Search

Fingolimod phosphate (FTY720), the first approved oral therapy for multiple sclerosis, primarily acts as an immunomodulator. Its concomitant effects in the central nervous system, however, indicate a potentially broader spectrum of activity in neurodegenerative diseases. In the present study, we investigated the possible effects of fingolimod in a mouse model of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by a strong neuroinflammatory component. Fingolimod (0.1 and 1 mg/kg i.p.) was administered to mSOD1G93A mice, a well-characterized mouse model of ALS, starting from the onset of motor symptoms to the end stage of the disease. The drug was able to improve the neurological phenotype (p < 0.05) and to extend the survival (p < 0.01) of ALS mice. The beneficial effect of fingolimod administration was associated with a significant modulation of neuroinflammatory and protective genes (CD11b, Foxp3, iNOS, Il1β, Il10, Arg1, and Bdnf) in motor cortex and spinal cord of animals. Our data show, for the first time, that fingolimod is protective in ALS mice and that its beneficial effects are accompanied by a modulation of microglial activation and innate immunity. Considering that the treatment was started in already symptomatic mice, our data strongly support fingolimod as a potential new therapeutic approach to ALS. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this review is to summarize and critically discuss the complex role played by adenosine A2A receptors (A2ARs) in Huntington''s disease (HD). Since A2ARs are mainly localized on the neurons, which degenerate early in HD, and given their ability to stimulate glutamate outflow and inflammatory gliosis, it was hypothesized that they could be involved in the pathogenesis of HD, and that A2AR antagonists could be neuroprotective. This was further sustained by the demonstration that A2ARs and underlying signaling systems undergo profound changes in cellular and animal models of HD. More recently, however, the equation A2A receptor blockade=neuroprotection has appeared too simplistic. First, it is now definitely clear that, besides mediating ‘bad’ responses (for example, stimulation of glutamate outflow and excessive glial activation), A2ARs also promote ‘good’ responses (such as trophic and antinflammatory effects). This implies that A2AR blockade results either in pro-toxic or neuroprotective effects according to the mechanisms involved in a given experimental model. Second, since HD is a chronically progressive disease, the multiple mechanisms involving A2ARs may play different relative roles along the degenerative process. Such different mechanisms can be influenced by A2AR activation or blockade in different ways, even leading to opposite outcomes depending on the time of agonist/antagonist administration. The number, and the complexity, of the possible scenarios is further increased by the influence of mutant Huntingtin on both the expression and functions of A2ARs, and by the strikingly different effects mediated by A2ARs expressed by different cell populations within the brain. [Copyright &y& Elsevier]

• Evidence on relative effectiveness (RVE) of a 2nd booster of COVID-19 vaccine is scarce. • We estimated RVE of a 2nd booster as compared to a 1st booster given ≥ 120 days earlier in elders ≥ 80 years. • RVE against severe COVID-19 was about 30 % 2–4 months after the 2nd booster dose. • However, RVE against infection was negligible in the same time interval. • Cost-benefit of a 3rd booster four months after the 2nd booster should be evaluated. Several countries started a 2nd booster COVID-19 vaccination campaign targeting the elderly population, but evidence around its effectiveness is still scarce. This study aims to estimate the relative effectiveness of a 2nd booster dose of COVID-19 mRNA vaccine in the population aged ≥ 80 years in Italy, during predominant circulation of the Omicron BA.2 and BA.5 subvariants. We linked routine data from the national vaccination registry and the COVID-19 surveillance system. On each day between 11 April and 6 August 2022, we matched 1:1, according to several demographic and clinical characteristics, individuals who received the 2nd booster vaccine dose with individuals who received the 1st booster vaccine dose at least 120 days earlier. We used the Kaplan-Meier method to compare the risks of SARS-CoV-2 infection and severe COVID-19 (hospitalisation or death) between the two groups, calculating the relative vaccine effectiveness (RVE) as (1 – risk ratio)X100. Based on the analysis of 831,555 matched pairs, we found that a 2nd booster dose of mRNA vaccine, 14–118 days post administration, was moderately effective in preventing SARS-CoV-2 infection compared to a 1st booster dose administered at least 120 days earlier [14.3 %, 95 % confidence interval (CI): 2.2–20.2]. RVE decreased from 28.5 % (95 % CI: 24.7–32.1) in the time-interval 14–28 days to 7.6 % (95 % CI: −14.1 to 18.3) in the time-interval 56–118 days. However, RVE against severe COVID-19 was higher (34.0 %, 95 % CI: 23.4–42.7), decreasing from 43.2 % (95 % CI: 30.6–54.9) to 27.2 % (95 % CI: 8.3–42.9) over the same time span. Although RVE against SARS-CoV-2 infection was much reduced 2–4 months after a 2nd booster dose, RVE against severe COVID-19 was about 30 %, even during prevalent circulation of the Omicron BA.5 subvariant. The cost-benefit of a 3rd booster dose for the elderly people who received the 2nd booster dose at least four months earlier should be carefully evaluated. [ABSTRACT FROM AUTHOR]

Abstract: The striatum is a subcortical area involved in sensorimotor, cognitive and emotional processes. Adenosine A2A receptors (A2ARs) are highly expressed in the striatum, and their ability to establish functional and molecular interactions with many other receptors attributes to a pivotal role in the modulation and integration of striatal neurotransmission. This review will focus on the interaction between A2ARs and cannabinoid CB1 receptors (CB1Rs), taking it as a paradigmatic example of synaptic integration. Indeed, A2ARs can exert an opposite (permissive vs. inhibitory) influence on CB1-dependent synaptic effect. These apparently irreconcilable functions could depend on a different role of pre- vs. postsynaptic A2ARs, on their interaction with other receptors (namely adenosine A1, metabotropic glutamate 5 and dopamine D2 receptors), and on whether A2ARs form or not heteromers with CB1Rs. Besides providing a good example of the intricate pattern of events taking place in striatal synapses, the A2A/CB1R interaction proves very informative to understand the physiology of the basal ganglia and the mechanisms of related diseases. This article is part of a Special Issue entitled: Brain Integration. [Copyright &y& Elsevier]

Huntington’s disease (HD) is a progressive neurodegenerative disorder, characterized by severe degeneration of basal ganglia, motor abnormalities, impaired cognitive functions and emotional disturbances. Intrastriatal injection of the excitotoxin quinolinic acid (QA), an N-methyl-d-aspartate receptor agonist, appears to reproduce in rats some of the clinical features of human HD, included motor and behavioural deficits. Aim of this study was to assess whether the behavioural alterations described in the QA rat model of HD progressed over time. We analysed the effects of bilateral striatal injection of QA (300 nmol/1 μl) to adult rats in the spatial open-field test, a nonaversive task in which exploratory activity and responses to both spatial rearrangement of familiar objects and object novelty are measured. Rats were tested 2 weeks, 2 and 6 months after the QA lesion. Lesioned rats showed progressive alterations in performance in this task. Whereas sham and QA rats did not markedly differ 2 weeks post-lesion, lesioned rats were significantly more active than controls 2 and 6 months after surgery. Specifically, frequency and duration of rearing and wall rearing increased progressively over time, while grooming was enhanced at 2 months post-lesion only. Spatial and object novelty discrimination was not affected. These results show that a single injection of QA excitotoxin can induce behavioural changes that progress over time. The main implication of these findings is that, besides genetic mice models of HD, QA-lesioned rats may represent a suitable mean to test the ability of new drugs to slow down disease progression. [Copyright &y& Elsevier]

The influence of the adenosine A2A receptor antagonist SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-trizolo[1,5-c] pyrimidine) (50, 200 nM, 1 μM) on quinolinic acid effects has been studied in rat striatal and hippocampal slices. Quinolinic acid induced disappearance of field potentials at concentrations of 500 μM and 2 mM in hippocampal and corticostriatal slices, respectively. We found that 1 μM SCH 58261 prevented quinolinic acid-induced field potential disappearance in corticostriatal but not in hippocampal slices. This finding demonstrates that the peculiar binding profile of SCH 58261 and the predominance in the hippocampus of “atypical” adenosine A2A receptor population (not recognized by SCH 58261) could have a functional relevance in the occurrence of region-specific neuroprotective effects. [Copyright &y& Elsevier]

• Fenretinide (N-(4-hydroxyphenyl)retinamide) prevents the toxicity of mutant SOD1 (mSOD1) in NSC-34 motoneurons. • Fenretinide partially overcome the toxic effect of mSOD1 expression on the myogenic program of C2C12 muscle cells. • Fenretinide Nanomicelles (NanoMFEN) delay paralysis onset and survival in the Amyotrophic Lateral Sclerosis mSOD1G93A mice. • Fenretinide efficacy in mSOD1G93A mice ALS mice is sex-related. Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease for which effective treatment options are still lacking. ALS occurs in sporadic and familial forms which are clinically indistinguishable; about 20% of familial ALS cases are linked to mutations of the superoxide dismutase 1 (SOD1) gene. Fenretinide (FEN), a cancer chemopreventive and antiproliferative agent currently used in several clinical trials, is a multi-target drug which also exhibits redox regulation activities. We analyzed the effects of FEN on mutant SOD1 (mSOD1) toxicity in motoneuronal (NSC34) and a muscle (C2C12) cell lines and evaluated the impacts of chronic administration of a new nanomicellar fenretinide formulation (NanoMFen) on ALS disease progression in the SOD1G93A mouse model. The results showed that FEN significantly prevents the toxicity of mSOD1 expression in NSC34 motor neuron; furthermore, FEN is able to partially overcome the toxic effect of mSOD1 on the myogenic program of C2C12 muscle cells. Administration of NanoMFen ameliorates the disease progression and increases median survival of mSOD1G93A ALS mice, even when given after disease onset; beneficial effects in ALS mice, however, is restricted to female sex. Our data support the therapeutic potential of FEN against ALS-associated SOD1G93A mutant protein toxicity and promote further studies to elucidate specific cellular targets of the drug in ALS. Furthermore, the sex-related efficacy of NanoMFen in mSOD1G93A ALS mice strengthens the importance, in the perspective of a precision medicine approach, of gender pharmacology in ALS research. [ABSTRACT FROM AUTHOR]

In the study of neurodegenerative diseases, rodent models provide experimentally accessible systems to study multiple pathogenetic aspects. The identification of early and robust behavioural changes is crucial to monitoring disease progression and testing potential therapeutic strategies in animals. Consistent experimental data support the translational value of rodent self-grooming as index of disturbed motor functions and perseverative behaviour patterns in different rodent models of brain disorders. Huntington’s disease (HD) is a progressive neurodegenerative disorder, characterized by severe degeneration of basal ganglia, cognitive and psychiatric impairments and motor abnormalities. In the rat species, intrastriatal injection of the excitotoxin quinolinic acid (QA) mimics some of the neuroanatomical and behavioural changes found in HD, including the loss of GABAergic neurons and the appearance of motor and cognitive deficits. We show here that striatal damage induced by unilateral QA injection in dorsal striatum of rats triggers aberrant grooming behaviour as early as three weeks post-lesion in absence of other motor impairments: specifically, both quantitative (frequency and duration) and qualitative (the sequential pattern of movements) features of self-grooming behaviour were significantly altered in QA-lesioned rats placed in either the elevated plus-maze and the open-field. The consistent abnormalities in self-grooming recorded in two different experimental contexts support the use of this behavioural marker in rodent models of striatal damage such as HD, to assess the potential effects of drug and cell replacement therapy in the early stage of disease. [ABSTRACT FROM AUTHOR]

Abstract: The effect of chronic treatment with the selective adenosine A2A 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.p.) for 3weeks and the expression levels of NMDA receptor subunits were then evaluated. In addition, to study CGS 21680-induced changes in NMDA receptor function, NMDA-induced toxicity in corticostriatal slices from both R6/2 and WT mice was investigated. We found that CGS 21680 increased NR2A subunit expression and the NR2A/NR2B ratio in the cortex of R6/2 mice, having no effect in WT mice. In the striatum, CGS 21680 reduced NR1 expression in both R6/2 and WT mice while the effect on NR2A and NR2/NR2B expression was genotype-dependent, reducing and increasing their expression in WT and R6/2 mice, respectively. On the contrary, NMDA-induced toxicity in corticostriatal slices was not modified by the treatment in WT or HD mice. These results demonstrate that in vivo activation of A2A receptors modulates the subunit composition of NMDA receptors in the brain of HD mice. [Copyright &y& Elsevier]

Abstract: Early phases of Parkinson''s disease (PD) are characterized by a mild reduction of dopamine (DA) in striatum and by emergence of psychiatric disturbances that precede overt motor symptoms. In order to characterize the neurochemical re-arrangements induced by such striatal impairment, we used a mouse model in which a low dose of 6-hydroxydopamine (6-OHDA) was bilaterally injected into the dorsal striatum. These mice showed a DA reduction of about 40% that remained stable up to 12 weeks after injection. This reduction was accompanied by changes in DA metabolite levels, such as HVA, transiently reduced at 4 weeks, and DOPAC, decreased at 12 weeks. No change in the 5-hydroxytryptamine (5-HT) levels was found but the 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio was increased at 4 weeks. In addition, at the same time-point, the levels of 15-F2t-IsoP, an index of oxidative stress, and of PGE2, a major product of cyclooxygenase-2, were decreased in different brain areas while BDNF levels were increased. These neurochemical changes were accompanied by altered behavioral responses concerning the emotional reactivity. Overall, the present findings suggest that a change of 5-HT metabolism and a modification of oxidative stress levels may play a role in the early PD degeneration phases. [Copyright &y& Elsevier]

Abstract: ST1535 (2-butyl-9-methyl-8-(2H-1,2,3-triazol 2-yl)-9 H-purin-6-ylamine) is a novel compound showing a preferential adenosine A2A receptor antagonist profile. To explore the potential neuroprotective profile of this compound, we evaluated whether ST1535 prevented quinolinic acid (QA)-induced glutamate outflow in the rat striatum (a reliable index of neuroprotective activity in vivo). Microdialysis experiments were performed in naive Wistar rats. In these experiments, a behaviourally active and inactive doses of ST1535 were used. Both doses significantly prevented QA-induced glutamate outflow in the striatum. These results show that ST1535 protects towards striatal excitotoxicity, even though its reduced A2A/A1 selectivity might limit its actual neuroprotective potential. [Copyright &y& Elsevier]

Abstract: Previous studies have shown an impairment of the endocannabinoid system in experimental models of Huntington''s disease. In transgenic R6/2 mice, created by inserting exon 1 of the human IT15 mutant gene into the mouse, and exhibiting 150 CAG repeats as well as signs of HD, a progressive decline of CB1 receptor expression and an abnormal sensitivity to CB1 receptor stimulation have been reported. Here, by using isotope-dilution liquid chromatography–mass spectrometry, we investigated whether the levels of three endogenous neuroprotective substances, the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and palmitoylethanolamide (PEA), are altered in different brain areas of transgenic R6/2 versus wild-type (WT) mice at two different disease phases, i.e. in pre-symptomatic (4.5 weeks) or overtly symptomatic (10 weeks) R6/2 mice versus age-matched WT mice (n =4/group). Except for a ∼25% decrease in 2-AG levels in the cortex, no significant changes in endocannabinoid and PEA levels were observed in pre-symptomatic R6/2 versus WT mice. By contrast, in symptomatic R6/2 mice the levels of all three compounds were significantly (∼30–60%) decreased in the striatum, whereas little changes were observed in the hippocampus, and a ∼28% decrease of 2-AG levels, accompanied by a ∼50% increase of AEA levels, was found in the cortex. These findings show that endocannabinoid levels change in a disease phase- and region-specific way in the brain of R6/2 mice and indicate that an impaired endocannabinoid system is a hallmark of symptomatic HD, thus suggesting that drugs inhibiting endocannabinoid degradation might be used to treat this disease. [Copyright &y& Elsevier]

Abstract: This review summarizes recent developments that have contributed to understand how adenosine receptors, particularly A2A receptors, modulate brain injury in various animal models of neurological disorders, including Parkinson''s disease (PD), stroke, Huntington''s disease (HD), multiple sclerosis, Alzheimer''s disease (AD) and HIV-associated dementia. It is clear that extracellular adenosine acting at adenosine receptors influences the functional outcome in a broad spectrum of brain injuries, indicating that A2ARs may modulate some general cellular processes to affect neuronal cells death. Pharmacological, neurochemical and molecular/genetic approaches to the complex actions of A2A receptors in different cellular elements suggest that A2A receptor activation can be detrimental or protective after brain insults, depending on the nature of brain injury and associated pathological conditions. An interesting concept that emerges from these studies is A2AR''s ability to fine tune neuronal and glial functions to produce neuroprotective effects. While the data presented here clearly highlight the complexity of using adenosinergic agents therapeutically in PD and other neurodegenerative disorders and point out many areas for further inquiry, they also confirm that adenosine receptor ligands, particularly A2A receptor ligands, have many promising characteristics that encourage the pursuit of their therapeutic potential. [Copyright &y& Elsevier]

Abstract: Huntington''s disease (HD) is an inherited neurodegenerative disorder. Adenosine A2A receptors (A2ARs) are involved in excitotoxic/neurodegenerative processes, and A2AR ligands may be neuroprotective in models of HD. However, changes in the transcription, expression and function of A2ARs have been reported to occur in HD models. The aim of the present work was to verify whether A2AR-mediated effects are altered in the striatum of transgenic HD (R6/2) versus wild-type (WT) mice. Extracellular field potentials (FPs) were recorded in corticostriatal slices from R6/2 mice in early (7–8 weeks) or frankly (12–13 weeks) symptomatic phases, and age-matched WT. In 12–13 weeks aged WT animals, the application of 75μM NMDA induced a transient disappearance of the FP followed by an almost complete recovery at washout. In slices from HD mice, the mean FP recovery was significantly reduced (P <0.01 versus WT). A2AR activation oppositely modulated NMDA-induced toxicity in the striatum of HD versus WT mice. Indeed, the A2AR agonist CGS21680 reduced the FP recovery in slices from WT mice, while it significantly increased it in slices from R6/2 mice. In early symptomatic (7–8 weeks) mice, no differences were observed between WT and HD animals in terms of basal synaptic transmission and response to NMDA. At the same age, the behavioural effects elicited by CGS21680 were qualitatively identical in WT and HD mice. These findings may have very important implications for the neuroprotective potential of A2AR ligands in HD. [Copyright &y& Elsevier]

Abstract: Huntington''s disease (HD) is a progressive neurodegenerative disorder, characterised by severe degeneration of basal ganglia, motor abnormalities, impaired cognitive function and emotional disturbances. Many of the distinct neuropathological features of HD are reproduced in rats by intrastriatal injections of the excitotoxin quinolinic acid (QA), and QA-induced excitotoxicity is partially prevented by administration of the A2A receptor antagonist prior to the QA injection. In this study, we assessed the neuroprotective effects of the adenosine A2A receptor antagonist SCH 58261 on the progressive behavioural alterations reported in the QA rat model of Huntington''s disease. Male rats received i.p. SCH 58261 (0.01mg/kg) or vehicle 20min before a bilateral injection of quinolinic acid (QA, 300nmol/1μl) or its vehicle in the dorsal striatum. Motor activity and anxiety levels were analyzed in an open-field arena and in an elevated plus-maze at 2 weeks, 2 months and 6 months post-lesion. In QA-lesioned rats SCH 58261 prevented alterations of wall rearing behaviour starting from 2 weeks post-lesion while emotional changes (reduced anxiety) were back to control levels by 6 months post-lesion. These findings extend to the behavioural parameters the protective effects of SCH 58261 in the QA model of Huntington''s disease. [Copyright &y& Elsevier]

In the quinolinic acid (QA)-rat model of Huntington’s disease (HD), 15 days after QA injection, striatal glutamate, measured by in vivo microdialysis, was unchanged while a significant decrease in adenosine occurred. The decrease in adenosine may depend on QA-induced striatal cell loss. Probe perfusion of the adenosine A2A receptor antagonist SCH 58261 significantly increased striatal glutamate outflow, suggesting a potential detrimental effect of A2A antagonism at later stages of the neurodegenerative process induced by QA. [Copyright &y& Elsevier]

Huntington''s disease (HD) is a devastating hereditary neurodegenerative disorder, the progression of which cannot be prevented by any neuroprotective approach, despite major advances in the understanding of its pathogenesis. The study of several animal models of the disease has led to the discovery of both loss-of-normal and gain-of-toxic functions of the mutated huntingtin protein and the elucidation of the mechanisms that underlie the formation of huntingtin aggregates and nuclear inclusions. Moreover, these models also provide good evidence of a role for excitotoxicity and mitochondrial metabolic impairments in striatal neuronal death. Adenosine has neuroprotective potential in both acute and chronic neurological disorders such as stroke or Parkinson''s disease. Here we review experimental data on the role of A1 and A2A adenosine receptors in HD that warrant further investigation of the beneficial effects of A1 agonists and A2A antagonists in animal models of HD. Future pharmacological analysis of adenosine receptors could justify the use of A1 agonists and A2A antagonists for the treatment of HDin clinical trials. [Copyright &y& Elsevier]

Interactions between subtypes of dopamine, glutamate and adenosine receptors seem to play an important integrative role in the function of striatal gamma-aminobutyric acid (GABA)ergic efferent neurons. Recent behavioral and biochemical studies suggest the existence of specific interactions between adenosine A2A receptors (A2AR), dopamine D2 receptors (D2R) and the group I metabotropic mGlu5 receptors (mGlu5R) in the dorsal striatum. The dual-probe approach in vivo microdialysis technique in freely moving rats was used to study the role of mGlu5R/A2AR/D2R interactions in the modulation of the ventral striopallidal GABA pathway. Perfusion of a selective mGlu5R agonist (CHPG) in the nucleus accumbens facilitated GABA release in the ipsilateral ventral pallidum. This effect was strongly potentiated by co-perfusion with the A2AR agonist CGS 21680. Co-perfusion with the D2R agonist quinpirole counteracted the increase in pallidal GABA levels induced by CGS 21680 and by CGS 21680 plus CHPG. These results demonstrate that mGlu5R/A2AR/D2R interactions play an important modulatory role in the function of the ventral striopallidal GABA pathway, which might have implications for the treatment of schizophrenia and drug addiction. [Copyright &y& Elsevier]

Pneumonia is the most frequent complication of COVID-19, due to an aberrant host immune response that is associated with an acute respiratory distress syndrome, and, in most critical patients, with a "cytokine storm". IL-6 might play a key role in the cytokine storm and might be a potential target to treat severe and critical COVID-19. Tocilizumab is a recombinant humanized monoclonal antibody, directed against IL-6 receptor. This multicentre study project includes a single-arm phase 2 study and a further parallel cohort, enrolling hospitalized patients with COVID-19 pneumonia and oxygen saturation at rest in ambient air ≤93% or requiring respiratory support. Patients receive tocilizumab 8 mg/kg (up to 800 mg) as one intravenous administration. A second administration (same dose) after 12 h is optional. Two-week and one-month lethality rates are the co-primary endpoints. Sample size planned for the phase 2 study is 330 patients. The parallel cohort will include patients who cannot enter the phase 2 study because being intubated from more than 24 h , or having already received tocilizumab, or the phase 2 study has reached sample size. Primary analysis will include patients enrolled in the phase 2 study. Results of the primary analysis will be validated in the prospective cohort of patients consecutively registered after phase 2 closure from March 20 to March 24, who were potentially eligible for the phase 2 study. This trial aims to verify the safety and efficacy of tocilizumab in the Italian population with COVID-19 pneumonia and respiratory impairment. EudraCT Number: 2020–001110-38; Clinicaltrials.gov ID NCT04317092 [ABSTRACT FROM AUTHOR]