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.

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.

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.

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.

EEG abnormalities and clinical phenotypes in pre-school children with autism spectrum disorder.

BACKGROUND: Abnormalities on electroencephalography (EEG) results have been reported in a high percentage of children with Autism Spectrum Disorder (ASD). The purpose of this study was to explore the prevalence of EEG abnormalities in a clinical population of pre-school children with Autism Spectrum Disorder and the differences in terms of the following phenotypic characteristics: adaptive behavior, executive functioning, severity of Autism Spectrum Disorder core symptoms, and comorbidity symptoms. METHODS: A cross-sectional analysis of 69 children who attended the Autism Spectrum Disorder early diagnosis program with electroencephalography and clinical diagnosis was performed. A battery of questionnaires was also made to parents to evaluate emotions, behavior, and functional skills for daily living. RESULTS: Out of 69 pre-school children with Autism Spectrum Disorder, twenty nine (42%) had abnormalities in electroencephalography results. The group with abnormal epileptiform electroencephalography exhibited more impairment in executive functioning and social-relationship coexisting symptoms. CONCLUSIONS: The presence of an abnormal epileptiform electroencephalography in pre-school children with ASD already suggests a worse development in clinical features.

Evaluación de la carga aterosclerótica en hipertensos con prediabetes / Evaluation of the atherosclerotic burden in hypertensive patients with prediabetes

Objetivo: Conocer la carga aterosclerótica (carga ATC) de pacientes hipertensos prediabéticos sin enfermedad cardiovascular. Pacientes y métodos: Seleccionamos pacientes hipertensos en situación de prediabetes (glucemia en ayunas 100-125 mg/dl y/o glicohemoglobina A1c 5,7-6,4%), excluyendo aquellos con enfermedad cardiovascular establecida o de muy alto riesgo. Registramos los principales factores de riesgo vascular. Se calculó el índice tobillo/brazo (ITB) y el grosor íntima-media (GIM) carotídeo. Se consideró enfermedad arteriosclerosa ligera cuando el GIM fue > percentil75 para edad y sexo y/o ITB de 0,70-0,90 y moderada-grave en presencia de placa ateromatosa y/o ITB < 0,7. Resultados: Incluimos 53 pacientes, de 63 ± 7años; mujeres: 50,9% (IC95%: 36,8-64,9). Se detectó carga ATC en el 66,0% (IC95%: 51,7-78,5) de los sujetos. El 24,5% (IC95%: 13,8-38,3) de los pacientes presentaron enfermedad arteriosclerosa ligera y un 41,5% (IC95%: 28,1-55,9) moderada-grave. Esto nos permitió reclasificar como de riesgo vascular muy alto a un 41,5% (IC95%: 28,1-55,9) de los pacientes. Un 45,4% (IC95%: 16-74,8) de los sujetos de riesgo inicial moderado pasaron a considerarse de alto o muy alto riesgo. En el análisis multivariante los fumadores o exfumadores presentaron 2,3 veces más riesgo (odds ratio = 2,3; IC95%: 0,6-7,6) de presentar carga ATC, aunque sin alcanzar significación estadística. Conclusiones: Dos tercios de los pacientes hipertensos con prediabetes tienen enfermedad arteriosclerótica silente cuando se evalúan mediante el ITB y la ecografía carotídea. Aproximadamente un 40% de los sujetos fueron reclasificados como de muy alto riesgo. Cerca de la mitad de los hipertensos prediabéticos clasificados inicialmente como de riesgo moderado pasaron a considerarse de riesgo alto o muy alto. El tabaquismo parece ser el factor de riesgo más relacionado con la presencia de carga ATC

Aim: To assess the atherosclerotic burden in hypertensive patients with prediabetes without cardiovascular disease. Patients and methods: We included patients with hypertension and prediabetes (fasting blood glucose: 100-125 mg/dL and/or glycohemoglobin A1c: 5.7-6.4%), excluding those with established cardiovascular disease or those at very high risk. We recorded major vascular risk factors. Subclinical arteriosclerosis was measured by the ankle/brachial index (ABI) and carotid intima-medial thickness (IMT). Subclinical arteriosclerosis was mild if IMT was > 75p adjusted by age and sex and/or ABI was 0.7-0.9 and was considered moderate-severe when there was plaque and/or ABI < 0.7. Results: We included 53 patients, 63±7 years-old; women: 50,9% (95%CI: 36.8-64.9). Atherosclerotic burden was detected in 66.0% (95%CI: 51.7-78.5) of subjects. 24,5% (95%CI: 13.8-38.3) of patients had mild arteriosclerosis disease and 41.5% (95%CI: 28.1-55.9) had moderate-severe. This allowed us to re-stratified as very high vascular risk the 41.5% (95%CI: 28.1-55.9) of patients. 45.4% (95%CI: 16-74.8) of subjects with moderate initial risk were considered high or very high risk. In multivariate analyses, only smoking was associated with atherosclerotic burden (P = .07). Conclusions: Two thirds of hypertensive patients with prediabetes had subclinical arteriosclerotic disease when they were evaluated by the ankle/brachial index and carotid ultrasonography. Approximately forty percent of patients were re-stratified as very high vascular risk. Nearly half of the prediabetic hypertensive patients initially classified as moderate risk were considered high or very high risk

Evaluation of the atherosclerotic burden in hypertensive patients with prediabetes. / Evaluación de la carga aterosclerótica en hipertensos con prediabetes.

AIM: To assess the atherosclerotic burden in hypertensive patients with prediabetes without cardiovascular disease. PATIENTS AND METHODS: We included patients with hypertension and prediabetes (fasting blood glucose: 100-125mg/dL and/or glycohemoglobin A1c: 5.7-6.4%), excluding those with established cardiovascular disease or those at very high risk. We recorded major vascular risk factors. Subclinical arteriosclerosis was measured by the ankle/brachial index (ABI) and carotid intima-medial thickness (IMT). Subclinical arteriosclerosis was mild if IMT was >75p adjusted by age and sex and/or ABI was 0.7-0.9 and was considered moderate-severe when there was plaque and/or ABI<0.7. RESULTS: We included 53 patients, 63±7 years-old; women: 50,9% (95%CI: 36.8-64.9). Atherosclerotic burden was detected in 66.0% (95%CI: 51.7-78.5) of subjects. 24,5% (95%CI: 13.8-38.3) of patients had mild arteriosclerosis disease and 41.5% (95%CI: 28.1-55.9) had moderate-severe. This allowed us to re-stratified as very high vascular risk the 41.5% (95%CI: 28.1-55.9) of patients. 45.4% (95%CI: 16-74.8) of subjects with moderate initial risk were considered high or very high risk. In multivariate analyses, only smoking was associated with atherosclerotic burden (P=.07). CONCLUSIONS: Two thirds of hypertensive patients with prediabetes had subclinical arteriosclerotic disease when they were evaluated by the ankle/brachial index and carotid ultrasonography. Approximately forty percent of patients were re-stratified as very high vascular risk. Nearly half of the prediabetic hypertensive patients initially classified as moderate risk were considered high or very high risk.