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The pharmacological exploitation of the galanin receptors as drug targets for treatment of epilepsy, depression, and pain has been hampered by the lack of workable compounds for medicinal chemists from random screening of large chemical libraries. The present work uses the tripeptidomimetic galnon and displays its presumed pharmacophores on a rigid molecular scaffold. The scaffold is related to marine natural products and presents three functional groups near one another in space, in a manner reminiscent of a protein surface. An active compound, Galmic, was identified from a small synthetic library and tested in vitro and in vivo for its affinity and efficacy at galanin receptors. Galmic has micromolar affinity for GalR1 receptors (Ki = 34.2 μM) and virtually no affinity for GaIR2 receptors. In vitro, Galmic, like galanin. suppresses long-term potentiation in the dentate gyrus; it blocks status epilepticus when injected intrahippocampally or administered i.p. Galmic applied i.p. shows antidepressant-like effects in the forced-swim test, and it is a potent inhibitor of flinching behavior in the inflammatory pain model induced by formalin injection. These data further implicate brain and spinal cord galanin receptors as drug targets and provide an example of a systemically active compound based on a scaffold that mimics protein surfaces. [ABSTRACT FROM AUTHOR]

Galanin is a neuroendocrine peptide involved in the regulation of feeding, pain, sexual behavior, learning, and memory. The recent discovery, that galanin antagonized excitatory glutamatergic neurotransmission in the hippocampus, provided a rationale for its possible antiepileptic effects. Here we summarize the data on the effects of galanin on seizure activity in several animal models of epilepsy. Pharmacological and molecular biological evidence suggest potent anticonvulsant effects of galanin. Exogenous administration of galanin receptor agonists attenuated seizures, whereas application of galanin receptor antagonists potentiated seizure expression. Genetically engineered mice, with either deletion or overexpression of galanin gene, showed altered resistance to seizures, which was in direct correlation with galanin gene expression. Possible mechanisms of the anticonvulsant action of galanin include its effects on synaptic potentiation in hippocampal circuits and inhibition of the release of the excitatory neurotransmitter glutamate from principal hippocampal neurons. NEUROSCIENTIST 7(6):506–517, 2001. [ABSTRACT FROM AUTHOR]

Background: Inflammatory signaling elicited by prolonged seizures can be contributory to neuronal injury as well as adverse plasticity leading to the development of spontaneous recurrent seizures (epilepsy) and associated co-morbidities. In this study, developing rat pups were subjected to lithium-pilocarpine status epilepticus (SE) at 2 and 3 weeks of age to study the effect of anti-inflammatory drugs (AID) on SE-induced hippocampal injury and the development of spontaneous seizures.Findings: We selected AIDs directed against interleukin-1 receptors (IL-1ra), a cyclooxygenase-2 (COX-2) inhibitor (CAY 10404), and an antagonist of microglia activation of caspase-1 (minocycline). Acute injury after SE was studied in the 2-week-old rats 24 h after SE. Development of recurrent spontaneous seizures was studied in 3-week-old rats subjected to SE 4 months after the initial insult.None of those AIDs were effective in attenuating CA1 injury in the 2-week-old pups or in limiting the development of spontaneous seizures in 3-week-old pups when administered individually. When empiric binary combinations of these drugs were tried, the combined targeting of IL-1r and COX-2 resulted in attenuation of acute CA1 injury, as determined 24 h after SE, in those animals. The same combination administered for 10 days following SE in 3-week-old rats, reduced the development of spontaneous recurrent seizures and limited the extent of mossy fiber sprouting.Conclusions: Deployment of an empirically designed 'drug cocktail' targeting multiple inflammatory signaling pathways for a limited duration after an initial insult like SE may provide a practical approach to neuroprotection and anti-epileptogenic therapy. [ABSTRACT FROM AUTHOR]

Objective: We examined whether posttraumatic epilepsy (PTE) is associated with measurable perturbations in gut microbiome. Methods: Adult Sprague Dawley rats were subjected to lateral fluid percussion injury (LFPI). PTE was examined 7 months after LFPI, during 4‐week continuous video‐electroencephalographic monitoring. 16S ribosomal RNA gene sequencing was performed in fecal samples collected before LFPI/sham‐LFPI and 1 week, 1 month, and 7 months thereafter. Longitudinal analyses of alpha diversity, beta diversity, and differential microbial abundance were performed. Short‐chain fatty acids (SCFAs) were measured in fecal samples collected before LFPI by liquid chromatography with tandem mass spectrometry. Results: Alpha diversity changed over time in both LFPI and sham‐LFPI subjects; no association was observed between alpha diversity and LFPI, the severity of post‐LFPI neuromotor impairments, and PTE. LFPI produced significant changes in beta diversity and selective changes in microbial abundances associated with the severity of neuromotor impairments. No association between LFPI‐dependent microbial perturbations and PTE was detected. PTE was associated with beta diversity irrespective of timepoint vis‐à‐vis LFPI, including at baseline. Preexistent fecal microbial abundances of four amplicon sequence variants belonging to the Lachnospiraceae family (three enriched and one depleted) predicted the risk of PTE, with area under the curve (AUC) of.73. Global SCFA content was associated with the increased risk of PTE, with AUC of.722, and with 2‐methylbutyric (depleted), valeric (depleted), isobutyric (enriched), and isovaleric (enriched) acids being the most important factors (AUC =.717). When the analyses of baseline microbial and SCFA compositions were combined, AUC to predict PTE increased to.78. Significance: Whereas LFPI produces no perturbations in the gut microbiome that are associated with PTE, the risk of PTE can be stratified based on preexistent microbial abundances and SCFA content. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social interactions, difficulty with communication, and repetitive behavior patterns. In humans affected by ASD, there is a male pre-disposition towards the condition with a male to female ratio of 4:1. In part due to the complex etiology of ASD including genetic and environmental interplay, there are currently no available medical therapies to improve the social deficits of ASD. Studies in rodent models and humans have shown promising therapeutic effects of oxytocin in modulating social adaptation. One pharmacological approach to stimulating oxytocinergic activity is the melanocortin receptor 4 agonist Melanotan-II (MT-II). Notably the effects of oxytocin on environmental rodent autism models has not been investigated to date. We used a maternal immune activation (MIA) mouse model of autism to assess the therapeutic potential of MT-II on autism-like features in adult male mice. The male MIA mice exhibited autism-like features including impaired social behavioral metrics, diminished vocal communication, and increased repetitive behaviors. Continuous administration of MT-II to male MIA mice over a seven-day course resulted in rescue of social behavioral metrics. Normal background C57 male mice treated with MT-II showed no significant alteration in social behavioral metrics. Additionally, there was no change in anxiety-like or repetitive behaviors following MT-II treatment of normal C57 mice, though there was significant weight loss following subacute treatment. These data demonstrate MT-II as an effective agent for improving autism-like behavioral deficits in the adult male MIA mouse model of autism. [ABSTRACT FROM AUTHOR]

The objective was to determine whether the depression comorbid with epilepsy could be predicted based on inherent premorbid patterns of monoaminergic transmission. In male Wistar rats, despair-like and anhedonia-like behaviors were examined using forced swimming and taste preference tests, respectively. Serotonergic raphe nucleus ( RN)-prefrontal cortex ( PFC) and dopaminergic ventral tegmental area ( VTA)-nucleus accumbens ( NAcc) pathways were interrogated by fast scan cyclic voltammetry ( FSCV). The assays were performed before and 2 months after pilocarpine status epilepticus. In a subset of naive rats, FSCV, coupled with the intensity-dependent stimulation paradigm, detected specific deviations in each pathway (six rats for RN- PFC and seven rats for VTA- NAcc, with overlap in two, of 19 total subjects) in the absence of behavioral impairments. During epilepsy, animals with preexisting deviations in RN- PFC invariably developed despair, and rats with deviations in VTA- NAcc developed anhedonia. Serotonergic and dopaminergic pathways, respectively, showed signs of explicit deterioration. We suggest that epilepsy triggers decompensations in the already vulnerable depression-relevant neuronal circuits, which culminate in depression. The established connection between the identified specific signatures in monoamine transmission in naive rats and specific symptoms of epilepsy-associated depression may help in understanding causes of comorbidity and in developing its early biomarkers. [ABSTRACT FROM AUTHOR]

Neurologic and psychiatric comorbidities are common in patients with epilepsy. Diagnostic, predictive, and pharmacodynamic biomarkers of such comorbidities do not exist. They may share pathogenetic mechanisms with epileptogenesis/ictogenesis, and as such are an unmet clinical need. The objectives of the subgroup on biomarkers of comorbidities at the XIII Workshop on the Neurobiology of Epilepsy (WONOEP) were to present the state-of-the-art recent research findings in the field that highlighting potential biomarkers for comorbidities in epilepsy. We review recent progress in the field, including molecular, imaging, and genetic biomarkers of comorbidities as discussed during the WONOEP meeting on August 31-September 4, 2015, in Heybeliada Island (Istanbul, Turkey). We further highlight new directions and concepts from studies on comorbidities and potential new biomarkers for the prediction, diagnosis, and treatment of epilepsy-associated comorbidities. The activation of various molecular signaling pathways such as the 'Janus Kinase/Signal Transducer and Activator of Transcription,' 'mammalian Target of Rapamycin,' and oxidative stress have been shown to correlate with the presence and severity of subsequent cognitive abnormalities. Furthermore, dysfunction in serotonergic transmission, hyperactivity of the hypothalamic-pituitary-adrenocortical axis, the role of the inflammatory cytokines, and the contributions of genetic factors have all recently been regarded as relevant for understanding epilepsy-associated depression and cognitive deficits. Recent evidence supports the utility of imaging studies as potential biomarkers. The role of such biomarker may be far beyond the diagnosis of comorbidities, as accumulating clinical data indicate that comorbidities can predict epilepsy outcomes. Future research is required to reveal whether molecular changes in specific signaling pathways or advanced imaging techniques could be detected in the clinical settings and correlate with epilepsy-associated comorbidities. A reliable biomarker will allow a more accurate diagnosis and improved treatment of epilepsy-associated comorbidities. [ABSTRACT FROM AUTHOR]

Objective Examine therapeutic potential of a selective serotonin reuptake inhibitor ( SSRI) and a norepinephrine reuptake inhibitor ( NERI) in an animal model of comorbidity between epilepsy, depression-like, and impulsive-like impairments. Methods Epilepsy was induced in male Wistar rats by LiCl and pilocarpine. An SSRI fluoxetine ( FLX), and an NERI reboxetine ( RBX) were administered either alone or as a combination over 1 week. Depressive-like and impulsive-like behaviors were examined using the forced swim test. Fast scan cyclic voltammetry was used to analyze serotonergic transmission in the raphe nucleus ( RN)-prefrontal cortex ( PFC) pathway, and noradrenergic transmission in locus coeruleus ( LC)- PFC, and LC- RN projections. Monoamine levels in PFC were measured using high-performance liquid chromatography (HPLC). Functional capacities of 5- HT1A receptors and α2A adrenoreceptors in PFC were analyzed by autoradiography. Results Epileptic rats showed behavioral signs of depression and hyperimpulsivity, suppressed serotonergic and noradrenergic tones, decreased levels of serotonin (5- HT), and norepinephrine ( NE); 5- HT1A receptor and α2A adrenoreceptors functions remained intact. FLX failed to improve behavioral deficits, but effectively raised 5- HT level and marginally improved RN- PFC serotonergic transmission. RBX reversed impulsive-like behavior, normalized content of NE and noradrenergic tone in LC- PFC and LC- RN. FLX- RBX combination fully reversed depressive-like behavior, and normalized RN- PFC serotonergic transmission. None of the treatment modified the function of 5- HT and NE receptors. Significance Depressive- and impulsive-like behaviors in the pilocarpine model of epilepsy stem respectively from dysfunctions of serotonergic and noradrenergic ascending pathways. At the same time, epilepsy-associated depression is SSRI resistant. The finding that an SSRI- NERI combination exerts antidepressant effect, along with RBX-induced improvement of LC- RN noradrenergic transmission point toward the involvement of LC- RN noradrenergic input in enabling therapeutic potential of FLX. Medications that improve serotonergic and noradrenergic transmission, such as serotonin-norepinephrine reuptake inhibitors may be effective in treating epilepsy-associated SSRI-resistant depression, as well as concurrent depression and attention-deficit/hyperactivity disorder ( ADHD). [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]

Lateral fluid percussion injury (LFPI) in rats is used to model post-traumatic epilepsy (PTE), with spontaneous seizures occurring in up to ½ of the subjects. Using the kindling paradigm, we examined whether animals without detectable seizures had an altered seizure susceptibility. Male Sprague Dawley rats were subjected to LFPI. Seven-nine months later, spontaneous seizures were monitored for two weeks. Afterward, the animals underwent kindling of basolateral amygdala. For kindling outcomes, the animals were categorized based on the 95% confidence intervals of mean number trials to kindling (ie 3 consecutive stage 4-5 seizures). Spontaneous seizures were detected in 7 out of 24 rats. There was no correlation between the severity of LFPI and either baseline afterdischarge properties, or kindling rates. Six LFPI rats kindled at a rate comparable to those in sham-LFPI (n = 10) and in naïve (n = 7) subjects. Ten LFPI rats kindled faster and 8-slower than controls. None of slow-kindling rats had spontaneous seizures during the prekindling monitoring. During the same period, six fast-kindling and three normal-kindling rats had been seizure-free. Thus, kindling reveals a diversity to seizure susceptibility after LFPI beyond an overt seizure symptomatology, ranging from the increased susceptibility to the increased resistance., (© 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The treatment of epilepsy is not limited to the achievement of a seizure-free state. It must also incorporate the management of common psychiatric and neurologic comorbidities, affecting on average between 30 and 50% of patients with epilepsy, which have a significant impact on their lives at various levels, including quality of life and the prognosis of the seizure disorder. Mood and anxiety disorders are the most frequent psychiatric comorbidities, whereas stroke and migraine are among the more common neurologic comorbidities, migraine among the younger patients and stroke among the older patients. Not only do these psychiatric and neurologic comorbidities each have a bidirectional relation with epilepsy, but primary mood disorders have a bidirectional relation with these 2 neurologic disorders. Furthermore, depression and migraine have been each associated with a more severe epilepsy course, whereas depression has been associated with a more severe course of stroke and migraines. The purpose of this article is to review the clinical implications of the complex relations among epilepsy and these 3 comorbid disorders, and to identify any clinical and/or experimental evidence that may suggest that having more than one of these comorbid disorders may increase the risk of and course of epilepsy.

The provided companion has been developed by the Behavioral Working Group of the Joint Translational Task Force of the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES) with the purpose of assisting the implementation of Preclinical Common Data Elements (CDE) for studying and for reporting neurobehavioral comorbidities in rodent models of epilepsy. Case Report Forms (CRFs) are provided, which should be completed on a per animal/per test basis, whereas the CDEs are a compiled list of the elements that should be reported. This companion is not designed as a list of recommendations, or guidelines for how the tests should be run-rather, it describes the different types of assessments, and highlights the importance of rigorous data collection and transparency in this regard. The tests are divided into 7 categories for examining behavioral dysfunction on the syndrome level: deficits in learning and memory; depression; anxiety; autism; attention deficit/hyperactivity disorder; psychosis; and aggression. Correspondence and integration of these categories into the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) is introduced. Developmental aspects are addressed through the introduction of developmental milestones. Discussion includes complexities, limitations, and biases associated with neurobehavioral testing, especially when performed in animals with epilepsy, as well as the importance of rigorous data collection and of transparent reporting. This represents, to our knowledge, the first such resource dedicated to preclinical CDEs for behavioral testing of rodents.

There has been growing interest in the role of intestinal microbiome in brain disorders. We examined whether dysbiosis can predispose to epilepsy. The study was performed in female and male Sprague-Dawley rats. To induce dysbiosis, the rats were subjected to chronic restraint stress (two 2-h long sessions per day, over 2 weeks). Cecal content from stressed and sham-stressed donors was transplanted via oral gavage to recipients, in which commensal microbiota had been depleted by the antibiotics. The study included the following groups: (1) Sham stress, no microbiota transplant; (2) Stress, no microbiota transplant; (3) Sham-stressed recipients transplanted with microbiota from sham-stressed donors; (4) Stressed recipients transplanted with microbiota from sham-stressed donors; (5) Sham-stressed recipients transplanted with microbiota from stressed donors; and (6) Stressed recipients transplanted with microbiota from stressed donors. After microbiota transplant, all animals were subjected to kindling of the basolateral amygdala. Both chronic stress and microbiome transplanted from stressed to sham-stressed subjects accelerated the progression and prolonged the duration of kindled seizures. Microbiome from sham-stressed animals transplanted to chronically stressed rats, counteracted proepileptic effects of restraint stress. These findings directly implicate perturbations in the gut microbiome, particularly those associated with chronic stress, in the increased susceptibility to epilepsy.

Background: Infectious encephalitides are most often associated with acute seizures during the infection period and are risk factors for the development of epilepsy at later times. Mechanisms of viral encephalitis-induced epileptogenesis are poorly understood. Here, we evaluated the contribution of viral encephalitis-associated inflammation to ictogenesis and epileptogenesis using a rapid kindling protocol in rats. In addition, we examined whether minocycline can improve outcomes of viral-like brain inflammation., Methods: To produce viral-like inflammation, polyinosinic-polycytidylic acid (PIC), a toll-like receptor 3 (TLR3) agonist, was applied to microglial/macrophage cell cultures and to the hippocampus of postnatal day 13 (P13) and postnatal day 74 (P74) rats. Cell cultures permit the examination of the inflammation induced by PIC, while the in vivo setting better suits the analysis of cytokine production and the effects of inflammation on epileptogenesis. Minocycline (50 mg/kg) was injected intraperitoneally for 3 consecutive days prior to the kindling procedure to evaluate its effects on inflammation and epileptogenesis., Results: PIC injection facilitated kindling epileptogenesis, which was evident as an increase in the number of full limbic seizures at both ages. Furthermore, in P14 rats, we observed a faster seizure onset and prolonged retention of the kindling state. PIC administration also led to an increase in interleukin 1β (IL-1β) levels in the hippocampus in P14 and P75 rats. Treatment with minocycline reversed neither the pro-epileptogenic effects of PIC nor the increase of IL-1β in the hippocampus in both P14 and P75 rats., Conclusions: Hippocampal injection of PIC facilitates rapid kindling epileptogenesis at both P14 and P75, suggesting that viral-induced inflammation increases epileptogenesis irrespective of brain maturation. Minocycline, however, was unable to reverse the increase of epileptogenesis, which might be linked to its absence of effect on hippocampal IL-1β levels at both ages.

The importance of comorbidities in determining the quality of life of individuals with epilepsy and their families has received increasing attention in the past decade. Along with it has come a recognition that in some individuals, certain comorbidities may have preexisted, and may have contributed to their developing epilepsy. Many mechanisms are capable of interconnecting different dysfunctions that manifest as distinct disorders, often diagnosed and managed by different specialists. We review the human data from the perspective of epidemiology as well as insights gathered from neurodiagnostic and endocrine studies. Animal studies are reviewed to refine our mechanistic understanding of the connections, because they permit the narrowing of variables, which is not possible when studying humans., (Copyright © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.)

The response of the developing brain to epileptic seizures and to status epilepticus is highly age-specific. Neonates with their low cerebral metabolic rate and fragmentary neuronal networks can tolerate relatively prolonged seizures without suffering massive cell death, but severe seizures in experimental animals inhibit brain growth, modify neuronal circuits, and can lead to behavioral deficits and to increases in neuronal excitability. Past infancy, the developing brain is characterized by high metabolic rate, exuberant neuronal and synaptic networks and overexpression of receptors and enzymes involved in excitotxic mechanisms. The outcome of seizures is highly model-dependent. Status epilepticus may produce massive neuronal death, behavioral deficits, synaptic reorganization and chronic epilepsy in some models, little damage in others. Long-term consequences are also highly age- and model-dependent. However, we now have some models which reliably lead to spontaneous seizures and chronic epilepsy in the vast majority of animals, demonstrating that seizure-induced epileptogenesis can occur in the developing brain. The mode cell death from status epilepticus is largely (but not exclusively) necrotic in adults, while the incidence of apoptosis increases at younger ages. Seizure-induced necrosis has many of the biochemical features of apoptosis, with early cytochrome release from mitochondria and capase activation. We speculate that this form of necrosis is associated with seizure-induced energy failure.