The Anticonvulsant Activity of a Flavonoid-Rich Extract from Orange Juice Involves both NMDA and GABA-Benzodiazepine Receptor Complexes.

The usage of dietary supplements and other natural products to treat neurological diseases has been growing over time, and accumulating evidence suggests that flavonoids possess anticonvulsant properties. The aim of this study was to examine the effects of a flavonoid-rich extract from orange juice (OJe) in some rodent models of epilepsy and to explore its possible mechanism of action. The genetically audiogenic seizures (AGS)-susceptible DBA/2 mouse, the pentylenetetrazole (PTZ)-induced seizures in ICR-CD1 mice and the WAG/Rij rat as a genetic model of absence epilepsy with comorbidity of depression were used. Our results demonstrate that OJe was able to exert anticonvulsant effects on AGS-sensible DBA/2 mice and to inhibit PTZ-induced tonic seizures, increasing their latency. Conversely, it did not have anti-absence effects on WAG/Rij rats. Our experimental findings suggest that the anti-convulsant effects of OJe are likely mediated by both an inhibition of NMDA receptors at the glycine-binding site and an agonistic activity on benzodiazepine-binding site at GABAA receptors. This study provides evidences for the antiepileptic activity of OJe, and its results could be used as scientific basis for further researches aimed to develop novel complementary therapy for the treatment of epilepsy in a context of a multitarget pharmacological strategy.

Protective effects of some statins on epileptogenesis and depressive-like behavior in WAG/Rij rats, a genetic animal model of absence epilepsy.

OBJECTIVE: Statins (3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors) exert cholesterol-independent pleiotropic effects that include antithrombotic, antiinflammatory, and antioxidative properties. Moreover, both in vitro and in vivo studies have shown neuroprotective, antiseizure, and antiexcitotoxic effects of statins, suggesting their potential role in the treatment of neurologic diseases. Only a few studies have investigated whether statins modulate absence seizure activity and epileptogenesis. METHODS: We investigated the effects of atorvastatin (5 and 10 mg/kg/day), simvastatin (10 mg/kg/day), and pravastatin (10 and 30 mg/kg/day), given orally for 17 consecutive weeks (starting at 45 days of age), on the development of absence seizures (electroencephalography [EEG] recordings), depressive-like behavior (forced swimming test [FST]), and anxiety levels (open field test [OF]) in Wistar Albino Glaxo/Rijswijk rats (WAG/Rij) rats at the age of 6 months (1 month after suspension). WAG/Rij rats are a genetic animal model of absence epilepsy, epileptogenesis, and mild-depression comorbidity. The effects of statins were also studied after acute intraperitoneal injection for 4 h after administration of various doses in 6-months-old rats. Plasma cholesterol levels were measured throughout drug treatment. RESULTS: We found that early long-term statin treatment possesses antiepileptogenic properties, reduced immobility time in the FST, and reduced anxiety in the OF, whereas they were not effective against established absence seizures when acutely administered. The observed effects were not related to changes in plasma cholesterol levels, which remained unchanged during drug treatment. SIGNIFICANCE: Our results suggest that statins administration might be a possible intervention and promising strategy for preventing the epileptogenesis and/or behavioral comorbidity.

Lamotrigine positively affects the development of psychiatric comorbidity in epileptic animals, while psychiatric comorbidity aggravates seizures.

Several clinical and preclinical studies have focused on the relationship between epilepsy and psychological disturbances. Although behavior in some experimental models of epilepsy has been studied, only few of them can be considered as models of epilepsy and mood disorder comorbidity. Since several models of epilepsy or psychiatric disorders are already available, we wondered whether a mixture of the two could experimentally represent a valid alternative to study such comorbidity. Here, we present a possible experimental protocol to study drug effects and physiopathogenesis of psychiatric comorbidity in epileptic animals. Pentylentetrazol-kindled animals were subjected to the chronic mild stress (CMS) procedure; furthermore, we tested the effects of chronic lamotrigine treatment on the development of comorbidity. We found that epileptic-depressed animals showed more pronounced behavioral alterations in comparison to other mice groups, indicating that kindled animals develop more pronounced CMS-induced behavioral alterations than nonepileptic mice; lamotrigine was able to prevent the development of comorbidities such as anxiety, depression-like behavior, and memory impairment.

Everolimus improves memory and learning while worsening depressive- and anxiety-like behavior in an animal model of depression.

Everolimus (EVR) is an orally-administered rapamycin analog that selectively inhibits the mammalian target of rapamycin (mTOR) kinase (mainly mTORC1 and likely mTORC2) and the related signaling pathway. mTOR is a serine/threonine protein kinase regulating multiple important cellular functions; dysfunction of mTOR signaling has also been implicated in the pathophysiology of several neurological, neurodegenerative, developmental and cognitive disorders. EVR is widely used as an anti-neoplastic therapy and more recently in children with tuberous sclerosis complex (TSC). However, no clear correlation exists between EVR use and development of central side effects e.g. depression, anxiety or cognitive impairment. We studied the effects of a 3 weeks administration of EVR in mice chronically treated with betamethasone 21-phosphate disodium (BTM) as a model of depression and cognitive decline. EVR treatment had detrimental effects on depressive- and anxiety-like behavior while improving cognitive performance in both control (untreated) and BTM-treated mice. Such effects were accompanied by an increased hippocampal neurogenesis and synaptogenesis. Our results therefore might support the proposed pathological role of mTOR dysregulation in depressive disorders and confirm some previous data on the positive effects of mTOR inhibition in cognitive decline. We also show that EVR, possibly through mTOR inhibition, may be linked to the development of anxiety. The increased hippocampal neurogenesis by EVR might explain its ability to improve cognitive function or protect from cognitive decline. Our findings suggest some caution in the use of EVR, particularly in the developing brain; patients should be carefully monitored for their psychiatric/neurological profiles in any clinical situation where an mTOR inhibitor and in particular EVR is used e.g. cancer treatment, TSC or immunosuppression.

Comparative analysis of the treatment of chronic antipsychotic drugs on epileptic susceptibility in genetically epilepsy-prone rats.

Antipsychotic drugs (APs) are of great benefit in several psychiatric disorders, but they can be associated with various adverse effects, including seizures. To investigate the effects of chronic antipsychotic treatment on seizure susceptibility in genetically epilepsy-prone rats, some APs were administered for 7 weeks, and seizure susceptibility (audiogenic seizures) was evaluated once a week during treatment and for 5 weeks after drug withdrawal. Furthermore, acute and subchronic (5-day treatment) effects were also measured. Rats received haloperidol (0.2-1.0 mg/kg), clozapine (1-5 mg/kg), risperidone (0.03-0.50 mg/kg), quetiapine (2-10 mg/kg), aripriprazole (0.2-1.0 mg/kg), and olanzapine (0.13-0.66 mg/kg), and tested according to treatment duration. Acute administration of APs had no effect on seizures, whereas, after regular treatment, aripiprazole reduced seizure severity; haloperidol had no effects and all other APs increased seizure severity. In chronically treated rats, clozapine showed the most marked proconvulsant effects, followed by risperidone and olanzapine. Quetiapine and haloperidol had only modest effects, and aripiprazole was anticonvulsant. Finally, the proconvulsant effects lasted at least 2-3 weeks after treatment suspension; for aripiprazole, a proconvulsant rebound effect was observed. Taken together, these results indicate and confirm that APs might have the potential to increase the severity of audiogenic seizures but that aripiprazole may exert anticonvulsant effects. The use of APs in patients, particularly in patients with epilepsy, should be monitored for seizure occurrence, including during the time after cessation of therapy. Further studies will determine whether aripiprazole really has a potential as an anticonvulsant drug and might also be clinically relevant for epileptic patients with psychiatric comorbidities.

Long-term betamethasone 21-phosphate disodium treatment has distinct effects in CD1 and DBA/2 mice on animal behavior accompanied by opposite effects on neurogenesis.

One of the most peculiar characteristics of the stress response is the pronounced inter-individual and inter-strain variability both in behavioral and neurochemical outcomes. Several studies confirm that rodents belonging to the same or different strain and/or gender, when exposed to a stressor, may show behavioral and cognitive differences. We compared the effects of long-term betamethasone 21-phosphate disodium (BTM), a widely clinically used corticosteroid, on animal behavior and neurogenesis in CD1 and DBA/2 mice. BTM treatment, in CD1 mice, increased body weight gain and anxiety parameters while having pro-depressant effects. Furthermore, BTM significantly reduced neurogenesis in the dentate gyrus of the hippocampus. Finally, BTM treatment induced a significant impairment in memory and learning performance in the Morris water maze. At odds, BTM administration, in DBA/2 mice, caused a significant reduction in the body weight while not modifying anxiety parameters. In addition, both an increased synaptogenesis and neurogenesis were found. Similarly to CD1 mice, also in DBA/2 mice, memory and learning were impaired. Our data confirm that long-term exposure to corticosteroids can generate or aggravate psychiatric/neurologic disorders such as depression, anxiety, memory and learning. Our study did not reveal significant differences between corticosterone and BTM treatment in CD1 mice. In contrast, BTM treatment in mice with an anxious phenotype (DBA/2 mice) revealed some contrasting results indicating that genetic factors can influence corticosteroids dependent effects. Finally, our data further underline the need for a re-evaluation of neurogenesis role; the increased neurogenesis observed in DBA/2 mice and behavioral effects might be distinguished phenomena.

Targeting α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors in epilepsy.

INTRODUCTION: Despite epilepsies being between the oldest and most studied neurological diseases, new treatment remains an unmet need of scientific research due to the high percentage of refractory patients. Several studies have identified new suitable anti-seizure targets. Glutamate activation of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) have long ago been identified as suitable targets for the development of anti seizure drugs. AREAS COVERED: Here, we describe: i) AMPARs' structure and their involvement and role during seizures and in epilepsy and ii) the efficacy of AMPAR antagonists in preclinical models of seizures and epilepsy. EXPERT OPINION: The physiological and pathological role of AMPAR in the CNS and the development of AMPAR antagonists have recently gained attention considering their recent involvement in status epilepticus and the marketing of perampanel. The need for new anti-seizure drugs represents a major challenge in both preclinical and clinical epilepsy. The introduction into the market of perampanel for the treatment of epilepsy will shed new light on the real potential of AMPAR antagonism in clinical settings outside the limited world of clinical trials. While research will go on in this area, fundamental will be the post-marketing evaluation of perampanel efficacy and tolerability and a better definition of the role of this receptor in the epileptic brain.

Niosomes from glucuronic acid-based surfactant as new carriers for cancer therapy: preparation, characterization and biological properties.

Niosomes are vesicular systems composed of surfactant molecules, claimed to be used as drug delivery carriers thanks to their physico-chemical and biological properties. The aim of this work was to design niosomes obtained with a surfactant synthesized from glucuronic acid. Doxorubicin and 5FU were used as model drugs. Niosomes were prepared with different ratios between surfactant and cholesterol, and characterized in terms of size, morphology, drugs entrapment efficiency and in vitro releases, to identify the optimal formulation to be used in pharmaceutical fields. In addition, the hemolytic activity of all formulations have been also evaluated. Results showed that dodecylglucuronamide surfactant was able to produce vesicular systems with or without the presence of cholesterol. Niosomes resulted regular in size and shape and they have been found to encapsulate and release in a controlled manner both doxorubicin and 5-fluorouracil. Hemolytic tests showed that the capability of disrupting erythrocyte only depend on the size of colloidal aggregates. Finally, our formulations could be potentially used as antitumoral delivery systems in anticancer therapy.

Informatics applied to pharmacovigilance: Future perspectives.

Spontaneous adverse drugs reaction (ADRs) reporting represents a precious resource for control and information about the drug's safety and pharmacovigilance. The current reporting system is mainly based on handwritten forms and later manually loaded into a national electronic database by few local pharmacovigilance centers. This reporting system is complicated for both reporters and pharmacovigilance centers which often avoid reporting ADRs for several reasons such as the lack of data on the report. The reporting system might be implemented by improving online platform for ADRs upload; this could allow inspecting all ADRs loaded. Currently, the database is only accessible by the Italian Medicine Agency (AIFA) and local pharmacovigilance centers; neither reporters nor other healthcare professionals can access the database. Finally, it would be right to implement pharmacovigilance centers with specific professional figures qualified in the pharmacovigilance to support both citizens and reporters on various aspects of ADRs reporting.

Vertigo/dizziness as a Drugs' adverse reaction.

INTRODUCTION: Vertigo, dizziness, and nausea encompass a spectrum of balance-related symptoms caused by a variety of etiologies. Balance is affected by many systems: Proprioceptive pathways and visual, cerebellar, vestibulocochlear, and vascular / vasovagal systems. Vertigo is a subtype of dizziness, in which a subject, as a result to a dysfunction of the vestibular system, improperly experiments the perception of motion. The most useful clinical subdivision is to categorize vertigo into true vertigo and pseudovertigo, whereas from a pathophysiological point of view, vertigo can be classified into central, peripheral, and psychogenic. It is not easy to identify the cause of vertigo since the patients often are not able to precisely describe their symptoms. An impressive list of drugs may cause vertigo or dizziness. MATERIALS AND METHODS: The aim of the present study was to analyze the data extracted from the reporting cards of the ADRs (adverse drug reactions), received at our Pharmacovigilance Regional Center (Calabria, Italy) in 2012. In particular, the data concerning the occurrence of vertigo and dizziness, after taking certain classes of drugs, have been considered. RESULTS: Our results show that, among the side-effects of different classes of drugs such as anti-convulsants, anti-hypertensives, antibiotics, anti-depressants, anti-psychotics, and anti-inflammatory, also vertigo or dizziness are included. CONCLUSIONS: Spontaneous reports of vertigo or dizziness, as side-effect of certain drugs, received at our Pharmacovigilance Center, represented the 5% of all reports in 2012. Considering the high incidence of such an ADR for several drugs' classes, it can be speculated that under-reporting also affect vertigo and dizziness. Despite the fact that these ADRs might not represent a direct threaten for life, indirectly they can cause secondary damage to patients such as falls, fractures etc. Balance should be accurately monitored during drug use and particularly in fragile patients.