Long-term enhancements in antidepressant efficacy and neurogenesis: Effects of intranasal co-administration of neuropeptide Y 1 receptor (NPY1R) and galanin receptor 2 (GALR2) agonists in the ventral hippocampus.

This study evaluates the sustained antidepressant-like effects and neurogenic potential of a 3-day intranasal co-administration regimen of galanin receptor 2 (GALR2) agonist M1145 and neuropeptide Y Y1 receptor (NPY1R) agonist [Leu31, Pro34]NPY in the ventral hippocampus of adult rats, with outcomes analyzed 3 weeks post-treatment. Utilizing the forced swimming test (FST), we found that this co-administration significantly enhances antidepressant-like behaviors, an effect neutralized by the GALR2 antagonist M871, highlighting the synergistic potential of these neuropeptides in modulating mood-related behaviors. In situ proximity ligation assay (PLA) indicated a significant increase in GALR2/NPYY1R heteroreceptor complexes in the ventral hippocampal dentate gyrus, suggesting a molecular basis for the behavioral outcomes observed. Moreover, proliferating cell nuclear antigen (PCNA) immunolabeling revealed increased cell proliferation in the subgranular zone of the dentate gyrus, specifically in neuroblasts as evidenced by co-labeling with doublecortin (DCX), without affecting quiescent neural progenitors or astrocytes. The study also noted a significant uptick in the number of DCX-positive cells and alterations in dendritic morphology in the ventral hippocampus, indicative of enhanced neuronal differentiation and maturation. These morphological changes highlight the potential of these agonists to facilitate the functional integration of new neurons into existing neural circuits. By demonstrating the long-lasting effects of a brief, 3-day intranasal administration of GALR2 and NPY1R agonists, our findings contribute significantly to the understanding of neuropeptide-mediated neuroplasticity and herald novel therapeutic strategies for the treatment of depression and related mood disorders, emphasizing the therapeutic promise of targeting neurogenesis and neuronal maturation processes.

Enhancement of neurogenesis and cognition through intranasal co-delivery of galanin receptor 2 (GALR2) and neuropeptide Y receptor 1 (NPY1R) agonists: a potential pharmacological strategy for cognitive dysfunctions.

BACKGROUND: Spatial memory deficits and reduced neuronal survival contribute to cognitive decline seen in the aging process. Current treatments are limited, emphasizing the need for innovative therapeutic strategies. This research explored the combined effects of intranasally co-administered galanin receptor 2 (GALR2) and neuropeptide Y1 receptor (NPY1R) agonists, recognized for their neural benefits, on spatial memory, neuronal survival, and differentiation in adult rats. After intranasal co-delivery of the GALR2 agonist M1145 and a NPY1R agonist to adult rats, spatial memory was tested with the object-in-place task 3 weeks later. We examined neuronal survival and differentiation by assessing BrdU-IR profiles and doublecortin (DCX) labeled cells, respectively. We also used the GALR2 antagonist M871 to confirm GALR2's crucial role in promoting cell growth. RESULTS: Co-administration improved spatial memory and increased the survival rate of mature neurons. The positive effect of GALR2 in cell proliferation was confirmed by the nullifying effects of its antagonist. The treatment boosted DCX-labeled newborn neurons and altered dendritic morphology, increasing cells with mature dendrites. CONCLUSIONS: Our results show that intranasal co-delivery of GALR2 and NPY1R agonists improves spatial memory, boosts neuronal survival, and influences neuronal differentiation in adult rats. The significant role of GALR2 is emphasized, suggesting new potential therapeutic strategies for cognitive decline.

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.

Plasma Concentrations of Neurofilament Light Chain Protein and Brain-Derived Neurotrophic Factor as Consistent Biomarkers of Cognitive Impairment in Alcohol Use Disorder.

For a long time, Substance Use Disorders (SUDs) were not considered a component in the etiology of dementia. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders introduced substance-induced neurocognitive disorders, incorporating this notion to clinical practice. However, detection and monitoring of neurodegenerative processes in SUD patients remain a major clinical challenge, especially when early diagnosis is required. In the present study, we aimed to investigate new potential biomarkers of neurodegeneration that could predict cognitive impairment in SUD patients: the circulating concentrations of Neurofilament Light chain protein (NfL) and Brain-Derived Neurotrophic Factor (BDNF). Sixty SUD patients were compared with twenty-seven dementia patients and forty healthy controls. SUD patients were recruited and assessed using the Psychiatric Research Interview for Substance and Mental (PRISM) and a battery of neuropsychological tests, including the Montreal Cognitive Assessment test for evaluation of cognitive impairment. When compared to healthy control subjects, SUD patients showed increases in plasma NfL concentrations and NfL/BDNF ratio, as well as reduced plasma BDNF levels. These changes were remarkable in SUD patients with moderate-severe cognitive impairment, being comparable to those observed in dementia patients. NfL concentrations correlated with executive function and memory cognition in SUD patients. The parameters "age", "NfL/BDNF ratio", "first time alcohol use", "age of onset of alcohol use disorder", and "length of alcohol use disorder diagnosis" were able to stratify our SUD sample into patients with cognitive impairment from those without cognitive dysfunction with great specificity and sensibility. In conclusion, we propose the combined use of NfL and BDNF (NfL/BDNF ratio) to monitor substance-induced neurocognitive disorder.

Outcomes from a Spanish Expanded Access Program on cannabidiol treatment in pediatric and adult patients with epilepsy.

AIM: To evaluate the effectiveness and tolerability of cannabidiol (CBD) in patients with developmental and epileptic encephalopathies, including Dravet syndrome (DS), and Lennox-Gastaut syndrome (LGS), in a Spanish Expanded Access Program (EAP). METHODS: This was a multicenter, retrospective, observational study of patients treated with purified CBD in 14 hospitals across Spain. Patients with (1) written informed consent and (2) at least 6 months follow-up before the closure of the database were included. Primary effectiveness endpoints included reductions (100 %, ≥75 %, ≥50 %, ≥25 %, or 0 %) or worsening in seizure frequency (all seizure types and most disabling seizures) at 1-, 3-, 6-, and 12-month visits and at the last visit, and median relative seizure reduction between baseline and last visit. Secondary effectiveness endpoints included retention rate, reduction in seizure severity, status epilepticus, healthcare utilization, and quality of life. Primary safety endpoints included rates of adverse events (AEs) and AEs leading to discontinuation. RESULTS: One hundred and two patients (DS 12 %; LGS 59 %; other epilepsy syndromes 29 %) with a mean age of 15.9 years were enrolled. Patients were highly refractory to antiseizure medications (ASMs); mean number of prior failed ASMs was 7.5 (SD 3.7). The mean CBD dose was 13.0 mg/kg/day at the last visit. The proportion of patients with ≥50 % reduction in the total number of seizures from baseline was 44.9 % at 6 months and 38.9 % at 12 months. The median number of total seizures per month reduced by 47.6 % from baseline to the last visit. At 12 months, seizure severity was lower in 33/54 patients (61.1 %) and unchanged in 17/54 patients (31.5 %). Quality of life, based on the CAVE scale, increased from a mean score of 17.9 ± 4.7 (n = 54) at baseline to 21.7 ± 5.5 (n = 51) at the last patient visit (21.2 % improvement). The mean treatment retention time was 10.3 months. There were no statistically significant changes in the number of status epilepticus episodes, but lower healthcare utilization was observed. Adverse events occurred in sixty-eight patients (66.7 %), and the most common were somnolence (34.3 %) and diarrhea (12.7 %). Cannabidiol was discontinued exclusively due to AEs in 7.8 % of patients, increasing to 25.5 % when both lack of efficacy and AEs were considered together. CONCLUSIONS: Cannabidiol demonstrated promising effectiveness and tolerability in patients with developmental and epileptic encephalopathies taking part in a Spanish EAP.

Identifying key unmet needs and value drivers in the treatment of focal-onset seizures (FOS) in patients with drug-resistant epilepsy (DRE) in Spain through Multi-Criteria Decision Analysis (MCDA).

INTRODUCTION: Epilepsy is a serious neurological disease, ranking high in the top causes of disability. Approximately 40% of patients with epilepsy are pharmacoresistant after their seizures failed at least two antiseizure medications (ASMs). Adult patients experiencing focal-onset seizures (FOS) account for approximately 60% of all patients with epilepsy and they are more likely to become drug-resistant epilepsy (DRE) than those with generalized onset. Drug-resistant epilepsy is associated with mortality, morbidity, and reduced quality of life. The information available on the clinical management, health outcomes, and unmet needs of the disease within the Spanish healthcare environment is very limited. Multi-Criteria Decision Analysis (MCDA) allows determination of what represents value in a given indication considering all relevant criteria for healthcare decision-making in a transparent and systematic manner and from the perspective of relevant stakeholders. PURPOSE: The aim of this study was to identify the burden of DRE (clinical, quality of life, and economic) and the unmet needs in Spain and to determine what represents value in the treatment of FOS in DRE patients from the perspective of Spanish epileptologists. METHODS: The steps taken to carry out the MCDA were based on previously published good methodological practices. A systematic literature review (combining biomedical databases and gray literature sources) was performed between March and April 2020. Results were reviewed and validated with three epileptologists in June 2020 and used to develop a MCDA value framework, adapted for FOS in DRE, composed of 12 quantitative criteria and 3 contextual criteria. A group of six Spanish epileptologists from four Spanish regions were trained in MCDA methodology before individually validating value criteria (and their definitions based on literature review findings) and assigned relative weights using an ordinal 6-points scale. Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology. RESULTS: Drug-resistant epilepsy is considered a very severe health problem with important unmet needs affecting a considerably sized population. While safety and impact on quality of life of available ASMs are considered adequate, efficacy remains insufficient for patients to achieve seizure freedom and maintain it over time. Hence, the therapeutic benefit of pharmacological treatments currently used is regarded as suboptimal. Drug-resistant epilepsy management is associated with moderate pharmacological, relevant direct medical and high indirect costs. Quality of evidence available for current treatments is moderate. It is considered that DRE does not currently stand as a key priority for the Spanish healthcare system. CONCLUSIONS: Drug-resistant epilepsy is considered a very severe health problem associated with relevant unmet needs. These include the lack of availability of specific treatment protocols, the need to improve early diagnosis by increasing the number of referrals to specialized epilepsy units and the availability of specific ASMs with improved efficacy and safety profiles, allowing to reach treatment objectives. Reflective MCDA provided a standardized, transparent approach to evaluate multiple criteria ascertaining what represents value from a holistic point of view and from the perspective of clinical experts, facilitating decision-making.

Current Status of Biomarkers in Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

The discovery of biomarkers in rare diseases is of paramount importance to allow a better diagnosis, improve predictions of outcomes, and prompt the development of new treatments. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a rare autoimmune disorder associated with the presence of antibodies targeting the GluN1 subunit of the NMDAR. Since it was discovered in 2007, large efforts have been made towards the identification of clinical, paraclinical, and molecular biomarkers to better understand the immune mechanisms that govern the course of the disease as well as to define predictors of treatment response and long-term outcomes. However, most of these biomarkers are still in an exploratory phase, with only a few candidates reaching the final phases of the always-complex process of biomarker development, mainly due to the low incidence of the disease and its recent description. Clinical and paraclinical markers are probably the most widely explored in anti-NMDAR encephalitis, five of them combined in a clinical score to predict 1 year outcome. On the contrary, soluble molecules, such as persistent antibody positivity, antibody titers, cytokines, and other inflammatory mediators, have been proposed as biomarkers of clinical activity, inflammation, prognosis, and treatment response, but further studies are required for their clinical validation including larger and more homogenous cohorts of patients. Similarly, genetic susceptibility biomarkers are still in the exploratory phase and, therefore, weak conclusions can for now only be achieved. Thus, further studies are warranted to define biomarkers and unravel the underlying mechanisms driving rare diseases such as anti-NMDAR encephalitis. Future international collaborative studies with prospective designs that enable the enrollment of large cohorts will allow for the identification and validation of novel biomarkers for clinical decision-making.

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.

Lipid-specific immunoglobulin M bands in cerebrospinal fluid are associated with a reduced risk of developing progressive multifocal leukoencephalopathy during treatment with natalizumab.

OBJECTIVE: Progressive multifocal leukoencephalopathy (PML) is a serious side effect associated with natalizumab treatment in multiple sclerosis (MS). PML risk increases in individuals seropositive for anti-John Cunningham virus (JC) antibodies, with prolonged duration of natalizumab treatment, and with prior exposure to immunosuppressants. We explored whether the presence of lipid-specific immunoglobulin M oligoclonal bands in cerebrospinal fluid (CSF; IgM bands), a recognized marker of highly inflammatory MS, may identify individuals better able to counteract the potential immunosuppressive effect of natalizumab and hence be associated with a reduced risk of developing PML. METHODS: We studied 24 MS patients who developed PML and another 343 who did not suffer this opportunistic infection during natalizumab treatment. Patients were recruited at 25 university hospitals. IgM bands were studied by isoelectric focusing and immunodetection. CSF lymphocyte counts were explored in 151 MS patients recruited at Ramon y Cajal Hospital in Madrid, Spain. RESULTS: IgM bands were independently associated with decreased PML risk (odds ratio [OR] = 45.9, 95% confidence interval [CI] = 5.9-339.3, p < 0.0001) in patients treated with natalizumab. They were also associated with significantly higher CSF CD4, CD8, and B-cell numbers. Patients positive for IgM bands and anti-JC antibodies had similar levels of reduced PML risk to those who were anti-JC negative (OR = 1.55, 95% CI = 0.09-25.2, p = 1.0). Higher risk was observed in patients positive for anti-JC antibodies and negative for IgM bands (19% of the total cohort, OR = 59.71, 95% CI = 13.6-262.2). INTERPRETATION: The presence of IgM bands reflects a process that may diminish the risk of PML by counteracting the excess of immunosuppression that may occur during natalizumab therapy.

Adult Prevalence of Epilepsy in Spain: EPIBERIA, a Population-Based Study.

BACKGROUND: This study assesses the lifetime and active prevalence of epilepsy in Spain in people older than 18 years. METHODS: EPIBERIA is a population-based epidemiological study of epilepsy prevalence using data from three representative Spanish regions (health districts in Zaragoza, Almería, and Seville) between 2012 and 2013. The study consisted of two phases: screening and confirmation. Participants completed a previously validated questionnaire (EPIBERIA questionnaire) over the telephone. RESULTS: A total of 1741 valid questionnaires were obtained, including 261 (14.99%) raising a suspicion of epilepsy. Of these suspected cases, 216 (82.75%) agreed to participate in phase 2. Of the phase 2 participants, 22 met the International League Against Epilepsy's diagnostic criteria for epilepsy. The estimated lifetime prevalence, adjusted by age and sex per 1,000 people, was 14.87 (95% CI: 9.8-21.9). Active prevalence was 5.79 (95% CI: 2.8-10.6). No significant age, sex, or regional differences in prevalence were detected. CONCLUSIONS: EPIBERIA provides the most accurate estimate of epilepsy prevalence in the Mediterranean region based on its original methodology and its adherence to ILAE recommendations. We highlight that the lifetime prevalence and inactive epilepsy prevalence figures observed here were compared to other epidemiological studies.

Analysis of factors influencing telephone call response rate in an epidemiological study.

Descriptive epidemiology research involves collecting data from large numbers of subjects. Obtaining these data requires approaches designed to achieve maximum participation or response rates among respondents possessing the desired information. We analyze participation and response rates in a population-based epidemiological study though a telephone survey and identify factors implicated in consenting to participate. Rates found exceeded those reported in the literature and they were higher for afternoon calls than for morning calls. Women and subjects older than 40 years were the most likely to answer the telephone. The study identified geographical differences, with higher RRs in districts in southern Spain that are not considered urbanized. This information may be helpful for designing more efficient community epidemiology projects.

Effect of Cenobamate on Cognition in Patients with Drug-Resistant Epilepsy with Focal Onset Seizures: An Exploratory Study.

BACKGROUND AND OBJECTIVE: Most second and third generation antiseizure medications (ASMs) are associated with cognitive adverse events, which are a major concern for patients. However, the profile of cognitive adverse events differs between ASMs. This study investigated the effects of cenobamate on cognition in patients with drug-resistant epilepsy (DRE) within the Spanish Expanded Access Program (EAP). METHODS: This was a retrospective, observational study. Inclusion criteria were age ≥ 18 years, DRE with focal seizures, and availability of cognition assessments and EAP authorization. Data were sourced from the clinical records of patients who took part in the Spanish cenobamate EAP. Primary endpoints included cognition (based on 20 neuropsychological outcomes, including verbal and visuospatial episodic memory, verbal fluency, executive function, working memory, attention, and speed of processing), seizure frequency, and concomitant antiseizure medication (ASM) usage at 6 months. RESULTS: The study included 20 patients; 10 patients (50%) had daily seizures, 7 (35%) had weekly seizures and 3 (15%) had monthly seizures. The median number of prior antiseizure medications (ASMs) and concomitant ASMs were 10 and 3, respectively. Mean cenobamate doses were 12.5 mg/day at baseline and 191.2 mg/day at 6 months. There was a statistically significant improvement in cognitive scores between baseline and 6 months for two measures of verbal episodic memory (p = 0.0056 and p = 0.0013) and one measure of visuospatial episodic memory (p = 0.011), and a significant worsening in cognitive score for attention (p = 0.030). At 6 months, 14 patients (70%) had a ≥ 50% reduction in seizure frequency, 3 patients (15%) had a ≥ 90% reduction, and 1 patient (5%) was seizure free. There were significant decreases in the mean number of concomitant ASMs (p = 0.0009), the sum of the ratios of prescribing daily dose/daily defined dose (total ratio of DDD) for concomitant ASMs (p < 0.0001), and concomitant ASM drug load (p = 0.038) between baseline and 6 months. Total ratio of DDD was significantly lower at 6 months for perampanel (p = 0.0016), benzodiazepines (p = 0.035), and sodium channel blockers (p = 0.0005) compared with baseline. Based on analysis of covariance, cognitive tests related to verbal or visuospatial episodic memory (e.g., RT of FCSRT, or ROCFT), executive functions (e.g., TMT-B), and processing speed (some 5-Digit Test subtests) appeared to be closely related to the reduction in pharmacological burden rather than the improvement in seizure control. CONCLUSIONS: Significant improvements in cognition, seizure frequency, and concomitant ASM usage were observed after the introduction of cenobamate in patients with DRE in a real-world setting. Covariance analysis supports the reduction in concomitant ASMs as the most important factor driving cognitive improvements with cenobamate. As this was an exploratory study with an uncontrolled, retrospective design and a low number of patients, further studies are required to confirm the findings.

Enhanced neuronal survival and BDNF elevation via long-term co-activation of galanin 2 (GALR2) and neuropeptide Y1 receptors (NPY1R): potential therapeutic targets for major depressive disorder.

BACKGROUND: Major Depressive Disorder (MDD) is a prevalent and debilitating condition, necessitating novel therapeutic strategies due to the limited efficacy and adverse effects of current treatments. We explored how galanin receptor 2 (GALR2) and Neuropeptide Y1 Receptor (NPYY1R) agonists, working together, can boost brain cell growth and increase antidepressant-like effects in rats. This suggests new ways to treat Major Depressive Disorder (MDD). RESEARCH DESIGN AND METHODS: In a controlled laboratory setting, adult naive Sprague-Dawley rats were administered directly into the brain's ventricles, a method known as intracerebroventricular (ICV) administration, with GALR2 agonist (M1145), NPYY1R agonist, both, or in combination with a GALR2 antagonist (M871). Main outcome measures included long-term neuronal survival, differentiation, and behavioral. RESULTS: Co-administration of M1145 and NPYY1R agonist significantly enhanced neuronal survival and maturation in the ventral dentate gyrus, with a notable increase in Brain-Derived Neurotrophic Factor (BDNF) expression. This neurogenic effect was associated with an antidepressant-like effect, an outcome partially reversed by M871. CONCLUSIONS: GALR2 and NPYY1R agonists jointly promote hippocampal neurogenesis and exert antidepressant-like effects in rats without adverse outcomes, highlighting their therapeutic potential for MDD. The study's reliance on an animal model and intracerebroventricular delivery warrants further clinical exploration to confirm these promising results.

Potentiation of antidepressant effects: NPY1R agonist and ketamine synergy enhances TrkB signaling and neurogenesis in the ventral hippocampus.

BACKGROUND: Major Depressive Disorder (MDD) poses a significant challenge to global health, with current treatments often limited by efficacy and onset delays. This study explores the synergistic antidepressant-like effects of an NPY1R agonist and Ketamine, targeting their neurobiological interactions within the ventral hippocampus. RESEARCH DESIGN AND METHODS: Utilizing a preclinical model, this study administered Neuropeptide Y receptor 1 (NPY1R) agonist and Ketamine, both separately and in combination, through intracerebroventricular (icv) and intranasal (i.n.) routes. The Forced Swimming Test (FST) was employed to assess antidepressant-like activity, while in situ Proximity Ligation Assay and immunohistochemistry were used to examine NPY1R/TrkB heteroreceptor complexes and BDNF expression in the ventral dentate gyrus (DG), along with neurogenesis markers. RESULTS: The combined treatment significantly reduced immobility in the FST, indicative of enhanced antidepressant-like effects, correlated with increased formation of NPY1R/TrkB complex and brain-derived neurotrophic factor (BDNF) expression in the ventral DG. These molecular alterations were associated with increased neurogenesis. CONCLUSIONS: The coadministration of an NPY1R agonist and Ketamine in a rodent model demonstrated potentiated antidepressant responses through synergistic neurobiological pathways, including TrkB signaling and hippocampal neurogenesis. This indicates a novel therapeutic strategy for MDD, warranting further clinical investigation to fully understand its implications.

Enhancing Cognitive Functions and Neuronal Growth through NPY1R Agonist and Ketamine Co-Administration: Evidence for NPY1R-TrkB Heteroreceptor Complexes in Rats.

This study investigates the combined effects of the neuropeptide Y Y1 receptor (NPY1R) agonist [Leu31-Pro34]NPY at a dose of 132 µg and Ketamine at 10 mg/Kg on cognitive functions and neuronal proliferation, against a backdrop where neurodegenerative diseases present an escalating challenge to global health systems. Utilizing male Sprague-Dawley rats in a physiological model, this research employed a single-dose administration of these compounds and assessed their impact 24 h after treatment on object-in-place memory tasks, alongside cellular proliferation within the dorsal hippocampus dentate gyrus. Methods such as the in situ proximity ligation assay and immunohistochemistry for proliferating a cell nuclear antigen (PCNA) and doublecortin (DCX) were utilized. The results demonstrated that co-administration significantly enhanced memory consolidation and increased neuronal proliferation, specifically neuroblasts, without affecting quiescent neural progenitors and astrocytes. These effects were mediated by the potential formation of NPY1R-TrkB heteroreceptor complexes, as suggested by receptor co-localization studies, although further investigation is required to conclusively prove this interaction. The findings also highlighted the pivotal role of brain-derived neurotrophic factor (BDNF) in mediating these effects. In conclusion, this study presents a promising avenue for enhancing cognitive functions and neuronal proliferation through the synergistic action of the NPY1R agonist and Ketamine, potentially via NPY1R-TrkB heteroreceptor complex formation, offering new insights into therapeutic strategies for neurodegenerative diseases.

Neuropeptide Y receptor 1 and galanin receptor 2 (NPY1R-GALR2) interactions in the dentate gyrus and their relevance for neurogenesis and cognition.

Introduction: This study may unveil novel insights into the interactions between neuropeptide Y receptor 1 (NPY1R) and galanin receptor 2 (GALR2), in the dentate gyrus of the dorsal hippocampus, shedding light on their role in neurogenesis and cognitive functions. Existing literature highlights the potential of these interactions in enhancing learning and memory, yet detailed mechanisms remain underexplored. Methods: Utilizing intracerebroventricular injections of GALR2 and NPY1R agonists in Sprague-Dawley male rats, we examined neurogenesis via markers PCNA and DCX, and memory consolidation through the object-in-place task over a three-week period. Results: Significant increases in NPY1R-GALR2 co-localization and neuroblast proliferation were observed, alongside enhanced memory consolidation. These findings suggest a synergistic effect of NPY1R and GALR2 activation on cognitive functions. Discussion: Our findings may foster the development of novel heterobivalent or multitargeting drugs, affecting NPY1R-GALR2 interaction, and suggest a future pharmacogical strategy for improving learning and memory found in many brain diseases. Further research is encouraged to explore these mechanisms in pathological models.

Control of seizures in different stages of partial epilepsy: LACO-EXP, a Spanish retrospective study of lacosamide.

Lacosamide is approved as adjunctive therapy for focal epilepsies. The number of antiepileptic drugs (AEDs) tried is associated with prognosis. This multicenter, retrospective, observational study (LACO-EXP) in Spain in 500 adult patients with focal epilepsies examined the efficacy and tolerability of add-on lacosamide. Factors associated with better efficacy/tolerability were analyzed. After 12months, the responder rate (≥50% reduction in seizure frequency) was 57.1%, and the seizure-free rate was 14.9%. Efficacy was better when lacosamide was the first or second add-on AED, although there was a small chance to be seizure-free even for patients who had received ≤10 prior AEDs. The mechanism of action of concomitant AEDs is important in all the stages, but differences are smaller in the early stages. Lacosamide was generally well tolerated. A slower dosage-titration schedule was associated with a lower adverse event rate. Further investigation of the timing of initiation of lacosamide add-on therapy and ideal combinations of AEDs is required.

Natalizumab-immunogenicity evaluation in patients with infusion related events or disease exacerbations.

Introduction: Natalizumab is a biologic drug for relapsing-remitting multiple sclerosis that may induce the generation of anti-drug antibodies in some patients. Anti-natalizumab antibodies (ANA) increase the risk of adverse events and reduce efficacy, being useful biomarkers for monitoring treatment response. Methods: Retrospective observational study including MS patients treated with natalizumab that experienced infusion-related events (IRE) or disease exacerbations (DE). ANA were tested by Elisa including a screening and a confirmation assay. Patients were further classified as transient (one positive result) or persistent (two or more positive results) ANA. Results: A total of 1251 MS patients were included and 153 (12.3%) had ANA with at least one single point determination, which were more frequent among patients with IRE compared to those with DE (21,6% vs.10.8%) during the first six infusions. Two or more determinations ANA were performed in 184 patients, being 31.5% permanently positive and 7.1% transiently positive. Interestingly, 26.1% of patients that experienced DE had persistent ANA, while 2.6% were transient. In contrast, 43% of patients with IRE had persistent ANA, and 9.3% had transient antibodies. Patients with persistent antibodies had more frequently high levels at the first sampling compared to patients with transient ANA. Conclusion: Real-world evidence shows that the presence of ANA is behind an important percentage of patients treated with natalizumab that experience IRE, as well as DE but in a lower degree. These findings support the need to systematically evaluate ANA towards a personalized management of these patients to avoid undesired complications.

Prognostic Value of Persistent CSF Antibodies at 12 Months in Anti-NMDAR Encephalitis.

BACKGROUND AND OBJECTIVES: Anti-NMDA receptor (NMDAR) encephalitis is defined by the presence of antibodies (Abs) targeting the NMDAR in the CSF. This study aimed to determine the prognostic value of persistent CSF NMDAR-Abs during follow-up. METHODS: This retrospective observational study included patients diagnosed with anti-NMDAR encephalitis in the French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis and for whom CSF samples were obtained at diagnosis and >4 months of follow-up to evaluate CSF NMDAR-Ab persistence. Because patients were tested for CSF NMDAR-Abs at different time points, samples were stratified into different periods of follow-up (i.e., 12 months was considered for the 9- to 16-month follow-up period). RESULTS: Among the 501 patients diagnosed with anti-NMDAR encephalitis between January 2007 and June 2020, 89 (17%) were tested between 4 and 120 months for CSF NMDAR-Abs after clinical improvement and included in the study (75/89 women, 84%; median age 20 years, interquartile range [IQR] 16-26). During follow-up, 21 of 89 (23%) patients had a relapse after a median time of 29 months (IQR 18-47), and 20 of 89 (22%) had a poor outcome (mRS ≥3) after a median last follow-up of 36 months (IQR 19-64). Most patients (69/89, 77%) were tested at the 12-month follow-up period, and 42 of 69 (60%) of them had persistent CSF NMDAR-Abs. When comparing patients with persistent or absent CSF NMDAR-Abs at 12 months, poor outcome at the last follow-up was more frequent in the former (38% vs 8%, p = 0.01), who had relapses more often (23% vs 7%), which also appeared earlier in the course of the disease (90% during the following 4 years of follow-up vs 20%), although no significant difference was observed at long-term follow-up (p = 0.15). In addition, patients with persistent CSF NMDAR-Abs at 12 months had higher titers of CSF NMDAR-Abs at diagnosis. DISCUSSION: In this study, patients with persistent CSF NMDAR-Abs at 12 months were more likely to have subsequent relapses and a poor long-term outcome. However, these findings should be interpreted with caution because of the variability in the time of sampling of this study. Future prospective studies are required to validate these results in larger cohorts.

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.