesized the (+)-enantiomer of CBD and its derivative (+)-CBD hydroxypentylester ((+)-CBD-HPE) that show...
Article
Full-text available
Dravet syndrome (DS) is an epileptic syndrome caused by mutations in the Scn1a gene encoding the α1 subunit of the sodium channel Nav1.1, which is associated with febrile seizures that progress to severe tonic-clonic seizures and associated comorbidities. Treatment with cannabidiol has been approved to reduce seizures in DS, but it may also be acti...
Article
Cannabinoids form a singular group of plant‐derived compounds, endogenous lipids and synthetic derivatives with multiple therapeutic effects exerted by targeting different elements of the so‐called endocannabinoid system. One of their therapeutic applications is the preservation of neuronal integrity exerted by attenuating the multiple neurotoxic e...
Article
Given that neuronal degeneration in Alzheimer's disease (AD) is caused by the combination of multiple neurotoxic insults, current directions in the research of novel therapies to treat this disease attempts to design multitarget strategies that could be more effective than the simply use of acetylcholinesterase inhibitors; currently, the most used...
Article
The quinone derivative of the non-psychotropic cannabinoid cannabigerol (CBG), so-called VCE-003.2, has been recently investigated for its neuroprotective properties in inflammatory models of Parkinson’s disease (PD) in mice. Such potential derives from its activity at the peroxisome proliferator-activated receptor-γ (PPAR-γ). In the present study,...
Chapter
Phytocannabinoids, the most singular chemical constituents present in the Cannabis sativa plant, were discovered and characterized up to the 1960s. By contrast, endocannabinoids and their receptors were discovered in the late 1980s and early 1990s, as a result of the efforts to identify the mechanism(s) of action of plant-derived cannabinoids. The...
Article
Full-text available
Single chemical entities with potential to simultaneously interact with two binding sites are emerging strategies in medicinal chemistry. We have designed, synthesized and functionally characterized the first bitopic ligands for the CB 2 receptor. These compounds selectively target CB 2 versus CB 1 receptors. Their binding mode was studied by molec...
Preprint
Full-text available
p>Single chemical entities with potential to simultaneously interact with two binding sites are emerging strategies in medicinal chemistry. We have designed, synthesized and functionally characterized the first bitopic ligands for the CB2 receptor. These compounds selectively target CB2 versus CB1 receptors. Their binding mode was studied by molecu...
Article
Background and purpose: Δ9 -THCA-A, the precursor of Δ9 -THC, is a non-psychotropic phytocannabinoid that shows PPARγ agonistic activity. Herein, we investigated Δ9 -THCA ability to modulate classic cannabinoid receptors (CB1 and CB2 ) and evaluated its anti-arthritis activity. Experimental approach: Cannabinoid receptors binding and intrinsic a...
Article
Full-text available
The antioxidant and CB2 receptor agonist properties of Δ⁹-tetrahydrocannabivarin (Δ⁹-THCV) afforded neuroprotection in experimental Parkinson's disease (PD), whereas its CB1 receptor antagonist profile at doses lower than 5 mg/kg caused anti-hypokinetic effects. In the present study, we investigated the anti-dyskinetic potential of Δ⁹-THCV (adminis...
Article
Full-text available
Pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating disease where no treatment exists, involves the compartmentalization of the nuclear protein TDP-43 (TAR DNA-binding protein 43) in the cytoplasm which is promoted by its aberrant phosphorylation and others posttranslational modifications. Recently, it was reported that CK-1δ (protei...
Article
Full-text available
The phytocannabinoid-based medicine Sativex® is currently marketed for the treatment of spasticity and pain in multiple sclerosis patients and is being investigated for other central and peripheral pathological conditions. It may also serve in Veterinary Medicine for the treatment of domestic animals, in particular for dogs affected by different pa...
Article
Cannabis use induces a plethora of actions on the CNS via its active chemical ingredients, the so-called phytocannabinoids. These compounds have been frequently associated with the intoxicating properties of cannabis preparations. However, not all phytocannabinoids are psychotropic, and, irrespective of whether they are psychotropic or not, they ha...
Article
Full-text available
Background: As a library of cannabinoid (CB) derivatives with (-)-trans-cannabidiol (CBD) or (-)-trans-cannabidivarin (CBDV) scaffold, we synthesized nine novel cannabinoids: 2-hydroxyethyl cannabidiolate (2-HEC), 2-hydroxypentyl cannabidiolate (2-HPC), 2,3-dihydroxypropyl cannabidiolate (GCBD), cyclohexyl cannabidiolate (CHC), n-hexyl-cannabidiola...
Article
Full-text available
In a recent study, we described the neuroprotective properties of VCE-003.2—an aminoquinone derivative of the non-psychotropic phytocannabinoid cannabigerol (CBG)—administered intraperitoneally (i.p.) in an inflammatory model of Parkinson’s disease (PD). We also demonstrated that these properties derive from its activity on the peroxisome prolifera...
Article
Full-text available
Spinocerebellar ataxias (SCAs) are a group of hereditary and progressive neurological disorders characterized by a loss of balance and motor coordination typically associated with cerebellar atrophy. The most prevalent SCA types are all polyQ disorders like Huntington’s disease, sharing the most relevant events in pathogenesis with this basal gangl...
Article
Background: Addiction is a chronic disorder with a high risk of relapse. The neural mechanisms mediating addictions require protein synthesis, which could be relevant for the development of more effective treatments. The mTOR signaling pathway regulates protein synthesis processes that have recently been linked to the development of drug addiction...
Article
Antioxidant phytocannabinoids, synthetic compounds targeting the CB2 receptor, and inhibitors of the endocannabinoid inactivation afforded neuroprotection in SOD1G93A mutant mice, a model of ALS. These effects may involve the activation of PPAR-γ too. Here, we have investigated the neuroprotective effects in SOD1G93A mutant mice of the cannabigerol...
Article
The endocannabinoid system (ECS) exerts a modulatory effect of important functions such as neurotransmission, glial activation, oxidative stress, or protein homeostasis. Dysregulation of these cellular processes is a common neuropathological hallmark in aging and in neurodegenerative diseases of the central nervous system (CNS). The broad spectrum...
Article
Background and purpose: The endocannabinoid system (ECS) as well as PPARγ are relevant targets for the development of novel compounds against fibrotic diseases such as Systemic Sclerosis (SSc), also called Scleroderma. The aim of this study was to characterize VCE-004.3, a novel cannabidiol derivative, and to study it anti-inflammatory and anti-fi...
Conference Paper
Amyotrophic lateral sclerosis (ALS) is a progressive and disabling disease characterized by progressive loss of upper and lower motor neurons, which produces muscle denervation, weakness and atrophy leading lastly to paralysis and death frequently by respiratory failure. In fact, 90% of patients are deceased within 3 years of diagnosis. At present,...
Article
At the beginning of the 21st century, the therapeutic management of neurodegenerative disorders remains a major biomedical challenge, particularly given the worldwide aging of the population over the past 50 years that is expected to continue in the forthcoming years. This review will focus on the promise of cannabinoid based therapies to address t...
Article
Background and purpose: CB2receptors up-regulate in reactive microglia in the spinal cord of TDP-43(A315T) transgenic mice, an experimental model of ALS. To determine whether such up-regulation may be pharmacologically exploited, we investigated different treatments modulating the CB2receptor function. Experimental approach: We treated TDP-43(A3...
Preprint
Full-text available
Addiction is a chronic disorder with an elevated risk of relapse, even after long periods of abstinence. Some of the neural mechanisms mediating addictions require protein synthesis, which could be relevant for the development of more effective treatments. The mTOR signaling pathway regulates protein synthesis processes that have recently been link...
Article
Dravet syndrome (DS) is a rare pediatric epileptic encephalopathy which, in approximately 60-80% of patients, is caused by mutations in the gene SCN1A that encodes the α1 subunit of the voltage-gated sodium channel NaV1.1 [1]. Clinically, DS patients present different types of epileptic seizures, which are normally accompanied by cognitive impairme...
Article
Full-text available
Background: Neuroprotection with cannabinoids in Parkinson's disease (PD) has been afforded predominantly with antioxidant or anti-inflammatory cannabinoids. In the present study, we investigated the anti-inflammatory and neuroprotective properties of VCE-003.2, a quinone derivative of the non-psychotrophic phytocannabinoid cannabigerol (CBG), whi...
Article
Objective: We have investigated the endocannabinoid system in the motor cortex of motor neuron disease (MND) patients. Methods: Post-mortem samples from MND patients and controls were used for immunostaining and/or Western blotting analysis of endocannabinoid elements. Results: We did not find any evidence of neuronal losses in the motor corte...
Article
A series of sulfenamide and sulfonamide derivatives was synthesized and evaluated for the affinity at CB1 and CB2 receptors. The N-bornyl-S-(5,6-di-p-tolylpyridazin-3-yl)-sulfenamide, compound 11, displayed good affinity and high selectivity for CB1 receptors (Ki values of 44.6 nM for CB1 receptors and >40 μM for CB2 receptors, respectively). The N...
Chapter
The increase in lifespan during the last 50 years, mainly in developed countries, has originated a progressive elevation in the incidence of chronic neurodegenerative disorders, for which aging is the key risk factor. This fact will definitively become the major biomedical challenge during the present century, in part because the expectation of a p...
Article
Spinocerebellar ataxia type-3 (SCA-3) is the most prevalent autosomal dominant inherited ataxia. We recently found that the endocannabinoid system is altered in the post-mortem cerebellum of SCA-3 patients, and similar results were also found in the cerebellar and brainstem nuclei of a SCA-3 transgenic mouse model. Given that the neuropathology of...
Article
Full-text available
Several cannabinoids afforded neuroprotection in experimental models of Huntington’s disease (HD). We investigated whether a 1:1 combination of botanical extracts enriched in either ∆⁹-tetrahydrocannabinol (∆⁹-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex®, is beneficial in R6/2 mice (a transgenic...
Article
Full-text available
Targeting the CB2 receptor afforded neuroprotection in SOD1(G93A) mutant mice, a model of amyotrophic lateral sclerosis (ALS). The neuroprotective effects of CB2 receptors were facilitated by their up-regulation in the spinal cord in SOD1(G93A) mutant mice. Herein, we have investigated whether a similar CB2 receptor up-regulation, as well as parall...
Article
In the last few years, cannabinoid type-2 receptor (CB2R) selective ligands have shown a great potential as novel therapeutic drugs in several diseases. With the aim of discovering new selective cannabinoid ligands, a series of pyridazinone-4-carboxamides was designed and synthesized, and the new derivatives tested for their affinity toward the hCB...
Article
With the objective of developing an antitumor agent, the synthesis of a chromenopyrazoledione conjugated to a tetraphenylporphyrin is described. A complete conformational analysis of the novel porphyrin conjugate was performed using ab initio Hartree-Fock calculations at the 6-31G∗level. The novel conjugate (14) shows stronger absorption intensity...
Article
Spinocerebellar ataxia type-3 (SCA-3) is a rare disease but it is the most frequent type within the autosomal dominant inherited ataxias. The disease lacks an effective treatment to alleviate major symptoms and to modify disease progression. Our recent findings that endocannabinoid receptors and enzymes are significantly altered in the post-mortem...
Poster
Background: Dravet syndrome (DS)is a rare genetic pediatric epilepsy caused by mutations in the SCN1A gene, which encodes the α-subunit of the voltage-gated sodium channel Nav1.1 whose function contributes to the rising phase of the action potential in neurons [1].The onset of DS is generally in the first year of life with febrile seizures that pro...
Article
Endocannabinoids activate two types of specific G-protein-coupled receptors (GPCRs), namely cannabinoid CB1 and CB2. Contrary to the psychotropic actions of agonists of CB1 receptors, and serious side effects of the selective antagonists of this receptor, drugs acting on CB2 receptors appear as promising drugs to combat CNS diseases (Parkinson's di...
Article
Full-text available
Cannabinoids have shown to exert neuroprotective actions in animal models by acting at different targets including canonical cannabinoid receptors and PPARγ. We previously showed that VCE-003, a cannabigerol (CBG) quinone derivative, is a novel neuroprotective and anti-inflammatory cannabinoid acting through PPARγ. We have now generated a non-thiop...
Article
Full-text available
Huntington’s disease (HD) is a neurodegenerative disease for which there is no curative treatment available. Given that the endocannabinoid system is involved in the pathogenesis of HD mouse models, stimulation of specific targets within this signaling system has been investigated as a promising therapeutic agent in HD. We conducted a double-blind,...
Article
A combination of molecular modeling and structure-activity relationship studies have been used to fine tune CB2 selectivity in the chromenopyrazole ring, a versatile CB1/CB2 cannabinoid scaffold. Thus, a series of 36 new derivatives covering a wide range of structural diversity have been synthesized and docking studies have been performed for some...
Poster
Background: CB1 receptors are expressed mainly by neurons of the central and peripheral nervous system whereas CB2 receptors occur centrally and peripherally in certain non-neuronal tissues, particularly in immune cells. Selective interactions with CB1 or CB2 may lead to targeted agonistic or antagonistic effects on the cannabinoid receptor affecte...
Article
Most of cases of Parkinson's disease (PD) have a sporadic origin, with their causes mostly unknown, although overexposure to some environmental factors has been found to occur in some cases. Other forms of parkinsonism are the consequence of dominant or recessive mutations in specific genes, e.g. α-synuclein, parkin and, more recently, leucine-rich...
Article
Full-text available
Cannabidiol (CBD) reduces seizures in childhood epilepsy syndromes including Dravet syndrome (DS). A formulation of CBD has obtained orphan drug designation for these syndromes and clinical trials are currently underway. The mechanism responsible for CBD effects is not known, although it could involve targets sensitive to CBD in other neurological...
Article
Cannabinoids have emerged as promising neuroprotective agents due to their capability to activate specific targets, which are involved in the control of neuronal homeostasis and survival. Specifically, those ligands that selectively target and activate the CB2 receptor may be useful for their anti-inflammatory and neuroprotective properties in vari...
Article
Full-text available
Scleroderma is a group of rare diseases associated with early and transient inflammation and vascular injury, followed by fibrosis affecting the skin and multiple internal organs. Fibroblast activation is the hallmark of scleroderma, and disrupting the intracellular TGFβ signaling may provide a novel approach to controlling fibrosis. Because of its...
Article
Previous studies have investigated the relevance and structure-activity relationships (SARs) of pyrazole derivatives in relation with cannabinoid receptors, and the series of tricyclic 1,4-dihydroindeno[1,2-c]pyrazoles emerged as potent CB2 receptor ligands. In the present study, novel 1,4-dihydroindeno[1,2-c]pyrazole and 1H-benzo[g]indazole carbox...
Article
The orphan G protein-coupled receptor GPR55 has been proposed as a novel receptor of the endocannabinoid system. However, the validity of this categorization is still under debate mainly due to the lack of potent and selective agonists and antagonists of GPR55. Binding assays are not yet available for GPR55 screening and GPR55 signal pathways discr...
Chapter
Cannabinoids form a singular family of plant-derived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the CNS and also in the periphery. One of these properties is the improvement of neuronal homeostasis and survival, which is ex...
Article
This review focuses on the role of the endocannabinoid signaling system in controlling neuronal survival, an extremely important issue to be considered when developing new therapies for neurodegenerative disorders. First, we will describe the cellular and molecular mechanisms, and the signaling pathways, underlying these neuroprotective properties,...
Article
Full-text available
Cannabinoids form a singular family of plant-derived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems. One of these properties is the regulation of neuronal homeostasis and survival, whi...
Article
Biochemical, pharmacological and genetic evidence suggests the involvement of the endocannabinoid system in alcohol dependence. The aim of the present study was to evaluate the state of CB1 receptors in post-mortem caudate nucleus, hippocampus and cerebellum of alcoholic subjects.CB1 protein levels were measured by Western blot, CB1 receptor densit...