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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 A2A receptors (A2ARs), modulators of neuronal damage, could play a role in FXS. A synaptic colocalization and a strong permissive interaction between A2A and mGlu5 receptors in the hippocampus have been previously reported, suggesting that blocking A2ARs might normalize the mGlu5R-mediated effects of FXS. To study the cross-talk between A2A and mGlu5 receptors in the absence of FMRP, we performed extracellular electrophysiology experiments in hippocampal slices of Fmr1 KO mouse. The depression of field excitatory postsynaptic potential (fEPSPs) slope induced by the mGlu5R agonist CHPG was completely blocked by the A2AR antagonist ZM241385 and strongly potentiated by the A2AR agonist CGS21680, suggesting that the functional synergistic coupling between the two receptors could be increased in FXS. To verify if chronic A2AR blockade could reverse the FXS phenotypes, we treated the Fmr1 KO mice with istradefylline, an A2AR antagonist. We found that hippocampal DHPG-induced long-term depression (LTD), which is abnormally increased in FXS mice, was restored to the WT level. Furthermore, istradefylline corrected aberrant dendritic spine density, specific behavioral alterations, and overactive mTOR, TrkB, and STEP signaling in Fmr1 KO mice. Finally, we identified A2AR mRNA as a target of FMRP. Our results show that the pharmacological blockade of A2ARs partially restores some of the phenotypes of Fmr1 KO mice, both by reducing mGlu5R functioning and by acting on other A2AR-related downstream targets.

In recent years there has been an increasing awareness of the role of P2X7, a receptor for extracellular ATP, in modulating physiopathological mechanisms in the central nervous system. In particular, P2X7 has been shown to be implicated in neuropsychiatry, chronic pain, neurodegeneration and neuroinflammation. Remarkably, P2X7 has also been shown to be a 'gene modifier' in amyotrophic lateral sclerosis (ALS): the receptor is upregulated in spinal cord microglia in human and rat at advanced stages of the disease; in vitro, activation of P2X7 exacerbates pro-inflammatory responses in microglia that have an ALS phenotype, as well as toxicity towards neuronal cells. Despite this detrimental in vitro role of P2X7, in SOD1-G93A mice lacking P2X7, the clinical onset of ALS was significantly accelerated and disease progression worsened, thus indicating that the receptor might have some beneficial effects, at least at certain stages of disease. In order to clarify this dual action of P2X7 in ALS pathogenesis, in the present work we used the antagonist Brilliant Blue G (BBG), a blood-brain barrier permeable and safe drug that has already been proven to reduce neuroinflammation in traumatic brain injury, cerebral ischemia-reperfusion, neuropathic pain and experimental autoimmune encephalitis. We tested BBG in the SOD1-G93A ALS mouse model at asymptomatic, pre-symptomatic and late pre-symptomatic phases of disease. BBG at late pre-onset significantly enhanced motor neuron survival and reduced microgliosis in lumbar spinal cord, modulating inflammatory markers such as NF-κB, NADPH oxidase 2, interleukin-1β, interleukin-10 and brain-derived neurotrophic factor. This was accompanied by delayed onset and improved general conditions and motor performance, in both male and female mice, although survival appeared unaffected. Our results prove the twofold role of P2X7 in the course of ALS and establish that P2X7 modulation might represent a promising therapeutic strategy by interfering with the neuroinflammatory component of the disease.

Amyotrophic lateral sclerosis (ALS) is a rare progressive motor neuron disease that, due to its high complexity, still lacks effective treatments. Development of a new drug is a highly costly and time-consuming process, and the repositioning of approved drugs can represent an efficient strategy to provide therapeutic opportunities. This is particularly true for rare diseases, which are characterised by small patient populations and therefore attract little commercial interest. Based on the overlap between the biological background of cancer and neurodegeneration, the repurposing of antineoplastic drugs for ALS has been suggested. The objective of this narrative review was to summarise the current experimental evidence on the use of approved anticancer drugs in ALS. Specifically, anticancer drugs belonging to different classes were found to act on mechanisms involved in the ALS pathogenesis, and some of them proved to exert beneficial effects in ALS models. However, additional studies are necessary to confirm the real therapeutic potential of anticancer drugs for repositioning in ALS treatment.

In recent years there has been an increasing awareness on the role of P2X7 receptor for extracellular ATP in modulating physiopathological mechanisms in the CNS. In particular, P2X7 was shown to be implicated in neuropsychiatry, chronic pain, neurodegeneration, neuroinflammation. Remarkably, P2X7 was shown to be a \"gene modifier\" in amyotrophic lateral sclerosis (ALS): the receptor is up-regulated in spinal cord microglia in human and rat at advanced stages of the disease; in vitro, activation of P2X7 exacerbates pro-inflammatory responses in ALS-microglia, as well as toxicity towards neuronal cells. Despite this detrimental in vitro role of P2X7, in P2X7−/−/SOD1-G93A mice the clinical onset of ALS was significantly accelerated and disease progression worsened, thus indicating that the receptor might have some beneficial effects at least at certain stages of disease. In order to clarify this dual action of P2X7 in ALS pathogenesis, in the present work we used the antagonist Brilliant Blue G (BBG), a blood-brain barrier permeable and safe drug already proven to reduce neuroinflammation in traumatic brain injury, cerebral ischemia/reperfusion, neuropathic pain and experimental autoimmune encephalitis. We tested BBG in SOD1-G93A ALS mouse model at asymptomatic, pre-symptomatic and late pre-symptomatic phases of disease. BBG at late pre-onset significantly enhances motoneuron survival and reduces microgliosis in lumbar spinal cord, modulating inflammatory markers such as NF-κB, NADPH oxidase 2, interleukin-1β, interleukin-10 and brain-derived neurotrophic factor. This is accompanied by delayed onset and improved general conditions and motor performance, in both male and female mice, although survival appears not affected. Our results prove the twofold role of P2X7 in the course of ALS, and establish that P2X7 modulation might represent a promising therapeutic strategy by interfering with the neuroinflammatory component of the disease.

Amyotrophic lateral sclerosis (ALS) is a fatal progressing neurodegenerative disease; to date, despite the intense research effort, only two therapeutic options, with very limited effects, are available. The purinergic system has been indicated as a possible new therapeutic target for ALS, but the results are often contradictory and generally confused. The present study was designed to determine whether P1 adenosine receptor ligands affected disease progression in a transgenic model of ALS. SOD1G93A mice were chronically treated, from presymptomatic stage, with a selective adenosine A2A receptor agonist (CGS21680), antagonist (KW6002) or the A1 receptor antagonist DPCPX. Body weight, motor performance and survival time were evaluated. The results showed that neither the stimulation nor the blockade of adenosine A2A receptors modified the progressive loss of motor skills or survival of mSOD1G93A mice. Conversely, blockade of adenosine A1 receptors from the presymptomatic stage significantly attenuated motor disease progression and induced a non-significant increase of median survival in ALS mice. Our data confirm that the modulation of adenosine receptors can elicit very different (and even opposite) effects during the progression of ALS course, thus strengthens the importance of further studies to elucidated their real therapeutic potential in this pathology.

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.

The surface-enhanced Raman scattering (SERS) spectra of three amphiphilic oligopeptides derived from EAK16 (AEAEAKAK)2 were examined to study systematic amino acid substitution effects on the corresponding interaction with Ag colloidal nanoparticles. Such self-assembling molecular systems, known as “molecular Lego”, are of particular interest for their uses in tissue engineering and as biomimetic coatings for medical devices because they can form insoluble macroscopic membranes under physiological conditions. Spectra were collected for both native and gamma-irradiated samples. Quantum mechanical data on two of the examined oligopeptides were also obtained to clarify the assignment of the prominent significative bands observed in the spectra. In general, the peptide–nanoparticles interaction occurs through the COO− groups, with the amide bond and the aliphatic chain close to the colloid surface. After gamma irradiation, mimicking a free oxidative radical attack, the SERS spectra of the biomaterials show that COO− groups still provide the main peptide–nanoparticle interactions. However, the spatial arrangement of the peptides is different, exhibiting a systematic decrease in the distance between aliphatic chains and colloid nanoparticles.

•Dog attacks today represent a health hazard.•Aggressor dog identification is critical to ascertain the owner.•This experimental study proposes a new forensic approach. Dog attacks today represent a health hazard considering that prevention strategies have not always been successful. The identification of the dog that attacked the victim is necessary, considering the civil or criminal consequences for the animal’s owner. An accurate scene analysis must be performed collecting a series of important information. Forensic investigations in dog attacks involve different methods, such as the evaluating of the canine Short Tandem Repeat (STR) typing in saliva traces on wounds or bite mark analysis, however, these techniques cannot always be applied. The effort to find new methods to identify the dog that attacked the victim represents a very interesting field for the forensic community. This study aims to propose an innovative approach, based on the identification of the victim's profile in the dog's mouth, using a buccal swab on the suspected aggressor dog, to find the victim’s genetic profile. In addition, a further goal of this study is to determine the persistence time of hexogen DNA in the dog’s mouth to define a timeframe for performing this particular technique. For this purpose, ten different dogs were used to aggressively bite a bovine sample (reference sample) to simulate the victim. For each dog two buccal swabs were taken at different time intervals: 30′, 45′, 60′, 90′, 120′, 150′, 180′ and 240′. The typing of the swabs provided an interpretable profile after 45′ while traces of bovine profile were found until 150′ after the dog attack simulation. These results could be improved using the human identification kit, which is more sensitive. In the light of this experimental study, the forensic community should consider using this approach in real casework studies with the aim of collecting new data, validating this technique for forensic use.

Mucopolysaccharidosis VI (MPS VI) is caused by deficient activity of arylsulfatase B (ARSB), resulting in intralysosomal storage of dermatan sulfate (DS) and multisystem disease without central nervous system involvement. After gene transfer, muscle or liver can theoretically be converted into factories for systemic ARSB secretion, leading to uptake by non-transduced cells. We have injected newborn MPS VI rats and cats with adeno-associated viral (AAV) vectors expressing ARSB under the control of liver-specific, muscle-specific, or universally active promoters. After systemic or intramuscular (IM) administration of AAV, therapeutic levels of circulating ARSB are achieved, resulting in skeletal improvements and significant decrease in glycosaminoglycan (GAG) storage, inflammation and apoptosis (despite a neutralizing immune response to ARSB in MPS VI rats). In addition, we have observed wide-spread dissemination of vector after IM AAV administration. This results in secretion of therapeutic levels of ARSB when the universally active cytomegalovirus (CMV) but not the muscle-specific muscle creatine kinase (MCK) promoter is used, suggesting that transduction of extramuscular sites rather than enzyme secretion from muscle occurs after muscle ARSB gene transfer. We conclude that AAV-mediated expression of ARSB from liver represents a feasible therapeutic strategy for MPS VI, potentially avoiding multiple infusions of costly recombinant enzyme associated with enzyme replacement therapy.

Objectives To explore the prevalence of obesity and risk of metabolic complications among workers of a harness plant in Durango, Mexico. Method A croos-sectional study was conducted on 300 workers. Measurements of body mass index (BMI) and waist hip ratio (WHR) were obtained. BMI (m/kg2) was classified into underweight (<18.5), normal range (18.5–24.9), pre-obese (25.0–29.9), obese class I (30.0–34.9), obese class II (35.0–39.9), and obese class III (≥40.0). Risk of metabolic complications (RMC) was considered high when WHR > 0.85 for women, and > 0.95 for men; and moderated between 0.80–0.85 for women and 0.90–0.95 for men. Analysis of variance (ANOVA) was applied for continuos variables, and χ2 test for categorical variables. Results The mean age (±SD) of the subjects was 28.7 (±8.9) yrs. In the sample, 51.7% were male. According to the BMI, 47.3% of participants were in the normal range, 35.3% pre-obese, and 15.7% showed obesity. According to the WHR, 30% were at high risk, and 28.6% at moderate risk for developing metabolic complications. The RMC (high and moderate) was significant more prevalent in women than in men, 77.5% vs 49.3%, (p < 0.0001). ANOVA yielded significant variation in obesity according to age (p < 0.001). Post hoc Tukey test showed differences of obese class II with normal range (p = 0.007) and underweight (p = 0.0169). Conclusions The prevalence of obesity and RMC are quite high in studied population. The risk is higher among women and increases with age.