C Guaza's research while affiliated with Cajal Institute and other places

Publications (52)

Article
Remyelination is an endogenous process by which functional recovery of damaged neurons is achieved by reinstating the myelin sheath around axons. Remyelination has been documented in multiple sclerosis (MS) lesions and experimental models, although it is often incomplete or fails to affect the integrity of the axon, thereby leading to progressive d...
Article
The gut microbiota plays a fundamental role on the education and function of the host immune system. Immunological dysregulation is the cause of numerous human disorders such as autoimmune diseases and metabolic disorders frequently associated with inflammatory processes therefore is critical to explore novel mechanisms involved in maintaining the...
Chapter
Cannabidiol (CBD), which constitutes up to 40% of the Cannabis sativa extract, have attracted special interest regarding putative therapeutic properties, excellent tolerability profile in humans, and lack of psychoactive actions. In animal models, CBD has been reported to act as an antiinflammatory, neuroprotective, and oligoprotective compound. Th...
Article
Full-text available
Recent studies have begun to point out the contribution of microbiota to multiple sclerosis (MS) pathogenesis. Theiler’s murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) is a model of progressive MS. Here, we first analyze the effect of intracerebral infection with TMEV on commensal microbiota and secondly, whether the early...
Article
Microglial cells are recognized as the brain´s intrinsic immune cells, mediating actions that range from the protection against harmful conditions that modify CNS homeostasis, to the control of proliferation and differentiation of neurons and their synaptic pruning. To perform these functions, microglia adopts different activation states, the so-ca...
Article
Full-text available
It is still controversial which mediators regulate energy provision to activated neural cells, as insulin does in peripheral tissues. Interleukin-1β (IL-1β) may mediate this effect as it can affect glucoregulation, it is overexpressed in the ‘healthy’ brain during increased neuronal activity, and it supports high-energy demanding processes such as...
Article
The ability of microglia to acquire diverse states of activation, or phenotypes, reflects different features that are determinant for their contribution to homeostasis in the adult CNS, and their activity in neuroinflammation, repair or immunomodulation. Despite the widely reported immunomodulatory effects of cannabinoids in both the peripheral imm...
Article
cyclic Adenosine monophosphate (cAMP) plays an important role in the transduction of signaling pathways involved in neuroprotection and immune regulation. Control of the levels of this nucleotide by inhibition of cAMP specific phosphodiesterases (PDEs) such as PDE7 may affect the pathological processes of neuroinflammatory diseases like multiple sc...
Article
Sativex® is an oromucosal spray, containing equivalent amounts of Δ(9) -tetrahydrocannabinol (Δ(9) -THC) and cannabidiol (CBD)-botanical drug substance (BDS), and which has been approved for the treatment of spasticity and pain associated to multiple sclerosis (MS). In this study, we investigated whether Sativex® may also serve as a disease-modifyi...
Article
Full-text available
Remyelination involves the generation of new myelin sheaths around axons, as occurs spontaneously in many multiple sclerosis (MS) lesions and other demyelinating diseases. When considering repairing a diseased brain, the adult mouse subventricular zone (SVZ) is of particular interest since the stem cells in this area can migrate and differentiate i...
Article
Full-text available
Inflammation in the central nervous system (CNS) is a complex process that involves a multitude of molecules and effectors, and it requires the transmigration of blood leukocytes across the blood-brain barrier (BBB) and the activation of resident immune cells. Cannabidiol (CBD), a non-psychotropic cannabinoid constituent of Cannabis sativa, has pot...
Article
Full-text available
Cannabidiol (CBD) is the most abundant cannabinoid in Cannabis sativa that has no psychoactive properties. CBD has been approved to treat inflammation, pain and spasticity associated with multiple sclerosis (MS), of which demyelination and oligodendrocyte loss are hallmarks. Thus, we investigated the protective effects of CBD against the damage to...
Article
Whether insulin-like growth factor I (IGF-I) signaling in Alzheimer's disease (AD) is beneficial or detrimental remains controversial. We now show that a competitive regulation by IGF-I of the phosphatase calcineurin in reactive, but not in quiescent astrocytes drives Alzheimer's pathology. Calcineurin de-phosphorylates the transcription factor Fox...
Article
The aim of this study was to evaluate how endocannabinoids interact with excitotoxic processes both in vitro, using primary neural cell cultures, and in vivo, in the TMEV-IDD model of multiple sclerosis. First, we observed that neuronal cells respond to excitotoxic challenges by the production of endocannabinoid molecules which in turn exerted neur...
Article
Adhesion molecules are critical players in the regulation of transmigration of blood leukocytes across the blood–brain barrier in multiple sclerosis (MS). Cannabinoids (CBs) are potential therapeutic agents in the treatment of MS, but the mechanisms involved are only partially known. Using a viral model of MS we observed that the cannabinoid agonis...
Article
Full-text available
It has been hypothesized that the maternal immune response to infection may influence fetal brain development and lead to schizophrenia. Animal experimentation has supported this notion by demonstrating altered sensorimotor gating (prepulse inhibition, PPI) in adult rats prenatally exposed to an immune challenge. In the present study, pregnant rats...
Article
Amongst the various demyelinating diseases that affect the central nervous system, those induced by an inflammatory response stand out because of their epidemiological relevance. The best known inflammatory-induced demyelinating disease is multiple sclerosis, but the immune response is a common pathogenic mechanism in many other less common patholo...
Article
Full-text available
Increasing evidence supports the idea of a beneficial effect of cannabinoid compounds for the treatment of multiple sclerosis (MS). However, most experimental data come from animal models of MS. We investigated the status of cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase (FAAH) enzyme in brain tissue samples obtained from MS patie...
Article
We have studied functional interactions between nicotine and the cannabinoid receptor agonist CP 55,940 (CP) in the modulation of behavioural and corticosterone responses of male and female adolescent Wistar rats. The animals underwent a subchronic nicotine treatment (0.4 mg/kg i.p., once daily) during the periadolescent period (postnatal days 34-4...
Article
We have studied the possible interaction between the cannabinoid receptor agonist CP 55,940 (1 and 50 microg/kg) and the 5-HT1A receptor antagonist WAY 100635 (1 mg/kg) in the modulation of plus-maze and holeboard activity in Wistar adult male rats. In the plus-maze, the higher dose of CP 55,940 induced an anxiogenic-like effect, whereas the lower...
Article
We have studied the possible interaction between three selective opioid-receptor antagonists, nor-binaltorphimine (NB: kappa) (5 mg/kg), cyprodime (CY: mu) (10 mg/kg) and naltrindole (NTI: delta) (1 mg/kg), and the cannabinoid receptor agonist CP 55,940, in the modulation of anxiety (plus-maze) and adrenocortical activity (serum corticosterone leve...
Article
Theiler's murine encephalomyelitis virus (TMEV) disease is induced following intracerebral inoculation of TMEV, a member of picornavirus family, in susceptible animals. The pathogenesis of paralytic syndrome is associated with a chronic progressive demyelinating disease characterized by perivascular of immune inflammatory cells. Although TMEV induc...
Article
The administration of the thiol compounds, N-acetylcysteine (NAC) and in particular thioproline (thiazolidine-4-carboxylic acid) at 0.1% w/w concentration in the diet, improves lymphocyte functions in old female Swiss mice, as has been shown in our previous studies. In the present work, adult mice from two different strains, namely BALB/c (an inbre...
Article
The pathological mechanisms that cause central nervous system (CNS) dysfunction in most neurological diseases are not well established. Theiler's murine encephalomyelitis virus (TMEV) is known to interact with cells of the CNS and its intracerebral inoculation to susceptible mice strains causes neurological disorders resembling multiple sclerosis (...
Article
This study investigated the effects of lipopolysaccharide (LPS) and interleukin-1beta (IL-1beta) on corticotropin releasing factor (CRF) and prostaglandin E2 (PGE2) release by brainstem slices in vitro. First, we characterized our experimental model and demonstrated that high potassium stimulates CRF release from rat brainstem slices in a calcium d...
Article
The effects of interleukin-1 beta (IL-1), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF) and lipopolysaccharide (LPS) on hippocampal corticosteroid receptors were studied in the rat. Type I (mineralocorticoid) and type II (glucocorticoid) receptors were measured in hippocampal cytosolic fractions with the radioligand binding technique, usi...
Article
The present work shows that interleukin-2 (IL-2) is able to increase in a dose-dependent manner (25-100 U/ml) CRF release from continuous perifused hypothalami. The effects of IL-2 and IL-1 on CRF secretion are potentiated by the simultaneous action of the two cytokines at the hypothalamus. The stimulatory effect of IL-2 on CRF secretion is signifi...
Article
The present work shows that interleukin-2 (IL-2) is able to increase in a dose-dependent manner (25-100 U/ml) CRF release from continuous perifused hypothalami. The effects of IL-2 and IL-1 on CRF secretion are potentiated by the simultaneous action of the two cytokines at the hypothalamus. The stimulatory effect of IL-2 on CRF secretion is signifi...
Article
Using an in vitro continuous perifusion system, the effects of interleukin-1 (IL-1) on adrenocorticotropin (ACTH) secretion at the pituitary level were investigated. On one hand, we observed that IL-1 beta increases ACTH secretion from perifused anterior pituitary cells in a dose-dependent manner, between 1.5 and 6 pM. This stimulatory action of IL...
Article
Continuous in vitro perifusion of rat hypothalami with interleukin-1 beta (IL-1) increased corticotropin-releasing factor (CRF) secretion in a dose-dependent manner, in the range of 1 to 5 U/ml. The stimulatory action of IL-1 was significantly attenuated by dexamethasone, both by addition to the perifusion medium and by in vivo dexamethasone pretre...
Article
Possible modulatory effects of psychoneurogenic stress and endotoxin-induced immune activation on the in vitro corticosterone-releasing effects of lymphokine-containing supernatants (LCS) and adrenocorticotropic hormone (ACTH) were studied in rats. We have found that activation of the immune system by endotoxin increases the in vitro sensitivity of...
Article
Products derived from the activated immune system have been reported to modulate neuroendocrine function. In addition, a direct connection between neuroendocrine and immune responses to stress has recently been proposed. We now provide evidence that heterogeneous lymphokine-containing supernatants from mitogen-stimulated rat spleen cells can stimul...
Article
Two opioid peptides, beta-endorphin and dynorphin1-17 were bioassayed with isolated rat adrenocortical cells. beta-Endorphin increases basal production of corticosterone as well as the adrenal responsiveness to low doses of ACTH, these effects being partially reversed by naloxone. Dynorphin1-17, without affecting basal corticosterone synthesis, inc...
Article
The variations in brain dopamine (DA) and norepinephrine (NE) levels after ethanol administration have been studied in rats. Acute ethanol administration significantly decreased brain DA and NE levels. After chronic ethanol intake no changes were observed in brain catecholamines. Ethanol withdrawal induced significant decreases in DA and NE concent...
Article
The action of ethanol on adrenal steroidogenesis "in vitro" has been studied. It has been found that ethanol did not change the basal production of corticosterone by dispersed adrenal cells, but significantly reduced its response to ACTH stimulation. It is suggested that the inhibitory action of ethanol on steroidogenesis "in vitro" could have a ph...
Article
The effects of the Met-enkephalin analog D-Ala2-Met-enkephalinamide (DALA) on basal and ACTH-stimulated corticosterone secretion from dispersed adrenal cells were investigated. Low doses (10(-10) and 10(-12) M) of DALA resulted in no apparent alteration in the response to ACTH (8 X 10(-9), 3.2 X 10(-8) or 1.6 X 10(-7) M). High doses of DALA (10(-8)...
Article
The influence of catecholamines (CA) on hypothalamic somatostatin (HPT-SRIF) was investigated in rats by using several drugs which interfere with brain CA metabolism. Depletion of brain CA stores by alpha-methyl-rho-tyrosine (AMT) increased HPT-SRIF, while augmented brain CA levels following L-dopa administration decreased HPT-SRIF content. Blockad...
Article
The response of the pituitary-adrenal axis of the male rat to sub-chronic dose treatment with phenobarbital and/or phenytoin under basal and stress conditions was investigated. Plasma corticosterone levels were measured in rats sacrificed either in the morning or in the afternoon, subjected or not to 2 hours of immobilization stress. Phenobarbital...
Article
The response of adrenal hormones and brain catecholamines to immobilization stress, applied in the morning or in the afternoon, was studied in rats. Immobilization induced greater increments in plasma corticosterone in the morning than in the afternoon; i.e. when the basal levels of this hormone were low rather than high. There was no significant d...
Article
The purpose of the present study was to investigate in rats, the effects of sound stimulation upon both the pituitary-adrenal activity (evaluated by the levels of serum corticosterone (B)) and brain dopamine (DA) and noradrenaline (NA). Serum B in rats placed inside the experimental chamber without any sound stimulation was increased and brain DA d...
Article
The aim of the present study was to investigate the effects of acute and chronic administration of morphine upon the pituitary-adrenal activity and adrenal catecholamines in rats and cats, two animal species with very different behavioural patterns of response to the opiate. Acute administration of the drug induced in both animal species an activat...

Citations

... M2a (alternative activation) is involved in repair and regeneration through the expression of antiinflammatory and neurotrophic factors [26]; however, this phenotype is rare in AD brains [27]. The M2b transitional state (type II alternative activation) is involved in immune responses, with the expression of pro-inflammatory and anti-inflammatory mediators; contrastingly, the M2c state (acquired deactivation) mediates myelin debris clearance [28], neuroprotection, and release of antiinflammatory cytokines [26]. ...
... Advances in understanding the pathological processes in Alzheimer's disease (AD) have led to extensive efforts to find promising targets to develop therapeutic strategies. Currently, the knowledge on the neuroand enteroendocrine regulations of the enteric nervous system (ENS), and the functions and regulation of both the neuroimmune axis and the microbiota-gut-brain axis support the notion that the gut microbiota (GM) may modulate: (i) factors that maintain the functional integrity of the intestine-especially through regulation of the endocannabinoid system (ECS) (Muccioli et al., 2010;Mestre et al., 2018) -, (ii) immunological status (Jiang et al., 2017), and (iii) brain functions (Spielman et al., 2018). ...
... Dysbiosis is characterised by disruption to microbial homeostasis, reduced microbial diversity and loss of beneficial bacteria. It is associated with a range of diseases and complications, including inflammation-induced pathology, 109 autoimmune diseases, 110-113 impaired immune response to vaccination and viral infection, 114,115 and defective brain function and brain inflammation. 116,117 Multiple factors are known to lead to microbial dysbiosis, and antibiotic usage is the most studied. ...
... This might constitute another potential therapeutic application for CBD in numerous TH17-driven pathologies, including psoriasis, multiple sclerosis (MS), rheumatoid arthritis, asthma, and Crohn's disease (CD). [74][75][76][77][78] Although, NF-jB is a major target for CBD's immunosuppressive effects, it has not yet been shown to be affected in T cells in comparison to other immune cells. 10 Clearly, further studies are needed to determine which of CBD's various molecular mechanisms contribute the most to its anti-inflammatory properties. ...
... Therefore, IL-2-induced ACTH responses may be driven by AVP rather than CRH. On the other hand, there are studies in which IL-2 has been shown to stimulate CRH release from rat perifused hypothalami (63), hypothalamic explants (150), and hypothalamic slices (244). Again, disparities between results may be due to species-specificity effects of the cytokine used. ...
... Whether and how CB1R regulates microglial function remains unclear. Moreover, CB1R is also expressed in astrocytes, shaping synaptic transmission and memory [35,[70][71][72][73]. ...
... For instance, weaning pups are generally very susceptible to the virus and often die due to encephalitis. 8 In addition, the viral infection typically causes major changes in immune activity, [9][10][11] which could directly skew results in immunological, microbiological, and cancer-related studies. Last, immunocompromised mice have been found to be highly susceptible to TMEV, which causes paralysis, death, and decreased growth. ...
... Pro-IL-18β is also regulated by the same caspase in a similar manner [136]. Thus, caspase-1 inhibition leads to decreased IL-1 and IL-18 cytokine abundance, reducing NF-κB pathway amplification via autocrine and paracrine signaling [137]. ...
... In addition, after this M1 response, aimed at eliminating noxious stimuli and restraining the initial inflammation from the area, the resolution of the inflammatory process is essential to bypass neurotoxicity and chronic inflammation [103]. For this resolving phase to occur, a shift in microglia phenotype along a spectrum of activation states from proinflammatory to phagocytic anti-inflammatory (M2, alternative activation state) is typically observed, which could increase the production of anti-inflammatory mediators, including transforming growth factor (TGF-β), interleukin 10 (IL-10), IL-13, and IL-4 [104,105]. ...
... Our lab has wide expertise using the viral TMEV model as a preclinical tool for new therapeutic compound discovery [8,9,27,28]. Our well-established protocol indicates that approximately 60-70 days post-infection mice start to show motor deficits. ...