RESUMEN
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease characterized by the degeneration of motor neurons that leads to muscle wasting and atrophy. Epidemiological and experimental evidence suggests a causal relationship between ALS and physical activity (PA). However, the impact of PA on motor neuron loss and sarcopenia is still debated, probably because of the heterogeneity and intensities of the proposed exercises. With this study, we aimed to clarify the effect of intense endurance exercise on the onset and progression of ALS in the SOD1-G93A mouse model. Methods: We randomly selected four groups of twelve 35-day-old female mice. SOD1-G93A and WT mice underwent intense endurance training on a motorized treadmill for 8 weeks, 5 days a week. During the training, we measured muscle strength, weight, and motor skills and compared them with the corresponding sedentary groups to define the disease onset. At the end of the eighth week, we analyzed the skeletal muscle-motor neuron axis by histological and molecular techniques. Results: Intense endurance exercise anticipates the onset of the disease by 1 week (age of the onset: trained SOD1-G93A = 63.17 ± 2.25 days old; sedentary SOD1-G93A = 70.75 ± 2.45 days old). In SOD1-G93A mice, intense endurance exercise hastens the muscular switch to a more oxidative phenotype and worsens the denervation process by dismantling neuromuscular junctions in the tibialis anterior, enhancing the Wallerian degeneration in the sciatic nerve, and promoting motor neuron loss in the spinal cord. The training exacerbates neuroinflammation, causing immune cell infiltration in the sciatic nerve and a faster activation of astrocytes and microglia in the spinal cord. Conclusion: Intense endurance exercise, acting on skeletal muscles, worsens the pathological hallmarks of ALS, such as denervation and neuroinflammation, brings the onset forward, and accelerates the progression of the disease. Our findings show the potentiality of skeletal muscle as a target for both prognostic and therapeutic strategies; the preservation of skeletal muscle health by specific intervention could counteract the dying-back process and protect motor neurons from death. The physiological characteristics and accessibility of skeletal muscle further enhance its appeal as a therapeutic target.
RESUMEN
Amyotrophic Lateral Sclerosis (ALS) is considered the prototype of motor neuron disease, characterized by motor neuron loss and muscle waste. A well-established pathogenic hallmark of ALS is mitochondrial failure, leading to bioenergetic deficits. So far, pharmacological interventions for the disease have proven ineffective. Trimetazidine (TMZ) is described as a metabolic modulator acting on different cellular pathways. Its efficacy in enhancing muscular and cardiovascular performance has been widely described, although its molecular target remains elusive. We addressed the molecular mechanisms underlying TMZ action on neuronal experimental paradigms. To this aim, we treated murine SOD1G93A-model-derived primary cultures of cortical and spinal enriched motor neurons, as well as a murine motor-neuron-like cell line overexpressing SOD1G93A, with TMZ. We first characterized the bioenergetic profile of the cell cultures, demonstrating significant mitochondrial dysfunction that is reversed by acute TMZ treatments. We then investigated the effect of TMZ in promoting autophagy processes and its impact on mitochondrial morphology. Finally, we demonstrated the effectiveness of TMZ in terms of the mitochondrial functionality of ALS-rpatient-derived peripheral blood mononuclear cells (PBMCs). In summary, our results emphasize the concept that targeting mitochondrial dysfunction may represent an effective therapeutic strategy for ALS. The findings demonstrate that TMZ enhances mitochondrial performance in motor neuron cells by activating autophagy processes, particularly mitophagy. Although further investigations are needed to elucidate the precise molecular pathways involved, these results hold critical implications for the development of more effective and specific derivatives of TMZ for ALS treatment.
Asunto(s)
Esclerosis Amiotrófica Lateral , Enfermedades Mitocondriales , Trimetazidina , Ratones , Animales , Humanos , Esclerosis Amiotrófica Lateral/metabolismo , Superóxido Dismutasa-1/metabolismo , Trimetazidina/farmacología , Trimetazidina/uso terapéutico , Ratones Transgénicos , Leucocitos Mononucleares/metabolismo , Superóxido Dismutasa/metabolismo , Autofagia , Modelos Animales de EnfermedadRESUMEN
Friedreich's ataxia (FA) is a neurodegenerative disease resulting from a mutation in the FXN gene, leading to mitochondrial frataxin deficiency. FA patients exhibit increased visceral adiposity, inflammation, and heightened diabetes risk, negatively affecting prognosis. We investigated visceral white adipose tissue (vWAT) in a murine model (KIKO) to understand its role in FA-related metabolic complications. RNA-seq analysis revealed altered expression of inflammation, angiogenesis, and fibrosis genes. Diabetes-like traits, including larger adipocytes, immune cell infiltration, and increased lactate production, were observed in vWAT. FXN downregulation in cultured adipocytes mirrored vWAT diabetes-like features, showing metabolic shifts toward glycolysis and lactate production. Metagenomic analysis indicated a reduction in fecal butyrate-producing bacteria, known to exert antidiabetic effects. A butyrate-enriched diet restrained vWAT abnormalities and mitigated diabetes features in KIKO mice. Our work emphasizes the role of vWAT in FA-related metabolic issues and suggests butyrate as a safe and promising adjunct for FA management.
RESUMEN
The TAR-DNA binding protein (TDP43) is a nuclear protein whose cytoplasmic inclusions are hallmarks of Amyotrophic Lateral Sclerosis (ALS). Acute stress in cells causes TDP43 mobilization to the cytoplasm and its aggregation through different routes. Although acute stress elicits a strong phenotype, is far from recapitulating the years-long aggregation process. We applied different chronic stress protocols and described TDP43 aggregation in a human neuroblastoma cell line by combining solubility assays, thioflavin-based microscopy and flow cytometry. This approach allowed us to detect, for the first time to our knowledge in vitro, the formation of 25 kDa C-terminal fragment of TDP43, a pathogenic hallmark of ALS. Our results indicate that chronic stress, compared to the more common acute stress paradigm, better recapitulates the cell biology of TDP43 proteinopathies. Moreover, we optimized a protocol for the detection of bona fide prions in living cells, suggesting that TDP43 may form amyloids as a stress response.
Asunto(s)
Esclerosis Amiotrófica Lateral , Proteínas de Unión al ADN , Humanos , Esclerosis Amiotrófica Lateral/genética , Línea Celular , Citoplasma/metabolismo , Proteínas de Unión al ADN/metabolismo , Neuroblastoma/metabolismo , Proteinopatías TDP-43/metabolismoRESUMEN
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of the upper and lower motor neurons. Despite the increasing effort in understanding the etiopathology of ALS, it still remains an obscure disease, and no therapies are currently available to halt its progression. Following the discovery of the first gene associated with familial forms of ALS, Cu-Zn superoxide dismutase, it appeared evident that mitochondria were key elements in the onset of the pathology. However, as more and more ALS-related genes were discovered, the attention shifted from mitochondria impairment to other biological functions such as protein aggregation and RNA metabolism. In recent years, mitochondria have again earned central, mechanistic roles in the pathology, due to accumulating evidence of their derangement in ALS animal models and patients, often resulting in the dysregulation of the energetic metabolism. In this review, we first provide an update of the last lustrum on the molecular mechanisms by which the most well-known ALS-related proteins affect mitochondrial functions and cellular bioenergetics. Next, we focus on evidence gathered from human specimens and advance the concept of a cellular-specific mitochondrial "metabolic threshold", which may appear pivotal in ALS pathogenesis.
RESUMEN
BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles and is currently incurable. Although considered to be a pure motor neuron disease, increasing evidence indicates that the sole protection of motor neurons by a single targeted drug is not sufficient to improve the pathological phenotype. We therefore evaluated the therapeutic potential of the multi-target drug used to treatment of coronary artery disease, trimetazidine, in SOD1G93A mice. EXPERIMENTAL APPROACH: As a metabolic modulator, trimetazidine improves glucose metabolism. Furthermore, trimetazidine enhances mitochondrial metabolism and promotes nerve regeneration, exerting an anti-inflammatory and antioxidant effect. We orally treated SOD1G93A mice with trimetazidine, solubilized in drinking water at a dose of 20 mg kg-1 , from disease onset. We assessed the impact of trimetazidine on disease progression by studying metabolic parameters, grip strength and histological alterations in skeletal muscle, peripheral nerves and the spinal cord. KEY RESULTS: Trimetazidine administration delays motor function decline, improves muscle performance and metabolism, and significantly extends overall survival of SOD1G93A mice (increased median survival of 16 days and 12.5 days for male and female respectively). Moreover, trimetazidine prevents the degeneration of neuromuscular junctions, attenuates motor neuron loss and reduces neuroinflammation in the spinal cord and in peripheral nerves. CONCLUSION AND IMPLICATIONS: In SOD1G93A mice, therapeutic effect of trimetazidine is underpinned by its action on mitochondrial function in skeletal muscle and spinal cord.
Asunto(s)
Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Trimetazidina , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Modelos Animales de Enfermedad , Reposicionamiento de Medicamentos , Femenino , Masculino , Ratones , Ratones Transgénicos , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1/genética , Trimetazidina/farmacología , Trimetazidina/uso terapéuticoRESUMEN
The Microbiota-Gut-Brain axis (MGBA) is a bidirectional communication pathway between gut bacteria and the central nervous system (CNS) (including the intestine) that exerts a profound influence on neural development, neuroinflammation, activation of stress response and neurotransmission, in addition to modulating complex behaviours, such as sociability and anxiety. Several MGBA modulating approaches are possible, such as probiotic administration. A reasonable pharmacological approach would also be the contemporarily administration of both prebiotics and postbiotics. To test this hypothesis, we probed the effects of α-lactalbumin (ALAC; a prebiotic in the dose range of 125-500 mg/kg) and sodium butyrate (NaB; a postbiotic in the dose range of 30-300 mg/kg) alone and in combination. We used two animal behavioural models of idiopathic autism, (BTBR mice) and anxiety/depression (chronic unexpected mild stress - CUMS mice) respectively, using several standard behavioural paradigms such as Three-chamber social interaction test, Marble burying assay, depression-, anxiety- and memory-tests. In BTBR autistic mice, we found that both ALAC and NaB improve animal sociability, and memory in the passive avoidance (PA); drug combination was more effective in almost all tests also reducing immobility time in the forced swimming test (FST), which was not affected by single drug administration. Similarly, in the CUMS mice, single drug administration was effective in improving: 1) depressive-like behaviour in the FST and sucrose preference test; 2) memory and learning in the PA, novel object recognition and Morris water maze tests. Drug combination was again more effective than single drug administration in most cases; however, in the CUMS model, neither single drug or combination was effective in the elevated plus maze test for anxiety. Our results suggest that in both models, ALAC and NaB combination is more effective in improving some pathological aspects of animal behaviour than single administration and that the prebiotic/postbiotic approach should be considered a reasonable approach for the manipulation of the MGBA to improve efficacy.
Asunto(s)
Trastorno Autístico/prevención & control , Eje Cerebro-Intestino , Depresión/prevención & control , Microbioma Gastrointestinal , Prebióticos , Animales , Ansiedad/psicología , Trastorno Autístico/psicología , Reacción de Prevención/efectos de los fármacos , Conducta Animal , Ácido Butírico/farmacología , Depresión/psicología , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Humanos , Lactalbúmina/farmacología , Masculino , Memoria , Ratones , Ratones Endogámicos C57BL , Conducta Social , Estrés Psicológico/psicología , Natación/psicologíaRESUMEN
OBJECTIVE: A large number of studies have highlighted the important role of the gut microbiota in the pathophysiology of neurological disorders, suggesting that its manipulation might serve as a treatment strategy. We hypothesized that the gut microbiota participates in absence seizure development and maintenance in the WAG/Rij rat model and tested this hypothesis by evaluating potential gut microbiota and intestinal alterations in the model, as well as measuring the impact of microbiota manipulation using fecal microbiota transplantation (FMT). METHODS: Initially, gut microbiota composition and intestinal histology of WAG/Rij rats (a well-recognized genetic model of absence epilepsy) were studied at 1, 4, and 8 months of age in comparison to nonepileptic Wistar rats. Subsequently, in a second set of experiments, at 6 months of age, untreated Wistar or WAG/Rij rats treated with ethosuximide (ETH) were used as gut microbiota donors for FMT in WAG/Rij rats, and electroencephalographic (EEG) recordings were obtained over 4 weeks. At the end of FMT, stool and gut samples were collected, absence seizures were measured on EEG recordings, and microbiota analysis and histopathological examinations were performed. RESULTS: Gut microbiota analysis showed differences in beta diversity and specific phylotypes at all ages considered and significant variances in the Bacteroidetes/Firmicutes ratio between Wistar and WAG/Rij rats. FMT, from both Wistar and ETH-treated WAG/Rij donors to WAG/Rij rats, significantly decreased the number and duration of seizures. Histological results indicated that WAG/Rij rats were characterized by intestinal villi disruption and inflammatory infiltrates already at 1 month of age, before seizure occurrence; FMT partially restored intestinal morphology while also significantly modifying gut microbiota and concomitantly reducing absence seizures. SIGNIFICANCE: Our results demonstrate for the first time that the gut microbiota is modified and contributes to seizure occurrence in a genetic animal model of absence epilepsy and that its manipulation may be a suitable therapeutic target for absence seizure management.
Asunto(s)
Antibacterianos/farmacología , Anticonvulsivantes/farmacología , Epilepsia Tipo Ausencia/microbiología , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/genética , Animales , Bacteroidetes , Butiratos/metabolismo , Colon/patología , ADN Bacteriano/análisis , ADN Ribosómico/genética , Modelos Animales de Enfermedad , Electroencefalografía , Epilepsia Tipo Ausencia/genética , Epilepsia Tipo Ausencia/fisiopatología , Epilepsia Tipo Ausencia/terapia , Etosuximida/farmacología , Ácidos Grasos Volátiles/metabolismo , Firmicutes , Motilidad Gastrointestinal , Haptoglobinas/metabolismo , Íleon/patología , Propionatos/metabolismo , Precursores de Proteínas/metabolismo , Proteobacteria , Ratas , Ratas Wistar , Convulsiones/genética , Convulsiones/microbiología , Convulsiones/fisiopatologíaRESUMEN
INTRODUCTION: Epilepsy represents the third most common neurological disorder in the elderly. Antiseizure medications (ASMs) are often used not only to treat epilepsy but also other disorders in this age group. Many physio-pathological changes occur in body composition and organ or system functions with aging. Furthermore, drug-drug interactions (DDIs) represent a major risk considering the prevalence of polytherapy in the elderly. AREAS COVERED: Relevant studies on the pharmacokinetics of ASMs in the elderly were identified through a literature search. We have reviewed all available data on known alterations in pharmacokinetic parameters of ASMs in elderly also considering pathophysiological alterations such as renal function impairment. Finally, we have highlighted the potential risk of DDIs with some drug classes. EXPERT OPINION: Large interindividual variability also due to co-morbidities and related co-therapies makes elderly patients a not homogeneous group. Overall, a reduction in loading and maintenance doses of almost all ASMs should be considered to avoid adverse events (AEs) as well as a slow titration, following the rule 'start low and go slow'. Therapeutic drug monitoring should be performed to apply the 'individual therapeutic concentration' and implemented to overcome the age-related differences between dose and plasma concentrations, to monitor DDIs and guide dosage adjustments.
Asunto(s)
Anticonvulsivantes/farmacocinética , Monitoreo de Drogas/métodos , Epilepsia/tratamiento farmacológico , Factores de Edad , Anciano , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/efectos adversos , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , HumanosRESUMEN
The link between epilepsy and type 2 diabetes (T2DM) and/or metabolic syndrome (MetS) has been poorly investigated. Therefore, we tested whether a high-fat diet (HFD), inducing insulin-resistant diabetes and obesity in mice, would increase susceptibility to develop generalized seizures induced by pentylentetrazole (PTZ) kindling. Furthermore, molecular mechanisms linked to glucose brain transport and the effects of the T2DM antidiabetic drug metformin were also studied along with neuropsychiatric comorbidities. To this aim, two sets of experiments were performed in CD1 mice, in which we firstly evaluated the HFD effects on some metabolic and behavioral parameters in order to have a baseline reference for kindling experiments assessed in the second section of our protocol. We detected that HFD predisposes towards seizure development in the PTZ-kindling model and this was linked to a reduction in glucose transporter-1 (GLUT-1) expression as observed in GLUT-1 deficiency syndrome in humans but accompanied by a compensatory increase in expression of GLUT-3. While we confirmed that HFD induced neuropsychiatric alterations in the treated mice, it did not change the development of kindling comorbidities. Furthermore, we propose that the beneficial effects of metformin we observed towards seizure development are related to a normalization of both GLUT-1 and GLUT-3 expression levels. Overall, our results support the hypothesis that an altered glycometabolic profile could play a pro-epileptic role in human patients. We therefore recommend that MetS or T2DM should be constantly monitored and possibly avoided in patients with epilepsy, since they could further aggravate this latter condition.
Asunto(s)
Dieta Alta en Grasa , Metformina/farmacología , Convulsiones/metabolismo , Animales , Ansiedad/complicaciones , Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Glucemia/metabolismo , Composición Corporal/efectos de los fármacos , Depresión/complicaciones , Susceptibilidad a Enfermedades , Transportador de Glucosa de Tipo 1/metabolismo , Transportador de Glucosa de Tipo 3/metabolismo , Excitación Neurológica/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Ratones , Prueba de Campo Abierto , Pentilenotetrazol , Convulsiones/sangre , Convulsiones/complicaciones , NataciónRESUMEN
Increased expression of interleukin-6 (IL-6) both in cerebrospinal fluid (CSF) and plasma is closely associated with convulsive epilepsy and symptom severity of depression. By comparison, at present, little is known about the role of this cytokine in childhood (non-convulsive) absence epilepsy. The aim of this work was to investigate the potential effects of acute and chronic treatment with tocilizumab (TCZ, 10 and 30 mg/kg/day), on absence seizures, their development, and related psychiatric comorbidity in WAG/Rij rats. It is known that lipopolysaccharide (LPS)-induced changes in inflammatory processes increase absence epileptic activity. In order to study the central effects of TCZ, we investigated whether administration of this anti-IL-6R antibody could modulate the lipopolysaccharide (LPS) or IL-6-evoked changes in absence epileptic activity in WAG/Rij rats. Our results demonstrate that TCZ, at both doses, significantly reduced the development of absence seizures in adult WAG/Rij rats at 6 months of age (1 month after treatment suspension) compared with untreated controls, thus showing disease-modifying effects. Decreased absence seizure development at 6 months of age was also accompanied by reduced comorbid depressive-like behavior, whereas no effects were observed on anxiety-related behavior. Acute treatment with TCZ, at 30 mg/kg, had anti-absence properties lasting ~25 h. The co-administration TCZ with i.c.v. LPS or IL-6 showed that TCZ inhibited the worsening of absence seizures induced by both proinflammatory agents in the WAG/Rij rats, supporting a central anti-inflammatory-like protective action. These results suggest the possible role of IL-6 and consequent neuroinflammation in the epileptogenic process underlying the development and maintenance of absence seizures in WAG/Rij rats. Accordingly, IL-6 signaling could be a promising pharmacological target in absence epilepsy and depressive-like comorbidity.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Modelos Animales de Enfermedad , Epilepsia Tipo Ausencia/tratamiento farmacológico , Epilepsia Tipo Ausencia/metabolismo , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/metabolismo , Animales , Anticuerpos Monoclonales Humanizados/farmacología , Relación Dosis-Respuesta a Droga , Epilepsia Tipo Ausencia/genética , Masculino , Ratas , Ratas Transgénicas , Ratas WistarRESUMEN
: Type 2 diabetes mellitus (T2DM) is a risk factor for cognitive impairment. Ranolazine, an anti-ischemic drug used in the treatment of angina pectoris, has been shown to possess hypoglycemic properties in pre-clinical and clinical studies. The aim of this study was to evaluate the effects of ranolazine on glucose metabolism and cognitive function in a T2DM model of Wistar rats. Diabetes was induced by a high fat diet (HFD) and streptozotocin (STZ). The control group received a normal caloric diet (NCD) and sodium citrate buffer. Metformin, an effective hypoglycemic drug, was employed as a positive control. Animals were divided into the following groups: HFD/STZ + Ranolazine, HFD/STZ + Metformin, HFD/STZ + Vehicle, NCD + Vehicle, NCD + Ranolazine, and NCD + Metformin. Rats received ranolazine (20 mg/kg), metformin (300 mg/kg), or water, for 8 weeks. At the end of the treatments, all animals underwent to an intraperitoneal glucose tolerance test (IPGTT) and behavioral tests, including passive avoidance, novel object recognition, forced swimming, and elevate plus maze tests. Interleukin-6 plasma levels in the six treatment groups were assessed by Elisa assay. Body mass composition was estimated by nuclear magnetic resonance (NMR). Glucose responsiveness significantly improved in the HFD/STZ + Ranolazine (p < 0.0001) and HFD/STZ + Metformin (p = 0.003) groups. There was a moderate effect on blood glucose levels in the NCD + Ranolazine and NCD + Metformin groups. Lean body mass was significantly increased in the HFD/STZ + Ranolazine and HFD/STZ + Metformin animals, compared to HFD/STZ + Vehicle animals. Ranolazine improved learning and long-term memory in HFD/STZ + Ranolazine compared to HFD/STZ + Vehicle (p < 0.001) and ameliorated the pro-inflammatory profile of diabetic mice. These results support the hypothesis of a protective effect of ranolazine against cognitive decline caused by T2DM.
Asunto(s)
Cognición/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Ranolazina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Glucemia/efectos de los fármacos , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/psicología , Diabetes Mellitus Tipo 2/inducido químicamente , Diabetes Mellitus Tipo 2/psicología , Dieta Alta en Grasa , Prueba de Tolerancia a la Glucosa , Aprendizaje por Laberinto/efectos de los fármacos , Metformina/farmacología , Ratas , Ratas Wistar , EstreptozocinaRESUMEN
Epigenetic mechanisms, such as alterations in histone acetylation based on histone deacetylases (HDACs) activity, have been linked not only to normal brain function but also to several brain disorders including epilepsy and the epileptogenic process. In WAG/Rij rats, a genetic model of absence epilepsy, epileptogenesis and mild-depression comorbidity, we investigated the effects of two HDAC inhibitors (HDACi), namely sodium butyrate (NaB), valproic acid (VPA) and their co-administration, on the development of absence seizures and related psychiatric/neurologic comorbidities following two different experimental paradigms. Treatment effects have been evaluated by EEG recordings (EEG) and behavioural tests at different time points. Prolonged and daily VPA and NaB treatment, started before absence seizure onset (P30), significantly reduced the development of absence epilepsy showing antiepileptogenic effects. These effects were enhanced by NaB/VPA co-administration. Furthermore, early-chronic HDACi treatment improved depressive-like behaviour and cognitive performance 1 month after treatment withdrawal. WAG/Rij rats of 7 months of age showed reduced acetylated levels of histone H3 and H4, analysed by Western Blotting of homogenized brain, in comparison to WAG/Rij before seizure onset (P30). The brain histone acetylation increased significantly during treatment with NaB or VPA alone and more markedly during co-administration. We also observed decreased expression of both HDAC1 and 3 following HDACi treatment compared to control group. Our results suggest that histone modifications may have a crucial role in the development of epilepsy and early treatment with HDACi might be a possible strategy for preventing epileptogenesis also affecting behavioural comorbidities.
Asunto(s)
Epilepsia/tratamiento farmacológico , Epilepsia/psicología , Inhibidores de Histona Desacetilasas/uso terapéutico , Acetilación , Potenciales de Acción/efectos de los fármacos , Animales , Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Ácido Butírico/farmacología , Ácido Butírico/uso terapéutico , Comorbilidad , Epilepsia/fisiopatología , Inhibidores de Histona Desacetilasas/farmacología , Histonas/metabolismo , Masculino , Ratas Wistar , Ácido Valproico/farmacología , Ácido Valproico/uso terapéuticoRESUMEN
Stroke is a severe clinical issue for global public health, representing the third leading cause of death and a major cause of disability in developed countries. Progresses in the pharmacological treatment of the acute stroke have given rise to a significant decrease in its mortality rate. However, as a result, there has been an increasing number of stroke survivors living with disability worldwide. Poststroke epilepsy (PSE) is a common clinical complication following stroke. Seizures can arise in close temporal association with stroke damage and/or after a variably longer interval. Overall, PSE have a good prognosis; in fact, its responding rate to antiepileptic drugs (AEDs) is higher than other types of epilepsy. However, regarding pharmacological treatment, some issues are still unresolved. To this aim, a deeper understanding of mechanisms underlying the transformation of infarcted tissue into an epileptic focus or better from a nonepileptic brain to an epileptic brain is also mandatory for PSE. However, studying epileptogenesis in patients with PSE clearly has several limitations and difficulties; therefore, modeling PSE is crucial. Until now, different experimental models have been used to study the etiopathology of cerebrovascular stroke with or without infarction, but few studies focused on poststroke epileptogenesis and PSE. In this review, we show a brief overview on the features emerging from preclinical research into experimental PSE, which could affect the discovery of biomarkers and therapy strategies for poststroke epileptogenesis. This article is part of the Special Issue "Seizures & Stroke".
Asunto(s)
Anticonvulsivantes/uso terapéutico , Encéfalo/efectos de los fármacos , Desarrollo de Medicamentos/métodos , Epilepsia/tratamiento farmacológico , Accidente Cerebrovascular/tratamiento farmacológico , Animales , Anticonvulsivantes/farmacología , Encéfalo/fisiología , Desarrollo de Medicamentos/tendencias , Epilepsia/diagnóstico , Epilepsia/etiología , Humanos , Factores de Riesgo , Convulsiones/diagnóstico , Convulsiones/tratamiento farmacológico , Convulsiones/etiología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnósticoRESUMEN
Introduction: Epilepsy is a common neurological disease requiring complex therapies, which are unable to achieve seizure control in 30% of patients. Poor adherence has been recognized as a possible determinant of drug-resistance. Prolonged-release formulations of antiepileptic drugs might help increase adherence and minimize side effects.Areas covered: Pregabalin (PGB) has peculiar pharmacodynamics and almost ideal pharmacokinetics, except for a short half-life and therefore requiring multiple daily dosing. PGB immediate-release (IR) is effective in focal-onset epilepsy (FOE), neuropathic pain, generalized anxiety disorder, and fibromyalgia, despite some tolerability issues, especially at higher doses. The controlled-release formulation (CR) shares PGB IR advantages and requires slight dose adjustments to guarantee bioavailability. In 2014, PGB CR (165 and 330 mg/day) failed to prove superior to placebo in a randomized placebo-controlled trial on 323 subjects with drug-resistant FOE, although it was just as tolerable. Therefore, PGB CR is not currently licensed for epilepsy.Expert opinion: Considering the disappointing results of the only controlled trial, PGB CR is unlikely to become an established epilepsy treatment anytime soon. Nevertheless, given its peculiar properties and potential advantages, PGB (in either formulation) should be further evaluated in specific populations of patients, especially fragile subjects with several comorbidities and complex polytherapies.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Epilepsias Parciales/tratamiento farmacológico , Pregabalina/uso terapéutico , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/farmacocinética , Preparaciones de Acción Retardada/uso terapéutico , Humanos , Pregabalina/administración & dosificación , Pregabalina/farmacocinéticaRESUMEN
We studied the effects of intestinal inflammation on pentylenetetrazole (PTZ)-induced seizures in mice and the effects thereon of some antiepileptic and anti-inflammatory treatments to establish if a link may exist. The agents tested were: alpha-lactoalbumin (ALAC), a whey protein rich in tryptophan, effective in some animal models of epilepsy and on colon/intestine inflammation, valproic acid (VPA), an effective antiepileptic drug in this seizure model, mesalazine (MSZ) an effective aminosalicylate anti-inflammatory treatment against ulcerative colitis and sodium butyrate (NaB), a short chain fatty acid (SCFA) normally produced in the intestine by gut microbiota, important in maintaining gut health and reducing gut inflammation and oxidative stress. Intestinal inflammation was induced by dextran sulfate sodium (DSS) administration for 6 days. Drug treatment was started on day 3 and lasted 11 days, when seizure susceptibility to PTZ was measured along with intestinal inflammatory markers (i.e. NF-κB, Iκ-Bα, COX-2, iNOS), histological damage, disease activity index (DAI) and SCFA concentration in stools. DSS-induced colitis increased seizure susceptibility and while all treatments were able to reduce intestinal inflammation, only ALAC and NaB exhibited significant antiepileptic properties in mice with induced colitis, while they were ineffective as antiepileptics at the same doses in control mice without colitis. Interestingly, in DSS-treated mice, VPA lost part of its antiepileptic efficacy in comparison to preventing seizures in non-DSS-treated mice while MSZ remained ineffective in both groups. Our study demonstrates that reducing intestinal inflammation through ALAC or NaB administration has specific anticonvulsant effects in PTZ-treated mice. Furthermore, it appears that intestinal inflammation may reduce the antiepileptic effects of VPA, although we confirm that it decreases seizure threshold in this group. Therefore, we suggest that intestinal inflammation may represent a valid antiepileptic target which should also be considered as a participating factor to seizure incidence in susceptible patients and also could be relevant in reducing standard antiepileptic drug efficacy.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Colitis/complicaciones , Convulsivantes , Epilepsia/complicaciones , Pentilenotetrazol , Ácido Valproico/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Anticonvulsivantes/farmacología , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/patología , Sulfato de Dextran , Modelos Animales de Enfermedad , Epilepsia/inducido químicamente , Epilepsia/tratamiento farmacológico , Epilepsia/patología , Masculino , Mesalamina/uso terapéutico , Ratones , Ácido Valproico/farmacologíaRESUMEN
Liraglutide (LIR) is a novel long-lasting glucagon-like peptide-1 (GLP-1) analogue that facilitates insulin signalling and shows also neuroprotective properties in different brain disease models. In this study, we explored the potential antiepileptogenic effects of LIR in two different animal models; namely, the mouse intrahippocampal kainic acid (KA) model of temporal lobe epilepsy and the WAG/Rij rat model of absence epileptogenesis. Moreover, we evaluated LIR effects on comorbidities in various behavioural tests. Mice with kainate-induced epilepsy were treated with LIR (300⯵g/kg/day s.c.) for 4 weeks after status epilepticus and then evaluated for drug effects on seizure development and behavioural alterations, whereas WAG/Rij rats were treated for 17 weeks (starting at 30 days of age, before seizure onset) with LIR (300⯵g/kg/day s.c.) in order to investigate whether an early chronic treatment was able to reduce the development of absence seizures and related comorbidities. Our results indicate that LIR was effective in reducing the development of spontaneous seizures in kainate-induced epilepsy; moreover, in this model, it prevented memory impairment and related anxiety-like behaviour in the open field (OF) test while in the forced swimming test (FST), LIR displayed an apparent pro-depressant effect that was instead related to reduced endurance as confirmed by rotarod test. In contrast, LIR was unable to modify the epileptogenic process underlying the development of absence seizures in WAG/Rij rats while being antidepressant in the FST in this strain. Our results indicate that LIR may represent a promising novel treatment to prevent and treat the epileptogenic process and its associated behavioural and cognitive alterations in some models of convulsive epilepsy characterized by neurodegeneration, since LIR effects are likely secondary to its recognised neuroprotective properties.
Asunto(s)
Epilepsia/tratamiento farmacológico , Epilepsia/metabolismo , Liraglutida/farmacología , Animales , Anticonvulsivantes/farmacología , Ansiedad/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Depresión/tratamiento farmacológico , Modelos Animales de Enfermedad , Electroencefalografía/métodos , Epilepsia Tipo Ausencia/inducido químicamente , Epilepsia Tipo Ausencia/tratamiento farmacológico , Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Liraglutida/metabolismo , Liraglutida/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Ratas , Ratas Wistar , Convulsiones/tratamiento farmacológicoRESUMEN
BACKGROUND: WAG/Rij rats represent a validated genetic animal model of epileptogenesis, absence epilepsy and depressive-like comorbidity. Some treatments (e.g. ethosuximide), using specific protocols, prevent the development of spontaneous absence seizures. Accordingly, ethosuximide increases remission occurrence in children with childhood absence epilepsy in comparison to valproic acid. Considering that in this animal model, antiepileptogenic effects are, in some cases, not retained over time, we studied whether the antiepileptogenic effects of both ethosuximide and levetiracetam (which also possesses antiepileptogenic effects in this and other animal epilepsy models) would be retained 5 months after drug suspension. METHODS: WAG/Rij rats of Ë1 month of age were treated long-term with one of the two drugs at a dose of Ë80 mg/kg/day for 17 consecutive weeks; 1 and 5 months after drug suspension, the development of absence seizures as well as depressive-like behaviour were assessed by EEG recordings and the forced swimming test (FST). RESULTS: In agreement with a previous report, both drugs continued to show antiepileptogenic effects 1 month after their discontinuation. Furthermore, ethosuximide improved depressive-like behaviour, whereas in contrast, levetiracetam worsened this symptom. However, none of the drugs maintained their antiepileptogenic effects 5 months after suspension, and in addition, animal behaviour in the FST returned to control conditions. CONCLUSION: Overall, these results demonstrate that the antiepileptogenic effects of both ethosuximide and levetiracetam on absence seizure development and associated depressive-like behaviour in this model are only temporary.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Epilepsia Tipo Ausencia/tratamiento farmacológico , Etosuximida/administración & dosificación , Levetiracetam/administración & dosificación , Convulsiones/tratamiento farmacológico , Animales , Anticonvulsivantes/uso terapéutico , Conducta Animal/efectos de los fármacos , Depresión/tratamiento farmacológico , Modelos Animales de Enfermedad , Duración de la Terapia , Etosuximida/uso terapéutico , Levetiracetam/uso terapéutico , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Endogámicas , Factores de TiempoRESUMEN
Neuropsychiatric comorbidities are common in patients with epilepsy, remaining still an urgent unmet clinical need. Therefore, the management of epileptic disorders should not only be restricted to the achievement of seizure-freedom but must also be able to counteract its related comorbidities. Experimental animal models of epilepsy represent a valid tool not only to study epilepsy but also its associated comorbidities. The WAG/Rij rat is a well-established genetically-based model of absence epilepsy with depressive-like comorbidity, in which learning and memory impairment was also recently reported. Aim of this study was to clarify whether this cognitive decline is secondary or not to absence seizures and/or depressive-like behavior. The behavioral performance of untreated and ethosuximide-treated (300â¯mg/kg/day; 17â¯days) WAG/Rij rats at 6 and 12â¯months of age were assessed in several tests: forced swimming test, objects recognition test, social recognition test, Morris water maze and passive avoidance. According to our results, it seems that cognitive impairment in this strain, similarly to depressive-like behavior, is secondary to the occurrence of absence seizures, which might be necessary for the expression of cognitive impairment. Furthermore, our results suggest an age-dependent impairment of cognitive performance in WAG/Rij rats, which could be linked to the age-dependent increase of spike wave discharges. Consistently, it is possible that absence seizures, depressive-like behavior and cognitive deficit may arise independently and separately in lifetime from the same underlying network disease, as previously suggested for the behavioral features associated with other epileptic syndromes.