Rodrigo A Cunha

Rodrigo A Cunha
University of Coimbra | UC · Center for Neurosciences and Cell Biology

PhD

About

348
Publications
70,582
Reads
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20,867
Citations
Citations since 2016
111 Research Items
10403 Citations
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Introduction
caffeine neuroprotection and purinergic modulation in ageing and neuropsychiatric diseases
Additional affiliations
March 2001 - present
University of Coimbra
Position
  • Principal Investigator
Education
March 2001 - December 2007
University of Coimbra
Field of study
  • Medicine
October 1994 - September 1995
Karolinska Institutet
Field of study
  • Neuroscience
January 1994 - December 1994
Rhone-Poulenc Rorer
Field of study
  • Clinical Reseach

Publications

Publications (348)
Article
Full-text available
Adenosine A2A receptors (A2AR) control fear memory and the underlying processes of synaptic plasticity in the amygdala. In other brain regions, A2AR activation is ensured by ATP-derived extracellular adenosine formed by ecto-5′-nucleotidase or CD73. We now tested whether CD73 is also responsible to provide for the activation of A2AR in controlling...
Article
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The molecular mechanisms underlying circuit re-wiring in the mature brain remains ill-defined. An eloquent example of adult circuit remodelling is the hippocampal mossy fiber (MF) sprouting found in diseases such as temporal lobe epilepsy. The molecular determinants underlying this retrograde re-wiring remain unclear. This may involve signaling sys...
Article
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The contribution of astrocytes to Alzheimer’s disease (AD) is still ill defined. AD involves an abnormal accumulation of amyloid-β peptides (Aβ) and increased production of danger signals such as ATP. ATP can direct or indirectly, through its metabolism into adenosine, trigger adaptive astrocytic responses resulting from intracellular Ca²⁺ oscillat...
Article
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Caffeine is the most consumed psychoactive substance worldwide. Strikingly, molecular pathways engaged by its regular consumption remain unclear. We herein addressed the mechanisms associated with habitual (chronic) caffeine consumption in the mouse hippocampus using untargeted orthogonal-omics techniques. Our results revealed that chronic caffeine...
Article
Anxiety involves abnormal glucocorticoid signalling and altered glia-neuron communication in brain regions processing emotional responses. Adenosine A2A receptor (A2AR) blockade ameliorates mood and memory impairments by preventing synaptic dysfunction and astrogliosis. Since the glucocorticoid dexamethasone (DEX) can mimic early life-stress condit...
Article
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Alzheimer’s disease (AD) is characterized by progressive memory deficits accompanied by synaptic and metabolic deficits, namely of mitochondrial function. AD patients also display a disrupted circadian pattern. Thus, we now compared memory performance, synaptic plasticity, and mitochondria function in 24-week-old non-transgenic (non-Tg) and triple...
Article
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Brain iron deficiency (BID) constitutes a primary pathophysiological mechanism in restless legs syndrome (RLS). BID in rodents has been widely used as an animal model of RLS, since it recapitulates key neurochemical changes reported in RLS patients and shows an RLS-like behavioral phenotype. Previous studies with the BID-rodent model of RLS demonst...
Article
Amyloid-β peptides (Aβ) accumulate in the brain since early Alzheimer's disease (AD) and dysregulate hippocampal synaptic plasticity, the neurophysiological basis of memory. Although the relationship between long-term potentiation (LTP) and memory processes is well established, there is also evidence that long-term depression (LTD) may be crucial f...
Article
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Increasing evidence implicates astrocytes and the associated purinergic modulation in Alzheimer’s disease (AD), characterized by cognitive deficits involving the extracellular amyloid-β peptides (Aβ) accumulation. Aβ can affect astrocytic gliotransmitters release, namely ATP, which is rapidly metabolized into adenosine by ecto-5’-nucleotidase, CD73...
Article
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Synapse stabilization Early in brain development, neurons connect to each other enthusiastically. With development, an overabundance of synapses is winnowed down to refine efficiently connected circuits. Inactive synapses are prime targets for elimination, whereas active synapses tend to be retained. Gomez-Castro et al . took a closer look at how t...
Article
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Increasing evidence shows that astrocytes, by releasing and uptaking neuroactive molecules, regulate synaptic plasticity, considered the neurophysiological basis of memory. This study investigated the impact of l‐α‐aminoadipate (l‐AA) on astrocytes which sense and respond to stimuli at the synaptic level and modulate hippocampal long‐term potentiat...
Article
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Host innate immunity is fundamental to the resistance against Candida albicans and Candida glabrata infection, two of the most important agents contributing to human fungal infections. Phagocytic cells, such as neutrophils, constitute the first line of host defense mechanisms, and the release of neutrophil extracellular traps (NETs) represent an im...
Article
Ecto-5′-nucleotidase or CD73 is the main source of extracellular adenosine involved in the activation of adenosine A2A receptors, responsible for the ergogenic effects of caffeine. We now investigated the role of CD73 in exercise by comparing female wild-type (WT) and CD73 knockout (KO) mice in a treadmill-graded test to evaluate running power, oxy...
Article
Full-text available
Extracellular ATP is a danger signal to the brain and contributes to neurodegeneration in animal models of Alzheimer's disease through its extracellular catabolism by CD73 to generate adenosine, bolstering the activation of adenosine A2A receptors (A2AR). Convulsive activity leads to increased ATP release, with the resulting morphological alteratio...
Article
Full-text available
Extracellular adenosine is produced with increased metabolic activity or stress, acting as a paracrine signal of cellular effort. Adenosine receptors are most abundant in the brain, where adenosine acts through inhibitory A1 receptors to decrease activity/noise and through facilitatory A2A receptors (A2AR) to promote plastic changes in physiologica...
Chapter
We here describe a methodology to carry out a fractionation procedure that separates presynaptic, postsynaptic, and extrasynaptic fractions, allowing to access the localization of proteins within synapses, which we exemplify in rodent and human brain tissue. The procedure begins with the fractionation of synaptosomes (synaptic compartments) and the...
Article
Cortical interneurons born in the subpallium reach the cortex through tangential migration, whereas pyramidal cells reach their final position by radial migration. Purinergic signaling via P2Y1 receptors controls the migration of intermediate precursor cells from the ventricular zone to the subventricular zone. It was also reported that the blockad...
Article
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Angelman syndrome (AS) is a neurogenetic disorder involving ataxia and motor dysfunction, resulting from the absence of the maternally inherited functional Ube3a protein in neurons. Since adenosine A2A receptor (A2AR) blockade relieves synaptic and motor impairments in Parkinson’s or Machado-Joseph’s diseases, we now tested if A2AR blockade was als...
Article
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The increased healthspan afforded by coffee intake provides novel opportunities to identify new therapeutic strategies. Caffeine has been proposed to afford benefits through adenosine A 2A receptors, which can control synaptic dysfunction underlying some brain disease. However, decaffeinated coffee and other main components of coffee such as chloro...
Article
Full-text available
Astrocytes, through their numerous processes, establish a bidirectional communication with neurons that is crucial to regulate synaptic plasticity, the purported neurophysiological basis of memory. This evidence contributed to change the classic “neurocentric” view of Alzheimer’s disease (AD), being astrocytes increasingly considered a key player i...
Article
Extracellular adenosine plays important roles in modulating the immune responses. We have previously demonstrated that infection of dendritic cells (DC) by Leishmania amazonensis leads to increased expression of CD39 and CD73 and to the selective activation of the low affinity A2B receptors (A2BR), which contributes to DC inhibition, without involv...
Article
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Depressive conditions precipitated by repeated stress are a major socio-economical burden in Western countries. Previous studies showed that ATP-P2X7 receptors (P2X7R) and adenosine A2A receptors (A2AR) antagonists attenuate behavioral modifications upon exposure to repeated stress. Since it is unknown if these two purinergic modulation systems wor...
Preprint
Full-text available
Ecto-5'-nucleotidase CD73 is the main source of extracellular adenosine involved in the activation of adenosine A2A receptors responsible for the ergogenic effects of caffeine. We now investigated the role of CD73 in exercise by comparing female wild-type (WT) and CD73 knockout (KO) mice in a treadmill graded test to evaluate running power, oxygen...
Article
Physical exercise attenuates the development of L-DOPA-induced dyskinesia (LID) in 6-hydroxydopamine-induced hemiparkinsonian mice through unknown mechanisms. We now tested if exercise normalizes the aberrant corticostriatal neuroplasticity associated with experimental murine models of LID. C57BL/6 mice received two unilateral intrastriatal injecti...
Article
Full-text available
Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of function of the maternally inherited Ube3a neuronal protein, whose main features comprise severe intellectual disabilities and motor impairments. Previous studies with the Ube3am−/p+ mouse model of AS revealed deficits in synaptic plasticity and memory. Since adenosine A2A re...
Article
This review discusses the evidence supporting a role for ATP signaling (operated by P2X and P2Y receptors) and adenosine signaling (mainly operated by A1 and A2A receptors) in the crosstalk between neurons, astrocytes, microglia and oligodendrocytes. An initial emphasis will be given to the cooperation between adenosine receptors to sharpen informa...
Article
The initial exploration using pharmacological tools of the role of adenosine receptors in the brain, concluded that adenosine released as such acted on A1R to inhibit excitability and glutamate release from principal neurons throughout the brain and that adenosine A2A receptors (A2AR) were striatal-‘specific’ receptors controlling dopamine D2R. Thi...
Article
Background Ethanol intake during adolescence has become an important public health issue. Although the detrimental effects of ethanol intake on the musculoskeletal system are well known, only a few studies have investigated its impact on the stomatognathic system of adolescents. This study aimed to investigate the effect of ethanol binge drinking o...
Article
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The health implications of acrylamide in food are a matter of concern based on toxicological studies in rodents, which showed that doses of acrylamide more than 100 times higher than those estimated to result from dietary exposure in humans are carcinogenic; however, the cancer types reported in rodents are species-specific, and whether these resul...
Article
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Ethanol consumption has been reported to negatively impact on periodontal disease. In particular, oral cavity disorders occur upon ethanol exposure during adolescence, a life period associated with particular patterns of short and intense (‘binge-like’) ethanol consumption that is most deleterious to oral health. The hazardous central effects of et...
Article
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Neuropeptide S is a recently discovered peptide signaling through its receptor NPSR, which is expressed throughout the brain. Since NPSR activation increases dopaminergic transmission, we now tested if NPSR modulates behavioural and neurochemical alterations displayed by an animal model of attention-deficit/hyperactivity disorder (ADHD), Spontaneou...
Article
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Attention deficit hyperactivity disorder (ADHD) is a prevalent and disabling disorder, mainly characterized by hyperactivity, inattention, and impulsivity, but also by olfactory and memory impairments that frequently persist throughout lifetime. The pathophysiology of ADHD is complex, involving several brain regions and neural pathways including al...
Article
The endocannabinoid system is implicated in a plethora of neuropsychiatric disorders. However, it is technically challenging to assess the turnover of 2‐arachidonoyl glycerol (2‐AG), the principal endocannabinoid molecule in the brain. Two recent studies showed that diacylglycerol lipase α (DAGLα), an enzyme chiefly responsible for the cerebral pro...
Article
Full-text available
Caffeine is one of the most used ergogenic aid for physical exercise and sports. However, its mechanism of action is still controversial. The adenosinergic hypothesis is promising due to the pharmacology of caffeine, a nonselective antagonist of adenosine A1 and A2A receptors. We now investigated A2AR as a possible ergogenic mechanism through pharm...
Article
Full-text available
Dopamine replacement therapy with L-3,4-dihydroxyphenylalanine (L-DOPA) is the only temporary therapy for Parkinson’s disease (PD), but it triggers dyskinesia over time. Since dyskinesia is associated with increased neuronal firing that bolsters purinergic signaling, we now tested whether the selective and blood-brain barrier-permeable P2X7 recepto...
Article
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Synaptic dysfunction plays a central role in Alzheimer’s disease (AD), since it drives the cognitive decline. An association between a polymorphism of the adenosine A2A receptor (A2AR) encoding gene—ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of A2AR in age-related condition...
Article
Exposure to fungicide ziram (zinc dimethyldithiocarbamate) has been associated with increased incidence of Parkinson’s disease (PD). We recently demonstrated that the intranasal (i.n.) administration of sodium dimethyldithiocarbamate (NaDMDC, a more soluble salt than ziram) induces PD-like behavioral and neurochemical alterations in mice. We now in...
Article
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After more than two decades of preclinical and clinical studies, on August 27, 2019, the US Food and Drug Administration (FDA) approved the adenosine A2A receptor antagonist Nourianz® (istradefylline) developed by Kyowa Hakko Kirin Inc., Japan, as an add-on treatment to levodopa in Parkinson’s disease (PD) with “OFF” episodes. This milestone achiev...
Article
Here we aimed to unify some previous controversial reports on changes in both cannabinoid CB1 receptor (CB1R) expression and glucose metabolism in the forebrain of rodent models of diabetes. We determined how glucose metabolism and its modulation by CB1R ligands evolve in the frontal cortex of young adult male Wistar rats, in the first 8 weeks of s...
Preprint
Full-text available
Ergogenic aid is a substance or method used for enhancing exercise and sports performance. Caffeine is the most used ergogenic aid for athletes, but the mechanisms are still unknown. Forty-two adult female (19±0.6 g) and 40 male mice (24±0.4 g) from a global and forebrain A2AR knockout and colony (FMUC, University of Coimbra) underwent an open fiel...
Article
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Adenosine is an endogenous anticonvulsant and neuroprotectant of the brain. Seizure activity produces large quantities of adenosine, and it is this seizure-induced adenosine surge that normally stops a seizure. However, within the context of epilepsy, adenosine plays a wide spectrum of different roles. It not only controls seizures (ictogenesis), b...
Article
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Background: It has been hypothesized that heteromers of adenosine A2A receptors (A2AR) and cannabinoid CB1 receptors (CB1R) localized in glutamatergic nerve terminals mediate the integration of adenosine and endocannabinoid signaling involved in the modulation of striatal excitatory neurotransmission. Previous studies have demonstrated the existen...
Article
This scientific commentary refers to ‘Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptors’, by Carvalho et al. (doi:10.1093/brain/awz288).
Article
Microglia cells exert a critical role in brain development, mainly supported by their immune functions, which predicts an impact on the genesis of psychiatric disorders. In fact, microglia stress during gestation is, for instance, associated with chronic anxiety and cognitive deficits accompanied by long‐lasting, region‐ and sex‐specific changes in...
Article
Full-text available
Caffeine is one of the most widely consumed psycho-stimulants. The study of the beneficial effects of caffeine consumption to decrease the risk of developing several neuropsychiatric pathologies is receiving increasing attention. Thus, accurate and sensitive methods have been developed, mainly by LC-MS/MS, in order to quantify caffeine and its meta...
Article
Adenosine A2A receptors (A2AR) overfunction causes synaptic and memory dysfunction in early Alzheimer's disease (AD). In a β-amyloid (Aβ1-42)-based model of early AD, we now unraveled that this involves an increased synaptic release of ATP coupled to an increased density and activity of ecto-5'-nucleotidase (CD73)-mediated formation of adenosine se...
Article
Full-text available
The hippocampus is a brain region involved in processing both memory and emotions, through a preferential involvement of the dorsal hippocampus (DH) and ventral hippocampus (VH), respectively. Adenosine A1 and A2A receptors (A1R and A2AR) control both mood and memory, but it is not known if there is a different adenosine modulation of synaptic plas...
Article
Background and purpose: Parkinson's disease (PD) involves an initial loss of striatal dopamine terminals evolving into degeneration of dopamine neurons in substantia nigra (SN), which can be modeled by 6-hydroxydopamine (6-OHDA) administration. Adenosine A2A receptor (A2A R) blockade attenuates PD features in animal models, but the source of the a...
Article
Caffeine is the most consumed psychoactive drug worldwide and its intake in moderate amounts prevents neurodegenerative disorders. However, the molecular targets of caffeine to modulate activity in brain circuits are ill-defined. By electrophysiologically recording synaptic transmission and plasticity in Schaffer fibers-CA1 pyramid synapses of mous...
Article
Full-text available
Traumatic brain injury (TBI) is a leading cause of disability worldwide, triggering chronic neurodegeneration underlying cognitive and mood disorder still without therapeutic prospects. Based on our previous observations that guanosine (GUO) attenuates short-term neurochemical alterations caused by TBI, this study investigated the effects of chroni...
Article
Calcium (Ca2+) is essential for the normal functioning of the brain: Ca2+ inflow into synaptic compartments is a major trigger of neurotransmitter release and of long‐term plastic changes of synaptic efficiency. Ca2+ influx depends on the gradient for this ion across the plasma membrane, and slight fluctuations of extracellular Ca2+ concentration h...
Article
Full-text available
Adenosine modulation is considered both a paracrine signal coordinating different cells in a tissue and a stress signal. Both functions are ensured by 4 types of adenosine receptors (ARs), which have been studied individually. Mice with knockout of all ARs (quad-AR-KO) now allow enquiring the overall function of the adenosine modulation system. The...
Article
Full-text available
Exercise can act as a disease-modifying agent in Parkinson's disease (PD), and we have previously demonstrated that voluntary exercise in running wheels during 2 weeks normalizes striatopallidal dopaminergic signaling and prevents the development of L-DOPA-induced dyskinesia (LID) in C57BL/6 mice. We now tested whether LID in Swiss albino mice coul...
Article
Attention deficit and hyperactivity disorder (ADHD) is characterized by impaired levels of hyperactivity, impulsivity and inattention. Adenosine and endocannabinoid systems tightly interact in the modulation of dopamine signaling, involved in the neurobiology of ADHD. In this study, we evaluated the modulating effects of the cannabinoid and adenosi...
Article
Full-text available
Diabetes affects the morphology and plasticity of the hippocampus, and leads to learning and memory deficits. Caffeine has been proposed to prevent memory impairment upon multiple chronic disorders with neurological involvement. We tested whether long-term caffeine consumption prevents type 2 diabetes (T2D)-induced spatial memory impairment and hip...
Article
Adenosine A2A receptors (A2AR) play a key role modulating dopamine‐dependent locomotor activity, as heralded by the sensitization of locomotor activity upon chronic A2AR blockade, which is associated with elevated dopamine levels and altered corticostriatal synaptic plasticity. Since the orphan receptor GPR37 has been shown to modulate A2AR functio...
Article
Full-text available
Adenosine A 2A receptors (A 2A Rs) were recently described to control synaptic plasticity and network activity in the prefrontal cortex (PFC). We now probed the role of these PFC A 2A R by evaluating the behavioral performance (locomotor activity, anxiety-related behavior, cost-benefit decision making and working memory) of rats upon downregulation...
Article
Full-text available
Neurodegeneration is a process transversal to neuropsychiatric diseases and the understanding of its mechanisms should allow devising strategies to prevent this irreversible step in brain diseases. Neurodegeneration caused by seizures is a critical step in the aggravation of temporal lobe epilepsy, but its mechanisms remain undetermined. Convulsion...