Two Signaling Modes Are Better than One: Flux-Independent Signaling by Ionotropic Glutamate Receptors Is Coming of Age.

Glutamate is the major excitatory neurotransmitter in the central nervous system. Glutamatergic transmission can be mediated by ionotropic glutamate receptors (iGluRs), which mediate rapid synaptic depolarization that can be associated with Ca2+ entry and activity-dependent change in the strength of synaptic transmission, as well as by metabotropic glutamate receptors (mGluRs), which mediate slower postsynaptic responses through the recruitment of second messenger systems. A wealth of evidence reported over the last three decades has shown that this dogmatic subdivision between iGluRs and mGluRs may not reflect the actual physiological signaling mode of the iGluRs, i.e., α-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid (AMPA) receptors (AMPAR), kainate receptors (KARs), and N-methyl-D-aspartate (NMDA) receptors (NMDARs). Herein, we review the evidence available supporting the notion that the canonical iGluRs can recruit flux-independent signaling pathways not only in neurons, but also in brain astrocytes and cerebrovascular endothelial cells. Understanding the signaling versatility of iGluRs can exert a profound impact on our understanding of glutamatergic synapses. Furthermore, it may shed light on novel neuroprotective strategies against brain disorders.

Circulating miRNAs as Novel Clinical Biomarkers in Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) represents the most common form of refractory focal epilepsy. The identification of innovative clinical biomarkers capable of categorizing patients with TLE, allowing for improved treatment and outcomes, still represents an unmet need. Circulating microRNAs (c-miRNAs) are short non-coding RNAs detectable in body fluids, which play crucial roles in the regulation of gene expression. Their characteristics, including extracellular stability, detectability through non-invasive methods, and responsiveness to pathological changes and/or therapeutic interventions, make them promising candidate biomarkers in various disease settings. Recent research has investigated c-miRNAs in various bodily fluids, including serum, plasma, and cerebrospinal fluid, of TLE patients. Despite some discrepancies in methodologies, cohort composition, and normalization strategies, a common dysregulated signature of c-miRNAs has emerged across different studies, providing the basis for using c-miRNAs as novel biomarkers for TLE patient management.

Deprescribing in Older Poly-Treated Patients Affected with Dementia.

Polypharmacy is an important issue in older patients affected by dementia because they are very vulnerable to the side effects of drugs'. Between October 2021 and September 2022, we randomly assessed 205 old-aged outpatients. The study was carried out in a Center for Dementia in collaboration with a university center. The primary outcomes were: (1) deprescribing inappropriate drugs through the Beers and STOPP&START criteria; (2) assessing duplicate drugs and the risk of iatrogenic damage due to drug-drug and drug-disease interactions. Overall, 69 men and 136 women (mean age 82.7 ± 7.4 years) were assessed. Of these, 91 patients were home care patients and 114 were outpatient. The average number of the drugs used in the sample was 9.4 drugs per patient; after the first visit and the consequent deprescribing process, the average dropped to 8.7 drugs per patient (p = 0.04). Overall, 74 potentially inappropriate drugs were used (36.1%). Of these, long half-life benzodiazepines (8.8%), non-steroidal anti-inflammatory drugs (3.4%), tricyclic antidepressants (3.4%), first-generation antihistamines (1.4%), anticholinergics (11.7%), antiplatelet drugs (i.e., ticlopidine) (1.4%), prokinetics in chronic use (1.4%), digoxin (>0.125 mg/day) (1.4%), antiarrhythmics (i.e., amiodarone) (0.97%), and α-blockers (1.9%) were included. The so-called "duplicate" drugs were overall 26 (12.7%). In total, ten potentially dangerous prescriptions were found for possible interactions (4.8%). We underline the importance of checking all the drugs taken periodically and discontinuing drugs with the lowest benefit-to-harm ratio and the lowest probability of adverse reactions due to withdrawal. Computer tools and adequately trained teams (doctors, nurses, and pharmacists) could identify, treat, and prevent possible drug interactions.

Humoral and T-cell response to SARS-CoV-2 mRNA vaccine in multiple sclerosis patients: Correlations with DMTs and clinical variables.

Disease-modifying therapies (DMTs) can affect vaccine responses in individuals with multiple sclerosis (MS). We assessed the humoral and T-cell responses following SARS-CoV-2 mRNA vaccination in MS patients receiving various DMTs. We prospectively enrolled 243 participants, including 113 healthy control subjects and 130 MS patients. Blood samples for detecting SARS-CoV-2 antibodies were collected at three time points: T0, before the first vaccine dose; T1, before the second dose; and T2, one month after the second dose. In a subgroup of 51 patients and 20 controls, samples were collected at T0 and T2 to assess the T-cell immune response to the Spike antigen of SARS-CoV-2 using ELISPOT-IFNγ. The IgG levels in patients treated with fingolimod and ocrelizumab (159.1 AU/ml and 467.1 AU/ml, respectively) were significantly lower than those in healthy controls and patients on other DMTs (P â€‹< â€‹0.0001). The mean Ig titers were higher in patients with an absolute lymphocyte count ≥1000 â€‹cells/mm3 compared to those with a count between 500 and 1000 and with a count <500 (mean â€‹± â€‹SD:7205.6 â€‹± â€‹7339.2, 2413.1 â€‹± â€‹4515.4 and 165.9 â€‹± â€‹152.2, respectively; p â€‹= â€‹0.008). We found correlations between antibody levels and age (r â€‹= â€‹0.233, p â€‹= â€‹0.008). A positive Spike-specific T-cell response was detectable in 100 â€‹% of vaccinated healthy controls and patients treated with teriflunomide, dimethyl-fumarate, and natalizumab, in 90.5 â€‹% of fingolimod patients, and in 63.8 â€‹% of ocrelizumab patients. There is a correlation between IgG-specific titer after SARS-CoV-2 vaccination and clinical variables (age, lymphocyte count). Notably, a T-cell-specific response to SARS-CoV-2 developed in patients treated with fingolimod and ocrelizumab, even with lower rates of humoral response.

Impact of micronutrients and nutraceuticals on cognitive function and performance in Alzheimer's disease.

Alzheimer's disease (AD) is a major global health problem today and is the most common form of dementia. AD is characterized by the formation of ß-amyloid (Aß) plaques and neurofibrillary clusters, leading to decreased brain acetylcholine levels in the brain. Another mechanism underlying the pathogenesis of AD is the abnormal phosphorylation of tau protein that accumulates at the level of neurofibrillary aggregates, and the areas most affected by this pathological process are usually the cholinergic neurons in cortical, subcortical, and hippocampal areas. These effects result in decreased cognitive function, brain atrophy, and neuronal death. Malnutrition and weight loss are the most frequent manifestations of AD, and these are also associated with greater cognitive decline. Several studies have confirmed that a balanced low-calorie diet and proper nutritional intake may be considered important factors in counteracting or slowing the progression of AD, whereas a high-fat or hypercholesterolemic diet predisposes to an increased risk of developing AD. Especially, fruits, vegetables, antioxidants, vitamins, polyunsaturated fatty acids, and micronutrients supplementation exert positive effects on aging-related changes in the brain due to their antioxidant, anti-inflammatory, and radical scavenging properties. The purpose of this review is to summarize some possible nutritional factors that may contribute to the progression or prevention of AD, understand the role that nutrition plays in the formation of Aß plaques typical of this neurodegenerative disease, to identify some potential therapeutic strategies that may involve some natural compounds, in delaying the progression of the disease.

Acute effects of a chewable beetroot-based supplement on cognitive performance: a double-blind randomized placebo-controlled crossover clinical trial.

BACKGROUND: Dietary nitrate (NO3-) has been shown to be useful as an ergogenic aid with potential applications in health and disease (e.g., blood pressure control). However, there is no consensus about the effects of dietary NO3- or beetroot (BR) juice supplementation on cognitive function. OBJECTIVE: The aim of this study was to evaluate the effects of a single dose of a chewable BR-based supplement on cognitive performance. METHODS: A double-blind randomized placebo-controlled two-period crossover clinical trial was carried out based on the extension of the CONSORT guidelines for randomized crossover trials. A total of 44 participants (24 F; 20 M; 32.7 [12.5] years; 66.3 [9.0] kg; 170 [9.2] cm; 22.8 [1.4] kg/m2) were randomly allocated to receive first either four BR-based chewable tablets (BR-CT) containing 3 g of a Beta vulgaris extract (RedNite®) or four tablets of a placebo (maltodextrin). A 4-day washout period was used before crossover. Ninety minutes after ingestion of the treatments, a neuropsychological testing battery was administered in each period. The trial was registered at clinicaltrials.gov NCT05509075. RESULTS: Significant improvements with moderate effect size were found on memory consolidation at the short and long term only after BR-CT supplementation via the Rey Auditory Verbal Learning Test immediate (+ 20.69%) and delayed (+ 12.34%) recalls. Likewise, enhancement on both frontal lobe functions (+ 2.57%) and cognitive flexibility (+ 11.16%) were detected after BR-CT. There was no significant change (p < 0.05) on verbal memory of short-term digits, working memory and information processing speed. Mixed results were found on mood and anxiety through the Beck Depression Inventory-II (BDI-II) and the State-Trait Anxiety Inventory (STAI-Y1 and STAI-Y2); however, sequence and period effects were seen on STAI-Y2. CONCLUSIONS: The acute administration of a chewable BR-based supplement improves certain aspects of cognitive function in healthy females and males, particularly memory capacity and frontal skills.

Cenobamate enhances the anticonvulsant effect of other antiseizure medications in the DBA/2 mouse model of reflex epilepsy.

Clinical studies documented that cenobamate (CNB) has a marked efficacy compared to other antiseizure medications (ASMs) in reducing focal seizures. To date, different aspects of CNB need to be clarified, including its efficacy against generalized seizures. Similarly, the pattern of drug-drug interactions between CNB and other ASMs also compels further investigation. This study aimed to detect the role of CNB on generalized seizures using the DBA/2 mouse model. We have also studied the effects of an adjunctive CNB treatment on the antiseizure properties of some ASMs against reflex seizures. The effects of this adjunctive treatment on motor performance, body temperature, and brain levels of ASMs were also evaluated. CNB was able to antagonize seizures in DBA/2 mice. CNB, at 5 mg/kg, enhanced the antiseizure activity of ASMs, such as diazepam, clobazam, levetiracetam, perampanel, phenobarbital, topiramate, and valproate. No synergistic effects were observed when CNB was co-administered with some Na+ channel blockers. The increase in antiseizure activity was associated with a comparable intensification in motor impairment; however, the therapeutic index of combined treatment of ASMs with CNB was more favorable than the combination with vehicle except for carbamazepine, phenytoin, and oxcarbazepine. Since CNB did not significantly influence the brain levels of the ASMs studied, we suggest that pharmacokinetic interactions seem not probable. Overall, this study shows the ability of CNB to counteract generalized reflex seizures in mice. Moreover, our data documented an evident synergistic antiseizure effect for the combination of CNB with ASMs including phenobarbital, benzodiazepines, valproate, perampanel, topiramate, and levetiracetam.

The Risk of Drug Interactions in Older Primary Care Patients after Hospital Discharge: The Role of Drug Reconciliation.

INTRODUCTION: Drug-drug interactions (DDIs) represent an important clinical problem, particularly in older patients, due to polytherapy, comorbidity, and physiological changes in pharmacodynamic and pharmacokinetic pathways. In this study, we investigated the association between drugs prescribed after discharge from the hospital or clinic and the risk of DDIs with drugs used daily by each patient. METHODS: We performed an observational, retrospective, multicenter study on the medical records of outpatients referred to general practitioners. DDIs were measured using the drug interaction probability scale. Potential drug interactions were evaluated by clinical pharmacologists (physicians) and neurologists. Collected data were analyzed using the Statistical Package for the Social Sciences. RESULTS: During the study, we evaluated 1772 medical records. We recorded the development of DDIs in 10.3% of patients; 11.6% of these patients required hospitalization. Logistic regression showed an association among DDIs, sex, and the number of drugs used (p = 0.023). CONCLUSIONS: This observational real-life study shows that the risk of DDIs is common in older patients. Physicians must pay more attention after hospital discharge, evaluating the treatment to reduce the risk of DDIs.

Metformin in Gestational Diabetes Mellitus: To Use or Not to Use, That Is the Question.

In recent years, there has been a dramatic increase in the number of pregnancies complicated by gestational diabetes mellitus (GDM). GDM occurs when maternal insulin resistance develops and/or progresses during gestation, and it is not compensated by a rise in maternal insulin secretion. If not properly managed, this condition can cause serious short-term and long-term problems for both mother and child. Lifestyle changes are the first line of treatment for GDM, but if ineffective, insulin injections are the recommended pharmacological treatment choice. Some guidance authorities and scientific societies have proposed the use of metformin as an alternative pharmacological option for treating GDM, but there is not yet a unanimous consensus on this. Although the use of metformin appears to be safe for the mother, concerns remain about its long-term metabolic effects on the child that is exposed in utero to the drug, given that metformin, contrary to insulin, crosses the placenta. This review article describes the existing lines of evidence about the use of metformin in pregnancies complicated by GDM, in order to clarify its potential benefits and limits, and to help clinicians make decisions about who could benefit most from this drug treatment.

Audiogenic epileptic DBA/2 mice strain as a model of genetic reflex seizures and SUDEP.

Epilepsy is a chronic neurological disease characterized by abnormal brain activity, which results in repeated spontaneous seizures. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of seizure-related premature death, particularly in drug-resistant epilepsy patients. The etiology of SUDEP is a structural injury to the brain that is not fully understood, but it is frequently associated with poorly controlled and repeated generalized tonic-clonic seizures (GTCSs) that cause cardiorespiratory and autonomic dysfunctions, indicating the involvement of the brainstem. Both respiratory and cardiac abnormalities have been observed in SUDEP, but not much progress has been made in their prevention. Owing to the complexity of SUDEP, experimental animal models have been used to investigate cardiac and/or respiratory dysregulation due to or associated with epileptic seizures that may contribute to death in humans. Numerous rodent models, especially mouse models, have been developed to better understand epilepsy and SUDEP physiopathology. This review synthesizes the current knowledge about dilute brown agouti coat color (DBA/2) mice as a possible SUDEP model because respiratory arrest (RA) and sudden death induced by audiogenic generalized seizures (AGSs) have been observed in these animals. Respiratory/cardiac dysfunction, brainstem arousal system dysfunction, and alteration of the neurotransmitter systems, which are observed in human SUDEP, have also been observed in these mice. In particular, serotonin (5-HT) alteration and adenosine neurotransmission appear to contribute to not only the pathophysiological mechanisms of medication but also seizure-related respiratory dysfunctions in this animal model. These neurotransmitter systems could be the relevant targets for medication development for chronic epilepsy and SUDEP prevention. We reviewed data on AGSs in DBA/2 mice and the relevance of this model of generalized tonic-clonic epilepsy to human SUDEP. Furthermore, the advantages of using this strain prone to AGSs for the identification of possible new therapeutic targets and treatment options have also been assessed.

Hyperkalemia in CKD: an overview of available therapeutic strategies.

Hyperkalemia (HK) is a life-threatening condition that often occurs in patients with chronic kidney disease (CKD). High serum potassium (sKsK) is responsible for a higher risk of end-stage renal disease, arrhythmias and mortality. This risk increases in patients that discontinue cardio-nephroprotective renin-angiotensin-aldosterone system inhibitor (RAASi) therapy after developing HK. Hence, the management of HK deserves the attention of the clinician in order to optimize the therapeutic strategies of chronic treatment of HK in the CKD patient. The adoption in clinical practice of the new hypokalaemic agents patiromer and sodium zirconium cyclosilicate (SZC) for the prevention and chronic treatment of HK could allow patients, suffering from heart failure and chronic renal failure, to continue to benefit from RAASi therapy. We have updated a narrative review of the clear variables, correct definition, epidemiology, pathogenesis, etiology and classifications for HK among non-dialysis CKD (ND CKD) patients. Furthermore, by describing the prognostic impact on mortality and on the progression of renal damage, we want to outline the strategies currently available for the control of potassium (K+) plasma levels.

Antiseizure Medications in Alzheimer's Disease from Preclinical to Clinical Evidence.

Alzheimer's disease (AD) and epilepsy are common neurological disorders in the elderly. A bi-directional link between these neurological diseases has been reported, with patients with either condition carrying almost a two-fold risk of contracting the other compared to healthy subjects. AD/epilepsy adversely affects patients' quality of life and represents a severe public health problem. Thus, identifying the relationship between epilepsy and AD represents an ongoing challenge and continuing need. Seizures in AD patients are often unrecognized because they are often nonconvulsive and sometimes mimic some behavioral symptoms of AD. Regarding this, it has been hypothesized that epileptogenesis and neurodegeneration share common underlying mechanisms. Targeted treatment to decrease epileptiform activity could represent a valuable strategy for delaying the neurodegenerative process and related cognitive impairment. Several preclinical studies have shown that some antiseizure medications (ASMs) targeting abnormal network hyperexcitability may change the natural progression of AD. However, to date, no guidelines are available for managing seizures in AD patients because of the paucity of randomized clinical trials sufficient for answering the correlated questions. Future AD clinical studies are mandatory to update clinicians about the symptomatic treatment of seizures in AD patients and recognize whether ASM therapy could change the natural progression of the disease, thereby rescuing cognitive performance.

The Effects of Andrographis paniculata (Burm.F.) Wall. Ex Nees and Andrographolide on Neuroinflammation in the Treatment of Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) affect millions of people worldwide, and to date, Alzheimer's and Parkinson's diseases are the most common NDs. Of the many risk factors for neurodegeneration, the aging process has the most significant impact, to the extent that it is tempting to consider neurodegenerative disease as a manifestation of accelerated aging. However, genetic and environmental factors determine the course of neurodegenerative disease progression. It has been proposed that environmental stimuli influence neuroplasticity. Some clinical studies have shown that healthy lifestyles and the administration of nutraceuticals containing bioactive molecules possessing antioxidant and anti-inflammatory properties have a preventive impact or mitigate symptoms in previously diagnosed patients. Despite ongoing research efforts, the therapies currently used for the treatment of NDs provide only marginal therapeutic benefits; therefore, the focus is now directly on the search for natural products that could be valuable tools in combating these diseases, including the natural compound Andrographis paniculata (Ap) and its main constituent, andrographolide (Andro). Preclinical studies have shown that the aqueous extract of Ap can modulate neuroinflammatory and neurodegenerative responses, reducing inflammatory markers and oxidative stress in various NDs. Therefore, in this review, we will focus on the molecular mechanisms by which Ap and Andro can modulate the processes of neurodegeneration and neuroinflammation, which are significant causes of neuronal death and cognitive decline.

An In Vivo Electroencephalographic Analysis of the Effect of Riluzole against Limbic and Absence Seizure and Comparison with Glutamate Antagonists.

BACKGROUND: Riluzole (RLZ) has demonstrated neuroprotective effects in several neurological disorders. These neuroprotective effects seem to be mainly due to its ability to inhibit the excitatory glutamatergic neurotransmission, acting on different targets located both at the presynaptic and postsynaptic levels. METHODS: In the present study, we evaluated the effects of Riluzole (RLZ) against limbic seizures, induced by AMPA, kainate, and NMDA receptor agonists in Sprague-Dawley rats, and in a well-validated genetic model of absence epilepsy, the WAG/Rij rat. Furthermore, in this latter model, we also studied the effect of RLZ in co-administration with the competitive NMDA receptor antagonist, CPP, or the non-competitive AMPA receptor antagonist, THIQ-10c, on spike-wave discharges (SWDs) in WAG/Rij rats, to understand the potential involvement of AMPA and NMDA receptors in the anti-absence effect of RLZ. RESULTS: In Sprague-Dawley rats, RLZ pretreatment significantly reduced the limbic seizure severity induced by glutamatergic agonists, suggesting an antagonism of RLZ mainly on NMDA rather than non-NMDA receptors. RLZ also reduced SWD parameters in WAG/Rij rats. Interestingly, the co-administration of RLZ with CPP did not increase the anti-absence activity of RLZ in this model, advocating a competitive effect on the NMDA receptor. In contrast, the co-administration of RLZ with THIQ-10c induced an additive effect against absence seizure in WAG/Rij rats. CONCLUSIONS: these results suggest that the antiepileptic effects of RLZ, in both seizure models, can be mainly due to the antagonism of the NMDA glutamatergic receptors.

Seizure susceptibility to various convulsant stimuli in the BTBR mouse model of autism spectrum disorders.

Background: Autism spectrum disorders (ASDs) are one of the most severe chronic childhood disorders in terms of prevalence, morbidity, and impact on society. Interestingly, several systematic reviews and meta-analyses documented a bidirectional link between epilepsy and ASD, supporting the hypothesis that both disorders may have common neurobiological pathways. According to this hypothesis, an imbalance of the excitatory/inhibitory (E/I) ratio in several brain regions may represent a causal mechanism underpinning the co-occurrence of these neurological diseases. Methods: To investigate this bidirectional link, we first tested the seizure susceptibility to chemoconvulsants acting on GABAergic and glutamatergic systems in the BTBR mice, in which an imbalance between E/I has been previously demonstrated. Subsequently, we performed the PTZ kindling protocol to study the impact of seizures on autistic-like behavior and other neurological deficits in BTBR mice. Results: We found that BTBR mice have an increased susceptibility to seizures induced by chemoconvulsants impairing GABAA neurotransmission in comparison to C57BL/6J control mice, whereas no significant difference in seizure susceptibility was observed after administration of AMPA, NMDA, and Kainate. This data suggests that deficits in GABAergic neurotransmission can increase seizure susceptibility in this strain of mice. Interestingly, BTBR mice showed a longer latency in the development of kindling compared to control mice. Furthermore, PTZ-kindling did not influence autistic-like behavior in BTBR mice, whereas it was able to significantly increase anxiety and worsen cognitive performance in this strain of mice. Interestingly, C57BL/6J displayed reduced sociability after PTZ injections, supporting the hypothesis that a tight connection exists between ASD and epilepsy. Conclusion: BTBR mice can be considered a good model to study epilepsy and ASD contemporarily. However, future studies should shed light on the mechanisms underpinning the co-occurrence of these neurological disorders in the BTBR model.

The Pharmacological Treatment of Chronic Pain: From Guidelines to Daily Clinical Practice.

In agreement with the International Association for the Study of Pain, chronic pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. To date, there are several types of pain: nociceptive, neuropathic, and nociplastic. In the present narrative review, we evaluated the characteristics of the drugs used for each type of pain, according to guidelines, and their effects in people with comorbidity to reduce the development of severe adverse events.

Can platelet-rich fibrin act as a natural carrier for antibiotics delivery? A proof-of-concept study for oral surgical procedures.

OBJECTIVES: Evaluate the role of platelet-rich fibrin (PRF) as a natural carrier for antibiotics delivery through the analysis of drug release and antimicrobial activity. MATERIALS AND METHODS: PRF was prepared according to the L-PRF (leukocyte- and platelet-rich fibrin) protocol. One tube was used as control (without drug), while an increasing amount of gentamicin (0.25 mg, G1; 0.5 mg, G2; 0.75 mg, G3; 1 mg, G4), linezolid (0.5 mg, L1; 1 mg, L2; 1.5 mg, L3; 2 mg, L4), vancomycin (1.25 mg, V1; 2.5 mg, V2; 3.75 mg, V3; 5 mg, V4) was added to the other tubes. At different times the supernatant was collected and analyzed. Strains of E. coli, P. aeruginosa, S. mitis, H. influenzae, S. pneumoniae, S. aureus were used to assess the antimicrobial effect of PRF membranes prepared with the same antibiotics and compared to control PRF. RESULTS: Vancomycin interfered with PRF formation. Gentamicin and linezolid did not change the physical properties of PRF and were released from membranes in the time intervals examined. The inhibition area analysis showed that control PRF had slight antibacterial activity against all tested microorganisms. Gentamicin-PRF had a massive antibacterial activity against all tested microorganisms. Results were similar for linezolid-PRF, except for its antibacterial activity against E. coli and P. aeruginosa that was comparable to control PRF. CONCLUSIONS: PRF loaded with antibiotics allowed the release of antimicrobial drugs in an effective concentration. Using PRF loaded with antibiotics after oral surgery may reduce the risk of post-operative infection, replace or enhance systemic antibiotic therapy while preserving the healing properties of PRF. Further studies are needed to prove that PRF loaded with antibiotics represents a topical antibiotic delivery tool for oral surgical procedures.

Inflammation and Obesity: The Pharmacological Role of Flavonoids in the Zebrafish Model.

A Mediterranean-style diet is highly encouraged thanks to its healthy food pattern, which includes valuable nutraceuticals such as polyphenols. Among these, flavonoids are associated with relevant biological properties through which they prevent or fight the onset of several human pathologies. Globally, the enhanced incidence of overweight and obese people has caused a dramatic increase in comorbidities, raising the need to provide better therapies. Therefore, the development of sophisticated animal models of metabolic dysregulation has allowed for a deepening of knowledge on this subject. Recent advances in using zebrafish (Danio rerio) as model for metabolic disease have yielded fundamental insights into the potential anti-obesity effects of flavonoids. Chronic low-grade inflammation and immune system activation seem to characterize the pathogenesis of obesity; thus, their reduction might improve the lipid profile of obese patients or prevent the development of associated metabolic illnesses. In this review, we highlight the beneficial role of flavonoids on obesity and related diseases linked to their anti-inflammatory properties. In light of the summarized studies, we suggest that anti-inflammatory therapies could have a relevant place in the prevention and treatment of obesity and metabolic disorders.

Metalloproteases in Pain Generation and Persistence: A Possible Target?

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent proteolytic enzymes associated with extracellular matrix protein turnover and tissue degradation. They participate to many different physiological reactions but are also hyperactivated in several diseases. Various literature studies have documented that MMPs play a role in the modulation of neuropathic and nociceptive pain. The heterogeneity of clinical and pre-clinical data is an important issue in this experimental context. Despite the presence of a good number of studies on MMP inhibitors, these drugs showed scarce efficacy and relevant side effects. In the present manuscript, we reviewed studies in the literature that define a possible role of MMPs in pain and the effects of their modulation.