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Abstract: In many experimental systems, proinflammatory stimuli exhibit proconvulsant properties. There are also accumulating data suggesting that inflammation may contribute to epileptogenesis in experimental models as well as in humans. Using two different models (Lithium-pilocarpine induced-status epilepticus (SE) and rapid kindling), we address this issue in the developing brain. Using P14 Wistar rat pups, we showed that inflammation induced by LPS results, after SE, into a more severe disease in adulthood. The main histological feature was an active gliosis that was observed only when inflammation and SE was combined. The use of a kindling model at P14, a model where seizure progress without any neurodegeneration, permits to show that systemic inflammation is responsible of an enhancement of epileptogenesis. The role of inflammation should be further explored in immature brain to identify therapeutic targets that may be relevant to clinical practice where the association of inflammation and epileptic events is common. [ABSTRACT FROM AUTHOR]

Abstract: Depression is a frequent comorbidity of temporal lobe epilepsy (TLE); however, its mechanisms remain poorly understood and effective therapies are lacking. Augmentation of hippocampal interleukin-1β (IL-1β) signaling may be a mechanistic factor of both TLE and clinical depression. We examined whether pharmacological blockade of hippocampal interleukin-1 receptor exerts antidepressant effects in an animal model of comorbidity between TLE and depression, which developed in Wistar rats following pilocarpine status epilepticus (SE). In post-SE animals, depression-like state was characterized by behavioral equivalents of anhedonia and despair; dysregulation of the hypothalamo–pituitary–adrenocortical axis; compromised raphe–hippocampal serotonergic transmission. Two-week long bilateral intrahippocampal infusion of human recombinant Interleukin-1 receptor antagonist (IL-1ra) improved all of the examined depressive impairments, without modifying spontaneous seizure frequency and without affecting normal parameters in naïve rats. These findings implicate hippocampal IL-1β in epilepsy-associated depression and provide a rationale for the introduction of IL-1β blockers in the treatment of depression in TLE. [Copyright &y& Elsevier]

Abstract: Objective: The endogenous hormone melatonin has previously been shown to exert anticonvulsant effects in a variety of experimental models. Accordingly, we asked whether ramelteon, a synthetic and selective melatonin receptor agonist, might also possess anticonvulsant and/or antiepileptogenic properties. Methods: The effects of ramelteon (30 or 100mg/kg intraperitoneally twice daily for 5days) were evaluated in two animal models of epilepsy. In the rat rapid kindling model, baseline hippocampal afterdischarge properties, kindling progression, and hippocampal excitability in kindled animals were measured. Anti-ictogenic efficacy was assessed after acute administration in untreated kindled rats. In the spontaneously epileptic Kcna1-null mouse model, we determined seizure frequency and periodicity using continuous video/EEG monitoring over 72hours. Further, circadian rest–activity rhythms in ramelteon-treated animals were studied with actigraphy. Results: In kindled animals, ramelteon reversed kindling-induced hippocampal excitability; however, it did not modify baseline afterdischarge properties, the progression and establishment of the kindled state in the rapid kindling model. However, in Kcna1-null mice, ramelteon (200mg/kg/day) significantly attenuated seizure periodicity and frequency and improved circadian rest–activity rhythms compared with control animals. Conclusions: The selective melatonin receptor agonist ramelteon possesses anticonvulsant properties in a chronic epilepsy model. Our findings provide further support for melatonin receptors being potential novel targets for anticonvulsant drug development. [Copyright &y& Elsevier]

Abstract: Depression is frequently reported in epilepsy patients; however, mechanisms of co-morbidity between epilepsy and depression are poorly understood. An important mechanism of depression is disinhibition within the hypothalamo–pituitary–adrenocortical (HPA) axis. We examined the functional state of the HPA axis in a rat model of co-morbidity between temporal lobe epilepsy and depression. Epilepsy was accompanied by the interictal elevation of plasma corticosterone, and by the positively combined dexamethasone/corticotropin releasing hormone test. The extent of the HPA hyperactivity was independent of recurrent seizures, but positively correlated with the severity of depressive behavior. We suggest that the observed hyperactivity of the HPA axis may underlie co-morbidity between epilepsy and depression. [Copyright &y& Elsevier]

Animal systems have been widely used to examine mechanisms of neurobehavioral comorbidities of epilepsy and to help in developing their effective therapies. Despite the progress made in the field, animal studies have their limitations stemming both from issues with modeling neuropsychiatric disorders in the laboratory and from drawbacks of animal models of epilepsy themselves. This review discusses advantages and weaknesses of experimental paradigms and approaches used to model and to analyze neurobehavioral comorbidities of epilepsy, from the perspectives of their needs, interpretation, ways of improvement, and clinical relevance. Developmental studies are required to adequately address age-specific aspects of the comorbidities. The deployment of preclinical Common Data Elements (pCDEs) for epilepsy research should facilitate the standardization and the harmonization of studies in question, while the application of Research Domain Criteria (RDoC) to characterize neurobehavioral disorders in animals with epilepsy should help in closing the bench-to-bedside gap. Special Issue: Epilepsy & Behavior's 20th Anniversary. [ABSTRACT FROM AUTHOR]

Abstract: During the last decade, experimental research has demonstrated a prominent role of glial cells, activated in brain by various injuries, in the mechanisms of seizure precipitation and recurrence. In particular, alterations in the phenotype and function of activated astrocytes and microglial cells have been described in experimental and human epileptic tissue, including modifications in potassium and water channels, alterations of glutamine/glutamate cycle, changes in glutamate receptor expression and transporters, release of neuromodulatory molecules (e.g. gliotransmitters, neurotrophic factors), and induction of molecules involved in inflammatory processes (e.g. cytokines, chemokines, prostaglandins, complement factors, cell adhesion molecules) (Seifert et al., 2006; Vezzani et al., 2011; Wetherington et al., 2008). In particular, brain injury or proconvulsant events can activate microglia and astrocytes to release a number of proinflammatory mediators, thus initiating a cascade of inflammatory processes in brain tissue. Proinflammatory molecules can alter neuronal excitability and affect the physiological functions of glia by paracrine or autocrine actions, thus perturbing the glioneuronal communications. In experimental models, these changes contribute to decreasing the threshold to seizures and may compromise neuronal survival (Riazi et al., 2010; Vezzani et al., 2008). In this context, understanding which are the soluble mediators and the molecular mechanisms crucially involved in glio–neuronal interactions is instrumental to shed light on how brain inflammation may contribute to neuronal hyperexcitability in epilepsy. This review will report the clinical observations in drug-resistant human epilepsies and the experimental findings in adult and immature rodents linking brain inflammation to the epileptic process in a causal and reciprocal manner. By confronting the clinical evidence with the experimental findings, we will discuss the role of specific soluble inflammatory mediators in the etiopathogenesis of seizures, reporting evidence for both their acute and long term effects on seizure threshold. The possible contribution of these mediators to co-morbidities often described in epilepsy patients will be also discussed. Finally, we will report on the anti-inflammatory treatments with anticonvulsant actions in experimental models highlighting possible therapeutic options for treating drug-resistant seizures and for prevention of epileptogenesis. [Copyright &y& Elsevier]

Anxiety is one of the most common comorbidities of epilepsy, which has major detrimental effects on the quality of life. Generalized anxiety disorder (GAD) associated with epilepsy has been receiving most attention. However, several other forms of anxiety reportedly present in patients with epilepsy, including panic disorder (PD). In this study, using an animal model of limbic epilepsy, we examined the interplay between epilepsy and panic-like behavior (PLB). Further, considering the high degree of comorbidity between depression on the one hand, and both epilepsy and PD on the other hand, we studied whether and how the presence of PLB in animals with epilepsy would affect their performance in depression-relevant tests. Fifty-day-old male Wistar rats were subjected to repeated alternating electrical stimulations of the basolateral amygdala (BLA) to induce kindling of limbic seizures, and the dorsal periaqueductal gray (DPAG) to induce panic-like episodes. Seizure susceptibility and panic reaction threshold were examined before the first and 24 h after the last stimulation. At the end of the stimulations, the rats were examined in depression-relevant tests: saccharin preference test (SPT) for anhedonia and forced swimming test (FST) for despair/hopelessness. With regard to kindling, BLA + DPAG stimulation induced more profound increase of seizure susceptibility than BLA stimulation alone (evident as the reduction of the afterdischarge threshold and the increase of the afterdischarge duration). With regard to PLB, the BLA + DPAG stimulation exacerbated the severity of panic-like episodes, as compared with the DPAG stimulation alone. Basolateral amygdala stimulation alone had no effects on panic-like reactions, and DPAG stimulation alone did not modify kindling epileptogenesis. Combined stimulation of BLA and DPAG induced depressive-like behavioral impairments. This is the first experimental study showing bidirectional, mutually exacerbating effect of epilepsy and PLB, and the precipitation of depressive-like state by the epilepsy–PLB comorbidity. [ABSTRACT FROM AUTHOR]

Status epilepticus (SE) in rats, along with chronic epilepsy, leads to the development of behavioral impairments resembling depressive disorder and/or attention deficit/hyperactivity disorder (ADHD), thus reflecting respective comorbidities in epilepsy patients. Suppressed neurotransmitter tone in the raphe nucleus (RN)-prefrontal cortex (PFC) serotonergic pathway and in the locus coeruleus (LC)-PFC noradrenergic pathway underlies depressive- and impulsive-like behavioral deficits respectively. We examined possible mechanisms leading to the monoamine dysfunction in brainstem efferents, namely modulatory effects of the neuropeptide galanin on serotonin (5-HT) and norepinephrine (NE) signaling. SE was induced in young adult male Wistar rats by LiCl and pilocarpine. Epileptic rats were categorized vis-à-vis behavioral deficits as not impaired, “depressed” and “impulsive”. Depressive- and impulsive-like behaviors were examined in the forced swimming test (FST). The strength of serotonergic transmission in RN-PFC and of noradrenergic transmission in LC-PFC was analyzed using in vivo fast scan cyclic voltammetry. Galanin receptor type 1 (GalR1)/type 2 (GalR2) antagonist M40, and a preferential GalR2 antagonist M871 were administered over 3 days locally into either RN or LC by means of ALZET osmotic minipumps connected to locally implanted infusion cannulas. Intra-RN injection of M40 improved serotonergic tone and depressive-like behavior in epileptic “depressed” rats. Intra-LC injection of M40 improved noradrenergic tone and impulsive-like behavior in epileptic “impulsive” rats. The effects of M40 were only observed in impaired subjects. The treatment did not modify neurotransmission and behavior in naïve and epileptic not impaired rats; in “depressed” rats the effects were limited to serotonergic transmission and immobility, while in “impulsive” rats – to noradrenergic transmission and struggling behavior. Intra-RN administration of M871 exacerbated depressive-like behavior, but had no effects on any other of the examined parameters in any category of animals. These findings suggest that endogenous galanin, acting through GalR1 may be involved in the pathophysiology of epilepsy-associated depression and ADHD via inhibiting RN-PFC serotonergic and LC-PFC noradrenergic transmissions respectively. [ABSTRACT FROM AUTHOR]

• Microbiome transfer from naïve rats modified seizure susceptibility in recipients. • The effect was consistent with the donors' history of post-traumatic epilepsy. • The effect was evident as a higher incidence of spontaneous seizures in recipients. • The effect was evident as the facilitation of kindling in recipients. It has been well established that traumatic brain injury (TBI) modifies the composition of gut microbiome. Epilepsy, which represents one of the common sequelae of TBI, has been associated with dysbiosis. Earlier study showed that the risk of post-traumatic epilepsy (PTE) after lateral fluid percussion injury (LFPI) in rats can be stratified based on pre-existing (i.e., pre-TBI) gut microbiome profile. In the present study, we examined whether fecal microbiota transfer (FMT) from naïve rats with different prospective histories of PTE would affect the trajectory of PTE in recipients. Fecal samples were collected from naïve adult male Sprague–Dawley rats, followed by LFPI. Seven months later, upon four weeks of vide-EEG monitoring (vEEG), the rats were categorized as those with and without PTE. Recipients were subjected to LFPI, followed by FMT from donors with and without impending PTE. Control groups included auto-FMT and no-FMT subjects. Seven month after LFPI, recipients underwent four-week vEEG to detect spontaneous seizures. After completing vEEG, rats of all groups underwent kindling of basolateral amygdala. Fecal microbiota transfer from donors with impending PTE exerted mild-to-moderate pro-epileptic effects in recipients, evident as marginal increase in multiple spontaneous seizure incidence, and facilitation of kindling. Analysis of fecal samples in selected recipients and their respective donors confirmed that FMT modified microbiota in recipients along the donors' lines, albeit without full microbiome conversion. The findings provide further evidence that gut microbiome may actively modulate the susceptibility to epilepsy. [ABSTRACT FROM AUTHOR]

Maternal immune activation (MIA) results in the development of autism in the offspring via hyperactivation of IL-6 signaling. Furthermore, experimental studies showed that the MIA-associated activation of interleukin-1β (IL-1β) concurrently with IL-6 increases the rate and the severity of hippocampal kindling in mice, thus, offering an explanation for autism–epilepsy comorbidity. We examined whether epileptic phenotype triggered by prenatal exposure to IL-6 and IL-1β combination is restricted to kindling or whether it is reproducible in another model of epilepsy, whereby spontaneous seizures develop following kainic acid (KA)-induced status epilepticus. We also examined whether in mice prenatally exposed to IL-6 and IL-6 + IL-1β, the presence of spontaneous seizures would exacerbate autism-like features. Between days 12 and 16 of pregnancy, C57BL/6J mice received daily injections of IL-6, IL-1β, or IL-6 + IL-1β combination. At postnatal day 40, male offspring were examined for the presence of social behavioral deficit, and status epilepticus was induced by intrahippocampal KA injection. After 6 weeks of monitoring for spontaneous seizures, sociability was tested again. Both IL-6 and IL-6 + IL-1β offspring presented with social behavioral deficit. Prenatal exposure to IL-6 alleviated, while such exposure to IL-6 + IL-1β exacerbated, the severity of KA-induced epilepsy. Increased severity of epilepsy in the IL-6 + IL-1β mice correlated with the improvement of autism-like behavior. We conclude that complex and not necessarily agonistic relationships exist between epileptic and autism-like phenotypes in an animal model of MIA coupled with KA-induced epilepsy and that the nature of these relationships depends on components of MIA involved. [ABSTRACT FROM AUTHOR]

Abstract: Attention deficit/hyperactivity disorder (ADHD) is encountered among patients with epilepsy at a significantly higher rate than in the general population. Mechanisms of epilepsy–ADHD comorbidity remain largely unknown. We investigated whether a model of chronic epilepsy in rats produces signs of ADHD, and thus, whether it can be used for studying mechanisms of this comorbidity. Epilepsy was induced in male Wistar rats via pilocarpine status epilepticus. Half of the animals exhibited chronic ADHD-like abnormalities, particularly increased impulsivity and diminished attention in the lateralized reaction-time task. These impairments correlated with the suppressed noradrenergic transmission in locus coeruleus outputs. The other half of animals exhibited depressive behavior in the forced swimming test congruently with the diminished serotonergic transmission in raphe nucleus outputs. Attention deficit/hyperactivity disorder and depressive behavior appeared mutually exclusive. Therefore, the pilocarpine model of epilepsy affords a system for reproducing and studying mechanisms of comorbidity between epilepsy and both ADHD and/or depression. [Copyright &y& Elsevier]