Upholding WAG/Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development

The WAG/Rij rat model has recently gathered attention as a suitable animal model of absence epileptogenesis. This latter term has a broad definition encompassing any possible cause that determines the development of spontaneous seizures; however, most of, if not all, preclinical knowledge on epileptogenesis is confined to the study of post-brain insult models such as traumatic brain injury or post-status epilepticus models. WAG/Rij rats, but also synapsin 2 knockout, Kv7 current-deficient mice represent the first examples of genetic models where an efficacious antiepileptogenic treatment (ethosuximide) was started before seizure onset. In this review, we have critically reconsidered all articles published regarding WAG/Rij rats, from the perspective that the period before SWD onset is considered as the latent period. In our new theory on seizure development, it is proposed that genes might be considered as the initial 'insult' responsible for all plastic changes underpinning the development of spontaneous seizures. According to this idea, in WAG/Rij rats, genetic predisposition would lead to the development of abnormal bilateral cortical epileptic foci, which would then non-genetically stimulate the rest of the brain to rearrange networks in order to phenotypically develop seizures similarly to what happens during electrical kindling

Synthesis of 5-substituted 7,9-dihydro-8H-[1,3]dioxolo[4,5-h][2,3]benzodiazepin-8-ones as anticonvulsant agents

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Biomimetic Sonar for Electrical Activation of the Auditory Pathway

Relying on the mechanism of bat’s echolocation system, a bioinspired electronic device has been developed to investigate the cortical activity of mammals in response to auditory sensorial stimuli. By means of implanted electrodes, acoustical information about the external environment generated by a biomimetic system and converted in electrical signals was delivered to anatomically selected structures of the auditory pathway. Electrocorticographic recordings showed that cerebral activity response is highly dependent on the information carried out by ultrasounds and is frequency-locked with the signal repetition rate. Frequency analysis reveals that delta and beta rhythm content increases, suggesting that sensorial information is successfully transferred and integrated. In addition, principal component analysis highlights how all the stimuli generate patterns of neural activity which can be clearly classified. The results show that brain response is modulated by echo signal features suggesting that spatial information sent by biomimetic sonar is efficiently interpreted and encoded by the auditory system. Consequently, these results give new perspective in artificial environmental perception, which could be used for developing new techniques useful in treating pathological conditions or influencing our perception of the surroundings

Can we ‘seize’ the gut microbiota to treat epilepsy?

The gut-microbiota, the complex intestinal microbial ecosystem essential to health, is an emerging concept in medicine. Several studies demonstrate a microbiota-gut-brain bidirectional connection via neural, endocrine, metabolic and immune pathways. Accordingly, the gut microbiota has a crucial role in modulating intestinal permeability, to alter local/peripheral immune responses and in production of essential metabolites and neurotransmitters. Its alterations may consequently influence all these pathways that contribute to neuronal hyper-excitability and mirrored neuroinflammation in epilepsy and similarly other neurological conditions. Indeed, pre- and clinical studies support the role of the microbiome in pathogenesis, seizure modulation and responses to treatment in epilepsy. Up to now, researchers have focussed attention above all on the brain to develop antiepileptic treatments, but considering the microbiome, could extend our possibilities for developing novel therapies in the future. We provide here a comprehensive overview of the available data on the potential role of gut microbiota in the physiopathology and therapy of epilepsy and the supposed underlying mechanisms

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

One of the major challenges in the epilepsy field is identifying disease-modifying drugs in order to prevent or delay spontaneous recurrent seizure onset or to cure already established epilepsy. It has been recently reported that fingolimod, currently approved for the treatment of relapsing-remitting multiple sclerosis, has demonstrated antiepileptogenic effects in 2 different preclinical models of acquired epilepsy. However, to date, no data exist regarding the role of fingolimod against genetic epilepsy. Therefore, we have addressed this issue by studying the effects of fingolimod in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats, a well-established genetic model of absence epilepsy, epileptogenesis, and neuropsychiatric comorbidity. Our results have demonstrated that an early long-term treatment with fingolimod (1 mg/kg/day), started before absence seizure onset, has both antiepileptogenic and antidepressant-like effects in WAG/Rij rats. However, these effects were transitory, as 5 months after treatment discontinuation, both absence seizure and depressive like-behavior returned to control levels. Furthermore, a temporary reduction of mTOR signaling pathway activity, indicated by reduced phosphorylated mammalian target of rapamycin and phosphorylated p70S6k levels, and by increased phosphorylated Akt in WAG/Rij rats of 6 months of age accompanied the transitory antiepileptogenic effects of fingolimod. Surprisingly, fingolimod has demonstrated longer-lasting positive effects on cognitive decline in this strain. This effect was accompanied by an increased acetylation of lysine 8 of histone H4 (at both 6 and 10 months of age). In conclusion, our results support the antiepileptogenic effects of fingolimod. However, the antiepileptogenic effects were transitory. Moreover, fingolimod might also have a positive impact on animal behavior and particularly in protecting the development of memory decline

Iatrogenic Delirium in an Elderly Patient: When Drugs are Harmful

Delirium is a global disorder of cognition that represents a medical emergency and, particularly in elderly, is often unrecognized or misdiagnosed and commonly mistaken for dementia, depression, mania, or an acute schizophrenic reaction. Drug-induced delirium is a common matter in the elderly and in this paper we report the onset of delirium induced by -drug interaction in a previously health elderly patient

Antiabsence effects of carbenoxolone in two genetic animal models of absence epilepsy (WAG/Rij rats and lh/lh mice)

Carbenoxolone (CBX), the succinyl ester of glycyrrhetinic acid, is an inhibitor of gap junctional intercellular communication. We have tested its possible effects upon two genetic animal models of epilepsy (WAG/Rij rats and lethargic (lh/lh) mice). Systemic administration of CBX was unable to significantly affect the occurrence of absence seizures in WAG/Rij rats. In particular, intravenous (5-40 mg/kg) or intraperitoneal (i.p.; 10-80 mg/kg) administration of CBX was unable to significantly modify the number and duration of spike-wave discharges (SWDs) in WAG/Rij rats, whereas the bilateral microinjection (0.05, 0.1, 0.5 and 1 microg/0.5 microl) of CBX into nucleus reticularis thalami (NRT) and nucleus ventralis posterolateralis (VPL) thalami produced a decrease in the duration and the number of SWDs. Bilateral microinjection of CBX into nucleus ventroposteromedial (VPM) thalami did not produce any significant decrease in the number and duration of SWDs. On the contrary, i.p. (5-40 mg/kg) or intracerebroventricular (0.5, 1, 2 and 4 microg/2 microl) administration of CBX in lh/lh mice induced a marked decrease in the number and duration of SWDs in a dose-dependent manner. At the doses used no movement disorders, or other behavioural changes, were recorded in both WAG/Rij rats and lh/lh mice. No effects were observed in both animal models following systemic or focal administration of glycyrrhizin into the same brain areas where CBX was shown to be effective

Safety profile of the newest antiepileptic drugs: a curated literature review

BACKGROUND: Despite the introduction of new antiepileptic drugs (AEDs), the quality of life and therapeutic response for patients with epilepsy remain unsatisfactory. In addition, whilst several antiepileptic drugs (AEDs) have been approved and consequently marketed in recent years, little is known about their long-term safety and tolerability. Availability of the newest AEDs, characterized by improved pharmacokinetic profiles, has positively impacted the treatment approach for patients with partial seizures in clinical practice. However, the main cause of treatment failure is still poor patient compliance due to the occurrence of adverse drug reactions (ADRs) that lead to treatment withdrawal in about 25% of cases before achieving maximal efficacy, and is associated with increasing health care costs. METHODS: In this Review, we conducted an online database search using Medline, PubMed, Embase, and the Cochrane Online Library to review the available studies highlighting the clinical relevance of side effects, pharmacological interactions, safety and tolerability of the newest AEDs: Brivaracetam (BRV), Cannabidiol (CBD), Eslicarbazepine acetate (ESL), Lacosamide (LCM), and Perampanel (PER). RESULTS: The principal benefit of the newest AEDs, in addition to reduced frequency and seizure severity, is the low number and severity of ADRs reported compared to more historic drugs. CONCLUSION: Early detection of ADRs could lead to an improvement in patients' quality of life, therefore it is important to monitor ADRs and to adequately perform post marketing surveillance in the clinical practice setting

Prevalence of type 2 diabetes and impaired fasting glucose in patients affected by rheumatoid arthritis

Although the better management of rheumatoid arthritis (RA) has significantly improved the long-term outcome of affected patients, a significant proportion of these may develop associated comorbidities including cardiometabolic complications. However, it must be pointed out that a comprehensive cardiometabolic evaluation is still poorly integrated into the management of RA patients, due to a limited awareness of the problem, a lack of appropriate clinical studies, and optimal strategies for cardiovascular (CV) risk reduction in RA. In addition, although several studies investigated the possible association between traditional CV risk factors and RA, conflicting results are still available. On this basis, we planned this cross-sectional study, aimed at investigating the prevalence of type 2 diabetes (T2D) and impaired fasting glucose (IFG) in RA patients compared with age- and gender- matched control individuals. Furthermore, we analyzed the role of both traditional and RA-related CV risk factors in predicting T2D and IFG. We observed an increased prevalence of T2D in RA patients when compared with age- and gender-matched controls. Regression analyses demonstrated that the presence of high blood pressure (HBP), a longer disease duration, and exposure to corticosteroids (CCS) were significantly associated with an increased likelihood of being classified as T2D. In addition, we observed an increased prevalence of IFG in RA patients when compared with age- and gender-matched controls. Regression analyses demonstrated that a higher body mass index (BMI), the presence of metabolic syndrome (MetS), higher levels of total cholesterol, the presence of radiographic damage, and higher serum levels of C-reactive protein (CRP) were significantly associated with an increased likelihood of presenting IFG. In this cross-sectional study, we observed an increased prevalence of T2D and IFG in an Italian cohort of RA patients when compared with age- and gender-matched control individuals. Interestingly, both RA-specific features, such as disease duration, CCS exposure, and radiographic damage, and traditional CV risk factors, such as HBP and MetS, were significantly associated with glucose metabolism abnormalities