A Systematic Review of the Predictive and Diagnostic Uses of Neuroinflammation Biomarkers for Epileptogenesis.

A central role for neuroinflammation in epileptogenesis has recently been suggested by several investigations. This systematic review explores the role of inflammatory mediators in epileptogenesis, its association with seizure severity, and its correlation with drug-resistant epilepsy (DRE). The study analysed articles published in JCR journals from 2019 to 2024. The search strategy comprised the MESH, free terms of "Neuroinflammation", and selective searches for the following single biomarkers that had previously been selected from the relevant literature: "High mobility group box 1/HMGB1", "Toll-Like-Receptor 4/TLR-4", "Interleukin-1/IL-1", "Interleukin-6/IL-6", "Transforming growth factor beta/TGF-ß", and "Tumour necrosis factor-alpha/TNF-α". These queries were all combined with the MESH terms "Epileptogenesis" and "Epilepsy". We found 243 articles related to epileptogenesis and neuroinflammation, with 356 articles from selective searches by biomarker type. After eliminating duplicates, 324 articles were evaluated, with 272 excluded and 55 evaluated by the authors. A total of 21 articles were included in the qualitative evaluation, including 18 case-control studies, 2 case series, and 1 prospective study. As conclusion, this systematic review provides acceptable support for five biomarkers, including TNF-α and some of its soluble receptors (sTNFr2), HMGB1, TLR-4, CCL2 and IL-33. Certain receptors, cytokines, and chemokines are examples of neuroinflammation-related biomarkers that may be crucial for the early diagnosis of refractory epilepsy or may be connected to the control of epileptic seizures. Their value will be better defined by future studies.

Comparing RNA extraction methods to face the variations in RNA quality using two human biological matrices.

BACKGROUND: Nucleic acids, RNA among them, are widely used in biomedicine and Biotechnology. Because of their susceptibility to degradation by RNases, the handling and extraction process of RNA from cells and tissues require specialized personnel and standardized methods to guarantee high purity and integrity. Due to the diversity of techniques found in the market, a comparative study between different RNA extraction methods is useful to facilitate the best choice for the researcher or in research service platforms such as biobanks to see the traceability of the samples. METHODS AND RESULTS: In this study, we have compared seven different RNA extraction methods: manual (TRIzol™), semiautomated (QIAGEN™, Bio-Rad, Monarch®, and Canvax™), and fully automated (QIAcube™ and Maxwell®) processes, from two biological matrices: human Jurkat T cells and peripheral blood mononuclear cells (PBMC). Results showed marked differences in the RNA quality and functionality according to the method employed for RNA extraction and the matrix used. DISCUSSION: QIAcube™ and semi-automated extraction methods were perceived as the best options because of their lower variability, good functionality, and lower cost (P < 0.001). These data contribute to facilitating researchers or research service platforms (Biobanks) in decision-making practices and emphasize the relevance of the selection of the RNA extraction method in each experimental procedure or traceability study to guarantee both quality standards and its reproducibility.

Response to immunotherapy in anti-IgLON5 disease: A systematic review.

The aim of this study was to evaluate the frequency of response to immunotherapy in patients with anti-IgLON5 disease through a systematic review of the literature. MEDLINE and Embase databases were searched for studies that included patients with anti-IgLON5 disease who received immunotherapy (IT). Review inclusion criteria were met by 18 studies. The main study variable was response to IT, defined as the frequency of patients with an improvement greater than mild in at least one of the main symptoms defined by the clinical phenotype. Data were also gathered on the rate of response to last follow-up, the line(s) of IT received, the administration of monotherapy or combination therapy, and clinical and analytical characteristics. Selected studies included a total of 46 patients. A response to IT was observed in 20 (43.4%) and the presence of response to last follow-up in 15 (32.6%). Response was achieved more frequently with combination therapy vs monotherapy (14/21 [66.6%] vs 7/22 [31.8%]) and second-line therapy vs first-line therapy (7/13 [53.8%] vs 15/46 [32.6%]). The response rate by drug was 34.2% (12/35) for steroids, 42.8% (9/21) for IVIg, 46% (7/15) for PLEX, 100% (5/5) for AZA and 75% (3/4) for MMF. Factors associated with a response to IT included the cognitive impairment and non-classical phenotypes, presence of HLA-DQB1*05:01 without HLA-DRB1*10:01 and cerebral spinal fluid inflammation. Patients with anti-IgLON5 disease respond to IT, and this response is associated with certain clinical and analytical characteristics of the patients. Also rate of response seems higher with second-line and combination treatment. However, the quality of available studies is inadequate to allow definitive conclusions to be drawn.

Lysophosphatidic acid-induced increase in adult hippocampal neurogenesis facilitates the forgetting of cocaine-contextual memory.

Erasing memories of cocaine-stimuli associations might have important clinical implications for addiction therapy. Stimulating hippocampal plasticity by enhancing adult hippocampal neurogenesis (AHN) is a promising strategy because the addition of new neurons may not only facilitate new learning but also modify previous connections and weaken retrograde memories. To investigate whether increasing AHN prompted the forgetting of previous contextual cocaine associations, mice trained in a cocaine-induced conditioned place preference (CPP) paradigm were administered chronic intracerebroventricular infusions of lysophosphatidic acid (LPA, an endogenous lysophospholipid with pro-neurogenic actions), ki16425 (an LPA1/3 receptor antagonist) or a vehicle solution, and they were tested 23 days later for CPP retention and extinction. The results of immunohistochemical experiments showed that the LPA-treated mice exhibited reduced long-term CPP retention and an approximately twofold increase in the number of adult-born hippocampal cells that differentiated into mature neurons. Importantly, mediation analyses confirmed a causal role of AHN in reducing CPP maintenance. In contrast, the ki16425-treated mice displayed aberrant responses, with initially decreased CPP retention that progressively increased across the extinction sessions, leading to no effect on AHN. The pharmacological treatments did not affect locomotion or general exploratory or anxiety-like responses. In a second experiment, normal and LPA1 -receptor-deficient mice were acutely infused with LPA, which revealed that LPA1 -mediated signaling was required for LPA-induced proliferative actions. These results suggest that the LPA/LPA1 pathway acts as a potent in vivo modulator of AHN and highlight the potential usefulness of pro-AHN strategies to treat aberrant cognition in those addicted to cocaine.

Activation of Lysophosphatidic Acid Receptor Type 1 Contributes to Pathophysiology of Spinal Cord Injury.

Lysophosphatidic acid (LPA) is an extracellular lipid mediator involved in many physiological functions that signals through six known G-protein-coupled receptors (LPA1-LPA6). A wide range of LPA effects have been identified in the CNS, including neural progenitor cell physiology, astrocyte and microglia activation, neuronal cell death, axonal retraction, and development of neuropathic pain. However, little is known about the involvement of LPA in CNS pathologies. Herein, we demonstrate for the first time that LPA signaling via LPA1 contributes to secondary damage after spinal cord injury. LPA levels increase in the contused spinal cord parenchyma during the first 14 d. To model this potential contribution of LPA in the spinal cord, we injected LPA into the normal spinal cord, revealing that LPA induces microglia/macrophage activation and demyelination. Use of a selective LPA1 antagonist or mice lacking LPA1 linked receptor-mediated signaling to demyelination, which was in part mediated by microglia. Finally, we demonstrate that selective blockade of LPA1 after spinal cord injury results in reduced demyelination and improvement in locomotor recovery. Overall, these results support LPA-LPA1 signaling as a novel pathway that contributes to secondary damage after spinal cord contusion in mice and suggest that LPA1 antagonism might be useful for the treatment of acute spinal cord injury. SIGNIFICANCE STATEMENT: This study reveals that LPA signaling via LPA receptor type 1 activation causes demyelination and functional deficits after spinal cord injury.

Pharmacological reduction of adult hippocampal neurogenesis modifies functional brain circuits in mice exposed to a cocaine conditioned place preference paradigm.

We investigated the role of adult hippocampal neurogenesis in cocaine-induced conditioned place preference (CPP) behaviour and the functional brain circuitry involved. Adult hippocampal neurogenesis was pharmacologically reduced with temozolomide (TMZ), and mice were tested for cocaine-induced CPP to study c-Fos expression in the hippocampus and in extrahippocampal addiction-related areas. Correlational and multivariate analysis revealed that, under normal conditions, the hippocampus showed widespread functional connectivity with other brain areas and strongly contributed to the functional brain module associated with CPP expression. However, the neurogenesis-reduced mice showed normal CPP acquisition but engaged an alternate brain circuit where the functional connectivity of the dentate gyrus was notably reduced and other areas (the medial prefrontal cortex, accumbens and paraventricular hypothalamic nucleus) were recruited instead of the hippocampus. A second experiment unveiled that mice acquiring the cocaine-induced CPP under neurogenesis-reduced conditions were delayed in extinguishing their drug-seeking behaviour. But if the inhibited neurons were generated after CPP acquisition, extinction was not affected but an enhanced long-term CPP retention was found, suggesting that some roles of the adult-born neurons may differ depending on whether they are generated before or after drug-contextual associations are established. Importantly, cocaine-induced reinstatement of CPP behaviour was increased in the TMZ mice, regardless of the time of neurogenesis inhibition. The results show that adult hippocampal neurogenesis sculpts the addiction-related functional brain circuits, and reduction of the adult-born hippocampal neurons increases cocaine seeking in the CPP model.

Involvement of IGF-II receptors in the antioxidant and neuroprotective effects of IGF-II on adult cortical neuronal cultures.

Insulin-like growth factor-II (IGF-II) is a naturally occurring peptide that exerts known pleiotropic effects ranging from metabolic modulation to cellular development, growth and survival. IGF-II triggers its actions by binding to and activating IGF (IGF-I and IGF-II) receptors. In this study, we assessed the neuroprotective effect of IGF-II on corticosterone-induced oxidative damage in adult cortical neuronal cultures and the role of IGF-II receptors in this effect. We provide evidence that treatment with IGF-II alleviates the glucocorticoid-induced toxicity to neuronal cultures, and this neuroprotective effect occurred due to a decrease in reactive oxygen species (ROS) production and a return of the antioxidant status to normal levels. IGF-II acts via not only the regulation of synthesis and/or activity of antioxidant enzymes, especially manganese superoxide dismutase, but also the restoration of mitochondrial cytochrome c oxidase activity and mitochondrial membrane potential. Although the antioxidant effect of IGF-I receptor activation has been widely reported, the involvement of the IGF-II receptor in these processes has not been clearly defined. The present report is the first evidence describing the involvement of IGF-II receptors in redox homeostasis. IGF-II may therefore contribute to the mechanisms of neuroprotection by acting as an antioxidant, reducing the neurodegeneration induced by oxidative insults. These results open the field to new pharmacological approaches to the treatment of diseases involving imbalanced redox homeostasis. In this study, we demonstrated that the antioxidant effect of IGF-II is at least partially mediated by IGF-II receptors.

Anatomical location of LPA1 activation and LPA phospholipid precursors in rodent and human brain.

Lysophosphatidic acid (LPA) is a signaling molecule that binds to six known G protein-coupled receptors: LPA1 -LPA6 . LPA evokes several responses in the CNS, including cortical development and folding, growth of the axonal cone and its retraction process. Those cell processes involve survival, migration, adhesion proliferation, differentiation, and myelination. The anatomical localization of LPA1 is incompletely understood, particularly with regard to LPA binding. Therefore, we have used functional [(35) S]GTPγS autoradiography to verify the anatomical distribution of LPA1 binding sites in adult rodent and human brain. The greatest activity was observed in myelinated areas of the white matter such as corpus callosum, internal capsule and cerebellum. MaLPA1 -null mice (a variant of LPA1 -null) lack [(35) S]GTPγS basal binding in white matter areas, where the LPA1 receptor is expressed at high levels, suggesting a relevant role of the activity of this receptor in the most myelinated brain areas. In addition, phospholipid precursors of LPA were localized by MALDI-IMS in both rodent and human brain slices identifying numerous species of phosphatides and phosphatidylcholines. Both phosphatides and phosphatidylcholines species represent potential LPA precursors. The anatomical distribution of these precursors in rodent and human brain may indicate a metabolic relationship between LPA and LPA1 receptors. Lysophosphatidic acid (LPA) is a signaling molecule that binds to six known G protein-coupled receptors (GPCR), LPA1 to LPA6 . LPA evokes several responses in the central nervous system (CNS), including cortical development and folding, growth of the axonal cone and its retraction process. We used functional [(35) S]GTPγS autoradiography to verify the anatomical distribution of LPA1 -binding sites in adult rodent and human brain. The distribution of LPA1 receptors in rat, mouse and human brains show the highest activity in white matter myelinated areas. The basal and LPA-evoked activities are abolished in MaLPA1 -null mice. The phospholipid precursors of LPA are localized by MALDI-IMS. The anatomical distribution of LPA precursors in rodent and human brain suggests a relationship with functional LPA1 receptors.

Voluntary exercise followed by chronic stress strikingly increases mature adult-born hippocampal neurons and prevents stress-induced deficits in 'what-when-where' memory.

We investigated whether voluntary exercise prevents the deleterious effects of chronic stress on episodic-like memory and adult hippocampal neurogenesis. After bromodeoxyuridine (BrdU) administration, mice were assigned to receive standard housing, chronic intermittent restraint stress, voluntary exercise or a combination of both (stress starting on the seventh day of exercise). Twenty-four days later, mice were tested in a 'what-when-where' object recognition memory task. Adult hippocampal neurogenesis (proliferation, differentiation, survival and apoptosis) and c-Fos expression in the hippocampus and extra-hippocampal areas (medial prefrontal cortex, amygdala, paraventricular hypothalamic nucleus, accumbens and perirhinal cortex) were assessed after behavior. Chronic intermittent restraint stress impaired neurogenesis and the 'when' memory, while exercise promoted neurogenesis and improved the 'where' memory. The 'when' and 'where' memories correlated with c-Fos expression in CA1 and the dentate gyrus, respectively. Furthermore, analysis suggested that each treatment induced a distinct pattern of functional connectivity among the areas analyzed for c-Fos. In the animals in which stress and exercise were combined, stress notably reduced the amount of voluntary exercise performed. Nevertheless, exercise still improved memory and counteracted the stress induced-deficits in neurogenesis and behavior. Interestingly, compared with the other three treatments, the stressed exercising animals showed a larger increase in cell survival, the maturation of new neurons and apoptosis in the dentate gyrus, with a considerable increase in the number of 24-day-old BrdU+cells that differentiated into mature neurons. The interaction between exercise and stress in enhancing the number of adult-born hippocampal neurons supports a role of exercise-induced neurogenesis in stressful conditions.

Cenobamate and Clobazam Combination as Personalized Medicine in Autoimmune-Associated Epilepsy With Anti-Gad65 Antibodies.

BACKGROUND AND OBJECTIVES: Autoimmune-associated epilepsy (AAE) with antiglutamic acid decarboxylase 65 (GAD65) antibodies is considered a T-cell-mediated encephalitis that evolves to drug-resistant epilepsy. We do not have an effective therapeutic strategy for these patients. Because the GAD enzyme is primarily responsible for the conversion of glutamate to GABA, the mechanism of epileptogenesis in this condition predicts decreased levels of GABA content in synaptic vesicles. Cenobamate (CNB) acts as a positive allosteric modulator at synaptic and extra synaptic GABAA receptors, producing increased inhibitory neurotransmission in the brain. This mechanism could be especially beneficial in AAE with anti-GAD65 antibodies because it would be able to correct the imbalance due to the GABAergic stimulation deficit in postsynaptic neurons. METHODS: We recruit a retrospective multicentric consecutive case series of AAE with anti-GAD65 antibodies from 5 epilepsy units in Spain who have received treatment with CNB. RESULTS: A total of 8 patients were recruited. This cohort of highly refractory patients have failed a mean of 9.50 (SD = 3.20) ASM without control of seizures for sustained periods of time. The average number of seizures per month during the previous 3 months before CNB treatment was 19.63 (SD = 17.03). After the introduction of CNB improvement was achieved in all our patients, with a median reduction in the number of seizures of 92.22% (interquartile range [IQR]: 57.25-98.75). The mean follow-up was 156.75 days (SD = 68.23). In patients with concomitant treatment with clobazam (CLB), the median percentage of seizure reduction was higher than those not taking CLB: 94.72% (IQR: 87.25-100) vs 41.50% (p = 0.044) and also higher than the control group of patients with refractory epilepsy not related to anti-GAD65 treated with the same combination: 94.72% (IQR: 87.25-100) vs 45.00% (IQR: 25.00-87.00) (p = 0.019). DISCUSSION: Treatment with the combination CNB + CLB could be a type of personalized medicine in patients with AAE with anti-GAD65. Our preliminary data will need to be endorsed with new prospective and controlled studies.

Chronic immobilization in the malpar1 knockout mice increases oxidative stress in the hippocampus.

The lysophosphatidic acid LPA1 receptor has recently been involved in the adaptation of the hippocampus to chronic stress. The absence of LPA1 receptor aggravates the chronic stress-induced impairment of both hippocampal neurogenesis and apoptosis that were accompanied with hippocampus-dependent memory deficits. Apoptotic death and neurogenesis in the hippocampus are regulated by oxidative stress. In the present work, we studied the involvement of LPA1 receptor signaling pathway in the regulation of the hippocampal redox after chronic stress. To this end, we used malpar1 knockout (KO) and wild-type mice assigned to either chronic stress (21 days of restraint, 3 h/day) or control conditions. Lipid peroxidation, the activity of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX), as well as mitochondrial function stimulation, monitored through the activity of cytochrome c oxidase (COX), were studied in the hippocampus. Our results showed that chronic immobilization stress enhanced lipid peroxidation as well as the activity of the antioxidant enzymes studied (CAT, SOD, and GPX). This effect was only observed in absence of LPA1 receptor. Furthermore, only malpar1 KO mice submitted to chronic stress exhibited a severe downregulation of the COX activity, suggesting the presence of mitochondrial damage. Altogether, these results suggest that malpar1 KO mice display enhanced oxidative stress in the hippocampus after chronic stress. This may be involved in the hippocampal abnormalities observed in this genotype after chronic immobilization, including memory, neurogenesis, and apoptosis.

Immune Mechanism of Epileptogenesis and Related Therapeutic Strategies.

Immunologic and neuroinflammatory pathways have been found to play a major role in the pathogenesis of many neurological disorders such as epilepsy, proposing the use of novel therapeutic strategies. In the era of personalized medicine and in the face of the exhaustion of anti-seizure therapeutic resources, it is worth looking at the current or future possibilities that neuroimmunomodulator or anti-inflammatory therapy can offer us in the management of patients with epilepsy. For this reason, we performed a narrative review on the recent advances on the basic epileptogenic mechanisms related to the activation of immunity or neuroinflammation with special attention to current and future opportunities for novel treatments in epilepsy. Neuroinflammation can be considered a universal phenomenon and occurs in structural, infectious, post-traumatic, autoimmune, or even genetically based epilepsies. The emerging research developed in recent years has allowed us to identify the main molecular pathways involved in these processes. These molecular pathways could constitute future therapeutic targets for epilepsy. Different drugs current or in development have demonstrated their capacity to inhibit or modulate molecular pathways involved in the immunologic or neuroinflammatory mechanisms described in epilepsy. Some of them should be tested in the future as possible antiepileptic drugs.

The cognitive and psychiatric subacute impairment in severe Covid-19.

Neurologic impairment persisting months after acute severe SARS-CoV-2 infection has been described because of several pathogenic mechanisms, including persistent systemic inflammation. The objective of this study is to analyze the selective involvement of the different cognitive domains and the existence of related biomarkers. Cross-sectional multicentric study of patients who survived severe infection with SARS-CoV-2 consecutively recruited between 90 and 120 days after hospital discharge. All patients underwent an exhaustive study of cognitive functions as well as plasma determination of pro-inflammatory, neurotrophic factors and light-chain neurofilaments. A principal component analysis extracted the main independent characteristics of the syndrome. 152 patients were recruited. The results of our study preferential involvement of episodic and working memory, executive functions, and attention and relatively less affectation of other cortical functions. In addition, anxiety and depression pictures are constant in our cohort. Several plasma chemokines concentrations were elevated compared with both, a non-SARS-Cov2 infected cohort of neurological outpatients or a control healthy general population. Severe Covid-19 patients can develop an amnesic and dysexecutive syndrome with neuropsychiatric manifestations. We do not know if the deficits detected can persist in the long term and if this can trigger or accelerate the onset of neurodegenerative diseases.

When is adult hippocampal neurogenesis necessary for learning? evidence from animal research.

The hippocampus is a key brain structure involved in the short- and long-term processing of declarative memory. Since adult hippocampal neurogenesis was first found, numerous studies have tried to establish the contribution of newborn neurons to hippocampus-dependent cognitive functions. However, this large amount of research has generated contradictory results. In this paper, we review the body of evidence investigating the relationship between hippocampal neurogenesis and learning to conclude the functional role of adult-born hippocampal neurons. First, factors that could explain discrepancies among experiments are taken into account. Then, in addition to methodological differences, we emphasize the importance of the age of the newborn neurons studied, as to how their maturation influences both their properties and potential functionality. Next, we discuss which declarative memory components could require involvement of adult hippocampal neurogenesis, taking into consideration the representational demands of the task, its difficulty and the level of performance reached by the subject. Finally, other factors that could modulate neurogenesis and memory, such as stress levels or previous experience of the animal, should also be taken into consideration in interpreting experiments focused on neurogenesis. In conclusion, our analysis of published studies suggests that new adult-born neurons, under certain circumstances, have a crucial and irreplaceable role in hippocampal learning.

Prevalence of Neural Autoantibodies in Epilepsy of Unknown Etiology: Systematic Review and Meta-Analysis.

BACKGROUND: The prevalence of neural autoantibodies in epilepsy of unknown etiology varies among studies. We aimed to conduct a systematic review and meta-analysis to determine the pooled global prevalence and the prevalence for each antibody. METHODS: A systematic search was conducted for studies that included prospectively patients ≥16 years old with epilepsy of unknown etiology and systematically determined neural autoantibodies. A meta-analysis was undertaken to estimate pooled prevalence in total patients with a positive result for at least one neural autoantibody in serum and/or cerebrospinal fluid (CSF) and for each autoantibody. RESULTS: Ten of the eleven studies that met the inclusion criteria and a total of 1302 patients with epilepsy of unknown etiology were included in themeta-analysis. The global pooled prevalence (IC95%) was 7.6% (4.6-11.2) in a total of 82 patients with a positive result for any neural autoantibody. None of the controls available in the studies had a positive result. Individual pooled prevalence for each autoantibody was: glycine receptor (GlyR) (3.2%), glutamic acid decarboxylase (GAD) (1.9%), N-methyl-d-aspartate receptor (NMDAR) (1.8%), leucine-rich glioma inactivated-1 protein (LGI1) (1.1%), contactin-2-associated protein (CASPR2) (0.6%) and onconeuronal (0.2%). CONCLUSIONS: The pooled prevalence of neural autoantibodies in patients with epilepsy of unknown etiology is small but not irrelevant. None of the controls had a positive result. There was high heterogeneity among studies. In the future, a homogeneous protocol for testing neural autoantibodies is recommended.

Activation of Macrophages by Lysophosphatidic Acid through the Lysophosphatidic Acid Receptor 1 as a Novel Mechanism in Multiple Sclerosis Pathogenesis.

Multiple sclerosis (MS) is a neuroinflammatory disease whose pathogenesis remains unclear. Lysophosphatidic acid (LPA) is an endogenous phospholipid involved in multiple immune cell functions and dysregulated in MS. Its receptor LPA1 is expressed in macrophages and regulates their activation, which is of interest due to the role of macrophage activation in MS in both destruction and repair. In this study, we studied the genetic deletion and pharmaceutical inhibition of LPA1 in the mouse MS model, experimental autoimmune encephalomyelitis (EAE). LPA1 expression was analyzed in EAE mice and MS patient immune cells. The effect of LPA and LPA1 on macrophage activation was studied in human monocyte-derived macrophages. We show that lack of LPA1 activity induces milder clinical EAE course and that Lpar1 expression in peripheral blood mononuclear cells (PBMC) correlates with onset of relapses and severity in EAE. We see the same over-expression in PBMC from MS patients during relapse compared with progressive forms of the disease and in stimulated monocyte-derived macrophages. LPA induced a proinflammatory-like response in macrophages through LPA1, providing a plausible way in which LPA and LPA1 dysregulation can lead to the inflammation in MS. These data show a new mechanism of LPA signaling in the MS pathogenesis, prompting further research into its use as a therapeutic target biomarker.

Prevalence of Neural Autoantibodies in Paired Serum and Cerebrospinal Fluid in Adult Patients with Drug-Resistant Temporal Lobe Epilepsy of Unknown Etiology.

In order to determine the prevalence of neural autoantibodies in adult patients with drug-resistant temporal lobe epilepsy (DRTLE) of unknown etiology, we compared the characteristics of patients with and without autoantibodies and applied antibody predictive scores to the patients. Patients aged ≥18 years with DRTLE of unknown etiology and ≥12 months of evolution were prospectively recruited. Neural autoantibodies in serum and CSF were systematically determined in all patients. We created the ARTE (antibody in drug-resistant temporal lobe epilepsy) score based on the variables associated with the presence of neural autoantibodies. Twenty-seven patients were included. The mean (SD) age in years at the index date was 52 (±14.2) and at epilepsy onset was 32 (±17.1). The mean epilepsy duration was 19 (±12.5) years. Neural autoantibodies were detected in 51.85% (14/27) of patients. The presence of bitemporal, independent, interictal epileptiform discharges (BIIED) had a higher frequency in patients with neural autoantibodies (57.1% vs. 15.4%; p = 0.025) as well as those patients with a previous history of status epilepticus (49.2% vs. 0.0%; p = 0.007). The ARTE score showed an area under the curve (AUC) of 0.854. Using a cut-off point of ≥1, the sensitivity was 100% and the specificity was 46.1%, whereas when using a cut-off point of ≥3, the results were 35.7% and 100%, respectively. We found a high prevalence of neural autoantibodies in patients with DRTLE of unknown etiology, indicating an autoimmune mechanism. The presence of BIIED and a history of SE in DRTLE of unknown etiology are possible markers for autoimmune-associated epilepsy. The proposed ARTE score requires future validation in larger independent cohorts.

Chronic central modulation of LPA/LPA receptors-signaling pathway in the mouse brain regulates cognition, emotion, and hippocampal neurogenesis.

Several studies have demonstrated that lysophosphatidic acid (LPA) acts through its LPA receptors in multiple biological and behavioral processes, including adult hippocampal neurogenesis, hippocampal-dependent memory, and emotional regulation. However, analyses of the effects have typically involved acute treatments, and there is no information available regarding the effect of the chronic pharmacological modulation of the LPA/LPA receptors-signaling pathway. Thus, we analyzed the effect of the chronic (21 days) and continuous intracerebroventricular (ICV) infusion of C18:1 LPA and the LPA1-3 receptor antagonist Ki16425 in behavior and adult hippocampal neurogenesis. Twenty-one days after continuous ICV infusions, mouse behaviors in the open field test, Y-maze test and forced swimming test were assessed. In addition, the hippocampus was examined for c-Fos expression and α-CaMKII and phospho-α-CaMKII levels. The current study demonstrates that chronic C18:1 LPA produced antidepressant effects, improved spatial working memory, and enhanced adult hippocampal neurogenesis. In contrast, chronic LPA1-3 receptor antagonism disrupted exploratory activity and spatial working memory, induced anxiety and depression-like behaviors and produced an impairment of hippocampal neurogenesis. While these effects were accompanied by an increase in neuronal activation in the DG of C18:1 LPA-treated mice, Ki16425-treated mice showed reduced neuronal activation in CA3 and CA1 hippocampal subfields. Treatment with the antagonist also induced an imbalance in the expression of basal/activated α-CaMKII protein forms. These outcomes indicate that the chronic central modulation of the LPA receptors-signaling pathway in the brain regulates cognition and emotion, likely comprising hippocampal-dependent mechanisms. The use of pharmacological modulation of this pathway in the brain may potentially be targeted for the treatment of several neuropsychiatric conditions.

GABAergic deficits in absence of LPA1 receptor, associated anxiety-like and coping behaviors, and amelioration by interneuron precursor transplants into the dorsal hippocampus.

Defects in GABAergic function can cause anxiety- and depression-like behaviors among other neuropsychiatric disorders. Therapeutic strategies using the transplantation of GABAergic interneuron progenitors derived from the medial ganglionic eminence (MGE) into the adult hippocampus reversed the symptomatology in multiple rodent models of interneuron-related pathologies. In turn, the lysophosphatidic acid receptor LPA1 has been reported to be essential for hippocampal function. Converging evidence suggests that deficits in LPA1 receptor signaling represent a core feature underlying comparable hippocampal dysfunction and behaviors manifested in common neuropsychiatric conditions. Here, we first analyzed the GABAergic interneurons in the hippocampus of wild-type and maLPA1-null mice, lacking the LPA1 receptor. Our data revealed a reduction in the number of neurons expressing GABA, calcium-binding proteins, and neuropeptides such as somatostatin and neuropeptide Y in the hippocampus of maLPA1-null mice. Then, we used interneuron precursor transplants to test links between hippocampal GABAergic interneuron deficit, cell-based therapy, and LPA1 receptor-dependent psychiatric disease-like phenotypes. For this purpose, we transplanted MGE-derived interneuron precursors into the adult hippocampus of maLPA1-null mice, to test their effects on GABAergic deficit and behavioral symptoms associated with the absence of the LPA1 receptor. Transplant studies in maLPA1-null mice showed that grafted cells were able to restore the hippocampal host environment, decrease the anxiety-like behaviors and neutralize passive coping, with no abnormal effects on motor activity. Furthermore, grafted MGE-derived cells maintained their normal differentiation program. These findings reinforce the use of cell-based strategies for brain disorders and suggest that the LPA1 receptor represents a potential target for interneuron-related neuropsychiatric disorders.

Exploratory, anxiety and spatial memory impairments are dissociated in mice lacking the LPA1 receptor.

Lysophosphatidic acid (LPA) is a new, intercellular signalling molecule in the brain that has an important role in adult hippocampal plasticity. Mice lacking the LPA(1) receptor exhibit motor, emotional and cognitive alterations. However, the potential relationship among these concomitant impairments was unclear. Wild-type and maLPA(1)-null mice were tested on the hole-board for habituation and spatial learning. MaLPA(1)-null mice exhibited reduced exploration in a novel context and a defective intersession habituation that also revealed increased anxiety-like behaviour throughout the hole-board testing. In regard to spatial memory, maLPA(1) nulls failed to reach the controls' performance at the end of the reference memory task. Moreover, their defective working memory on the first training day suggested a delayed acquisition of the task's working memory rule, which is also a long term memory component. The temporal interval between trials and the task's difficulty may explain some of the deficits found in these mice. Principal components analysis revealed that alterations found in each behavioural dimension were independent. Therefore, exploratory and emotional impairments did not account for the cognitive deficits that may be attributed to maLPA(1) nulls' hippocampal malfunction.