Dipyridamole Ameliorates Memory Impairment and Increases Hippocampal Calbindin Expression in Niemann Pick C1 Mice.

Niemann Pick type C1 (NPC1) is a rare, fatal disorder characterized by endosomal lipid accumulation that leads to damage of both peripheral organs and central nervous system (cerebellum and hippocampus are especially affected). Currently, miglustat is the only approved drug for NPC1, thus the identification of new treatments is mandatory. We have previously demonstrated that the drug dipyridamole (DIP), an enhancer of adenosine signaling, can reduce the pathological phenotype in patient-derived fibroblasts.

Fmr1-KO mice failure to detect object novelty associates with a post-test decrease of structural and synaptic plasticity upstream of the hippocampus.

Mice with deletion of the FMR1 gene show episodic memory impairments and exhibit dendritic spines and synaptic plasticity defects prevalently identified in non-training conditions. Based on evidence that synaptic changes associated with normal or abnormal memory emerge when mice are cognitively challenged, here we examine whether, and how, fragile entorhinal and hippocampal synapses are remodeled when mice succeed or fail to learn. We trained Fmr1 knockout (KO) and wild-type C57BL/6J (WT) mice in the novel object recognition (NOR) paradigm with 1 h or 24 h training-to-test intervals and then assessed whether varying the time between the presentation of similar and different objects modulates NOR performance and plasticity along the entorhinal cortex-hippocampus axis.

Repurposing Dipyridamole in Niemann Pick Type C Disease: A Proof of Concept Study.

Niemann Pick type C disease (NPC) is a rare disorder characterized by lysosomal lipid accumulation that damages peripheral organs and the central nervous system. Currently, only miglustat is authorized for NPC treatment in Europe, and thus the identification of new therapies is necessary. The hypothesis addressed in this study is that increasing adenosine levels may represent a new therapeutic approach for NPC.

Myelin Defects in Niemann-Pick Type C Disease: Mechanisms and Possible Therapeutic Perspectives.

Niemann-Pick type C (NPC) disease is a wide-spectrum clinical condition classified as a neurovisceral disorder affecting mainly the liver and the brain. It is caused by mutations in one of two genes, and , coding for proteins located in the lysosomes. NPC proteins are deputed to transport cholesterol within lysosomes or between late endosome/lysosome systems and other cellular compartments, such as the endoplasmic reticulum and plasma membrane.

Insight into the Role of the STriatal-Enriched Protein Tyrosine Phosphatase (STEP) in A Receptor-Mediated Effects in the Central Nervous System.

The STriatal-Enriched protein tyrosine phosphatase STEP is a brain-specific tyrosine phosphatase that plays a pivotal role in the mechanisms of learning and memory, and it has been demonstrated to be involved in several neuropsychiatric diseases. Recently, we found a functional interaction between STEP and adenosine A receptor (AR), a subtype of the adenosine receptor family widely expressed in the central nervous system, where it regulates motor behavior and cognition, and plays a role in cell survival and neurodegeneration. Specifically, we demonstrated the involvement of STEP in AR-mediated cocaine effects in the striatum and, more recently, we found that in the rat striatum and hippocampus, as well as in a neuroblastoma cell line, the overexpression of the AR, or its stimulation, results in an increase in STEP activity.

Adenosine A receptor inhibition reduces synaptic and cognitive hippocampal alterations in Fmr1 KO mice.

In fragile X syndrome (FXS) the lack of the fragile X mental retardation protein (FMRP) leads to exacerbated signaling through the metabotropic glutamate receptors 5 (mGlu5Rs). The adenosine A receptors (ARs), modulators of neuronal damage, could play a role in FXS. A synaptic colocalization and a strong permissive interaction between A and mGlu5 receptors in the hippocampus have been previously reported, suggesting that blocking ARs might normalize the mGlu5R-mediated effects of FXS.

Adenosine A receptor stimulation restores cell functions and differentiation in Niemann-Pick type C-like oligodendrocytes.

Niemann Pick type C (NPC) disease is a rare neurovisceral disorder. Mutations in npc1 gene induce an intracellular accumulation of unesterified cholesterol in the endosomal/lysosomal system causing cell death. We recently showed that stimulation of adenosine A receptors (AR) restores cholesterol accumulation in late endosomes/lysosomes in human NPC fibroblasts and neural cell lines transiently transfected with NPC1 siRNA, suggesting that these receptors might be targeted to contrast the disease.

Adenosine A receptor as potential therapeutic target in neuropsychiatric disorders.

Adenosine A receptor (AR) is a G-protein coupled receptor that regulates several important functions in the central nervous system. Large amount of preclinical data suggests that the AR could represent a target for the development of new therapeutic strategies for different neuropsychiatric conditions. In this review we will recapitulate and discuss the most relevant studies on the role of ARs in neurodegenerative, neurodevelopmental and psychiatric diseases, which led to suggest a therapeutic use of AR agonists in certain diseases (Niemann-Pick disease, autism-spectrum disorders, schizophrenia) and AR antagonists in others (Alzheimer's disease, Parkinson's disease, attention-deficit hyperactivity disorder, fragile X syndrome, depression, anxiety).

Neuroprotective potential of adenosine A receptor partial agonists in experimental models of cerebral ischemia.

Cerebral ischemia is the second most common cause of death and a major cause of disability worldwide. Available therapies are based only on anticoagulants or recombinant tissue plasminogen activator. Extracellular adenosine increases during ischemia and acts as a neuroprotective endogenous agent mainly by activating adenosine A receptors (A Rs) which control calcium influx, glutamate release, membrane potential, and metabolism.

Neuronal adenosine A receptor overexpression is neuroprotective towards 3-nitropropionic acid-induced striatal toxicity: a rat model of Huntington's disease.

The A adenosine receptor (AR) is widely distributed on different cellular types in the brain, where it exerts a broad spectrum of pathophysiological functions, and for which a role in different neurodegenerative diseases has been hypothesized or demonstrated. To investigate the role of neuronal ARs in neurodegeneration, we evaluated in vitro and in vivo the effect of the neurotoxin 3-nitropropionic acid (3-NP) in a transgenic rat strain overexpressing ARs under the control of the neural-specific enolase promoter (NSEA rats). We recorded extracellular field potentials (FP) in corticostriatal slice and found that the synaptotoxic effect of 3-NP was significantly reduced in NSEA rats compared with wild-type animals (WT).

The adenosine A receptor agonist T1-11 ameliorates neurovisceral symptoms and extends the lifespan of a mouse model of Niemann-Pick type C disease.

Niemann-Pick C is a fatal neurovisceral disorder caused, in 95% of cases, by mutation of NPC1 gene. Therapeutic options are extremely limited and new "druggable" targets are highly warranted. We previously demonstrated that the stimulation of the adenosine A receptor (AR) normalized the pathological phenotype of cellular models of NPC1.

Striatal adenosine-cannabinoid receptor interactions in rats over-expressing adenosine A2A receptors.

Adenosine A2A receptors (A2 A Rs) and cannabinoid CB1 receptors (CB1 Rs) are highly expressed in the striatum, where they functionally interact and form A2A /CB1 heteroreceptor complexes. We investigated the effects of CB1 R stimulation in a transgenic rat strain over-expressing A2 A Rs under the control of the neural-specific enolase promoter (NSEA2A rats) and in age-matched wild-type (WT) animals. The effects of the CB1 R agonist WIN 55,212-2 (WIN) were significantly lower in NSEA2A rats than in WT animals, as demonstrated by i) electrophysiological recordings of synaptic transmission in corticostriatal slices; ii) the measurement of glutamate outflow from striatal synaptosomes and iii) in vivo experiments on locomotor activity.

Modulation of Rho GTPases rescues brain mitochondrial dysfunction, cognitive deficits and aberrant synaptic plasticity in female mice modeling Rett syndrome.

Rho GTPases are molecules critically involved in neuronal plasticity and cognition. We have previously reported that modulation of brain Rho GTPases by the bacterial toxin CNF1 rescues the neurobehavioral phenotype in MeCP2-308 male mice, a model of Rett syndrome (RTT). RTT is a rare X-linked neurodevelopmental disorder and a genetic cause of intellectual disability, for which no effective therapy is available.

Expression, pharmacology and functional activity of adenosine A1 receptors in genetic models of Huntington's disease.

Adenosine A1 receptor (A1R) stimulation exerts beneficial effects in response to various insults to the brain and, although it was found neuroprotective in a lesional model of Huntington's disease (HD), the features of this receptor in genetic models of HD have never been explored. In the present study we characterized the expression, affinity and functional effects of A1Rs in R6/2 mice (the most widely used transgenic model of HD) and in a cellular model of HD. Binding studies revealed that the density of A1Rs was significantly reduced in the cortex and the striatum of R6/2 mice compared to age-matched wild-type (WT), while receptor affinity was unchanged.

The stimulation of adenosine A2A receptors ameliorates the pathological phenotype of fibroblasts from Niemann-Pick type C patients.

Niemann-Pick type C1 (NPC1) disease is a rare neurovisceral disorder characterized by intracellular accumulation of unesterified cholesterol, sphingolipids, and other lipids in the lysosomal compartment. A deregulation of lysosomal calcium has been identified as one of the earliest steps of the degenerative process. Since adenosine A2A receptors (A2ARs) control lysosome trafficking and pH, which closely regulates lysosomal calcium, we hypothesized a role for these receptors in NPC1.

Cocaine-induced changes of synaptic transmission in the striatum are modulated by adenosine A2A receptors and involve the tyrosine phosphatase STEP.

The striatum is a brain area implicated in the pharmacological action of drugs of abuse. Adenosine A2A receptors (A2ARs) are highly expressed in the striatum and mediate, at least in part, cocaine-induced psychomotor effects in vivo. Here we studied the synaptic mechanisms implicated in the pharmacological action of cocaine in the striatum and investigated the influence of A2ARs.

BDNF prevents NMDA-induced toxicity in models of Huntington's disease: the effects are genotype specific and adenosine A2A receptor is involved.

NMDA receptor-mediated excitotoxicity is thought to play a pivotal role in the pathogenesis of Huntington's disease (HD). The neurotrophin brain-derived neurotrophic factor (BDNF), which is also highly involved in HD and whose effects are modulated by adenosine A2 ARs, influences the activity and expression of striatal NMDA receptors. In electrophysiology experiments, we investigated the role of BDNF toward NMDA-induced effects in HD models, and the possible involvement of A2ARs.

Effects of chronic caffeine intake in a mouse model of amyotrophic lateral sclerosis.

Caffeine is a nonselective adenosine receptor antagonist; chronic consumption has proved protective toward neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. The present study was designed to determine whether caffeine intake affected survival and/or motor performance in a transgenic model of amyotrophic lateral sclerosis (ALS). SOD1(G93A) mice received caffeine through drinking water from 70 days of age until death.

Unbalance of CB1 receptors expressed in GABAergic and glutamatergic neurons in a transgenic mouse model of Huntington's disease.

Cannabinoid CB1 receptors (CB1Rs) are known to be downregulated in patients and in animal models of Huntington's disease (HD). However, the functional meaning of this reduction, if any, is still unclear. Here, the effects of the cannabinoid receptor agonist WIN 55,212-2 (WIN) were investigated on striatal synaptic transmission and on glutamate and GABA release in symptomatic R6/2 mice, a genetic model of HD.

Complex behavioral and synaptic effects of dietary branched chain amino acids in a mouse model of amyotrophic lateral sclerosis.

Scope: We hypothesized that chronic supplementation with branched chain amino acids (BCAAs) affects neurobehavioral development in vulnerable gene backgrounds.

Methods And Results: A murine model of amyotrophic lateral sclerosis (ALS), G93A mice bearing the mutated human superoxide dismutase 1 (SOD1) gene, and control mice received from 4 to 16 wk of age dietary supplementation with BCAAs at doses comparable to human usage. Motor coordination, exploratory behaviors, pain threshold, synaptic activity and response to glutamatergic stimulation in primary motor cortex slices were evaluated between the 8th and 16th week.

Role of adenosine A(2A) receptors in modulating synaptic functions and brain levels of BDNF: a possible key mechanism in the pathophysiology of Huntington's disease.

In the last few years, accumulating evidence has shown the existence of an important cross-talk between adenosine A(2A) receptors (A(2A)Rs) and brain-derived neurotrophic factor (BDNF). Not only are A(2A)Rs involved in the mechanism of transactivation of BDNF receptor TrkB, they also modulate the effect of BDNF on synaptic transmission, playing a facilitatory and permissive role. The cAMP-PKA pathway, the main transduction system operated by A(2A)Rs, is involved in such effects.

Influence of CGS 21680, a selective adenosine A(2A) receptor agonist, on NMDA receptor function and expression in the brain of Huntington's disease mice.

The effect of chronic treatment with the selective adenosine A(2A) receptor agonist CGS 21680 on N-Methyl-d-Aspartate (NMDA) receptor function and expression has been studied in the striatum and cortex of R6/2 mice, a genetic mouse model of Huntington's disease (HD). Starting from 8weeks of age, R6/2 and wild type (WT) mice were treated daily with CGS 21680 (0.5mg/kg i.

Remodeling of striatal NMDA receptors by chronic A(2A) receptor blockade in Huntington's disease mice.

Excitotoxicity plays a major role in the pathogenesis of Huntington disease (HD), a fatal neurodegenerative disorder. Adenosine A(2A) receptors (A(2A)Rs) modulate excitotoxicity and have been suggested to play a pathogenetic role in HD. The main aim of this study was to evaluate the effect of A(2A)R blockade on the expression and functions of NMDA receptors in the striatum of HD mice (R6/2).

Adenosine A2A receptors enable the synaptic effects of cannabinoid CB1 receptors in the rodent striatum.

Adenosine A(2A), cannabinoid CB(1) and metabotropic glutamate 5 (mGlu(5)) receptors are all highly expressed in the striatum. The aim of the present work was to investigate whether, and by which mechanisms, the above receptors interact in the regulation of striatal synaptic transmission. By extracellular field potentials (FPs) recordings in corticostriatal slices, we demonstrated that the ability of the selective type 1 cannabinoid receptor (CB(1)R) agonist WIN55,212-2 to depress synaptic transmission was prevented by the pharmacological blockade or the genetic inactivation of A(2A)Rs.

Region-specific neuroprotective effect of ZM 241385 towards glutamate uptake inhibition in cultured neurons.

Active uptake by neurons and glial cells is the main mechanism for maintaining extracellular glutamate at low, non-toxic concentrations. Adenosine A(2A) receptors regulate extracellular glutamate levels by acting on both the release and the uptake of glutamate. The aim of this study was to evaluate whether the inhibition of the effects of glutamate uptake blockers by adenosine A(2A) receptor antagonists resulted in neuroprotection.