RESUMEN
Significant efforts are increasingly directed towards identifying novel therapeutic targets for autism spectrum disorder (ASD) with a rising role of aberrant glutamatergic transmission in the pathogenesis of ASD-associated cellular and behavioral deficits. This study aimed at investigating the role of chronic memantine (20 mg/kg/day) and aripiprazole (3 mg/kg/day) combination therapy in the management of prenatal sodium valproate (VPA)-induced autistic-like/cognitive deficits in male Wistar rats. Pregnant female rats received a single intraperitoneal injection of VPA (600 mg/kg) to induce autistic-like behaviors in their offspring. Prenatal VPA induced autistic-like symptoms (decreased social interaction and the appearance of stereotyped behavior) with deficits in spatial learning (in Morris water maze) and cognitive flexibility (in the attentional set-shifting task) in addition to decreased hippocampal protein levels of phosphorylated cAMP response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and gene expression of glutamate transporter-1 (Glt-1) with a decline in GABA/glutamate ratio (both measured by HPLC). These were accompanied by the appearance of numerous neurofibrillary tangles (NFTs) with enhanced apoptosis in hippocampal sections. Memantine/aripiprazole combination increased the protein levels of p-CREB, BDNF, and Glt-1 gene expression with restoration of GABA/glutamate balance, attenuation of VPA-induced neurodegenerative changes and autistic-like symptoms, and improvement of cognitive performance. This study draws attention to the favorable cognitive effects of memantine/aripiprazole combination in autistic subjects which could be mediated via enhancing CREB/BDNF signaling with increased expression of astrocytic Glt-1 and restoration of GABA/glutamate balance, leading to inhibition of hippocampal NFTs formation and neuronal apoptosis.
Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Disfunción Cognitiva , Animales , Femenino , Masculino , Embarazo , Ratas , Aripiprazol/efectos adversos , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno Autístico/inducido químicamente , Trastorno Autístico/tratamiento farmacológico , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/complicaciones , Modelos Animales de Enfermedad , Ácido gamma-Aminobutírico/farmacología , Glutamatos/efectos adversos , Hipocampo , Homeostasis , Memantina/efectos adversos , Ratas Wistar , Ácido ValproicoRESUMEN
Autism spectrum disorder (ASD) is a neurodevelopmental disorder of heterogenous etiology exhibiting a challenge in understanding its exact neuro-pathophysiology. Recently, peroxisome proliferator activated receptor (PPAR)-α activation was found to play a fundamental role in neuroprotection and improving autistic-like-behaviors in experimental animal models of ASD through alleviating neuroinflammation, oxidative-stress, astrocyte reactivity, tauopathy in addition to its favorable role in metabolic regulation, thus attracting attention as a possible target in treatment of ASD. This study aimed to investigate the role of PPAR-α, astrocytic dysfunction and tauopathy in ASD and detect the possible neuroprotective effects of metformin (MET), through PPAR-α activation, and risperidone (RIS) either monotherapy or in combination in alleviating autistic-like-changes at behavioral and neurobiological levels in male Wistar rats. Pregnant female Wistar rats received valproic-acid (VPA) to induce autistic-like-behavioral and neurobiological alterations in their offspring. Chronic intra-peritoneal MET (100 mg/kg/day) and RIS (1 mg/kg/day) either monotherapy or in combination started from postnatal day (PND) 24 till PND61 (38 days). Prenatal VPA exposure simulated the autistic core behaviors associated with neurochemical and histopathological neurodevelopmental degenerative changes. Both MET and RIS either monotherapy or in combination were able to reverse these changes. The effect of MET was comparable to RIS. Moreover, MET was able to alleviate the RIS induced weight gain and improve cognitive functions highlighting its promising adjunctive role in alleviating ASD pathophysiology. Our study highlighted the favorable effects of MET and RIS both in monotherapy and in combination in alleviating the autistic-like-changes and proposed PPAR-α activation along with restoring astrocytes homeostasis as promising targets in novel therapeutic strategies in ASD.
Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Metformina , Efectos Tardíos de la Exposición Prenatal , Tauopatías , Animales , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/metabolismo , Trastorno Autístico/inducido químicamente , Conducta Animal , Modelos Animales de Enfermedad , Femenino , Masculino , Metformina/efectos adversos , Receptores Activados del Proliferador del Peroxisoma/efectos adversos , Embarazo , Ratas , Ratas Wistar , Risperidona/farmacología , Risperidona/uso terapéutico , Ácido Valproico/farmacologíaRESUMEN
BACKGROUND: The link between types and severity of attention deficit hyperactivity disorder (ADHD) symptoms and trait emotional intelligence (TEI) is still underinvestigated, especially in children. We aimed to examine the relationship between TEI and ADHD symptoms in a sample of Egyptian children. METHOD: The study included 50 children with ADHD, who were compared on the basis of their TEI and contrasted with 25 matched healthy controls. They were subjected to the Arabic version of the following scales: Connors scale 3rd edition, parent rating form, Kiddie-Schedule for affective disorders and Schizophrenia present and Lifetime Version (K-SADS-PL), Stanford Binet intelligence scale, 4th edition and Trait Emotional Intelligence Child form (TEI) and a semistructured clinical data sheet for sociodemographic data. RESULTS: Using TEI scale, the control group was shown to have higher scores in TEI than cases, there was a high significant difference with regards to eight of nine TEI facets together with the TEI global score. Moreover, the control group significantly outperformed ADHD children with mixed and hyperactive subtypes on TEI global score in all facets except for adaptability. Meanwhile, the inattentive group performed significantly poorer than those in the control group on TEI global score, adaptability, emotional expression, self-motivation and emotion regulation facets. Trait Emotional Intelligence was negatively correlated with four of ADHD symptom groups assessed by Connors test, namely; impulsivity, cognitive, social problem, and emotional liability symptoms. However, Impulsivity was negatively correlated with all the domains of TEI except for adaptability and emotional expression. On the other hand, oppositional symptoms did not show a significant correlation with any of the TEI facets. CONCLUSIONS: Trait emotional intelligence is highly impaired in children with ADHD and emotional deficits are corner stone features of that disorder, low impulsivity facet of TEI is highly correlated with social problems and poor peer relations.
RESUMEN
BACKGROUND: There were few studies on the outcome of schizophrenia in developing countries. Whether the outcome is similar to or different from developed world is still a point for research. The main aim of the current study was to know if patients with early onset non affective psychosis can behave and function properly after few years from start of the illness or not. Other aims included investigation of possible predictors and associated factors with remission and outcome. METHOD: The study prospectively investigated a group of 56 patients with onset of psychosis during childhood or adolescence. Diagnosis made according to DSM-IV criteria and included; schizophrenia, psychotic disorder not otherwise specified and acute psychosis. Severity of psychosis was measured by PANSS. Measures of the outcome included; remission criteria of Andreasen et al 2005, the children's global assessment scale and educational level. RESULTS: Analysis of data was done for only 37 patients. Thirty patients diagnosed as schizophrenia and 7 with Psychotic disorder not otherwise specified. Mean duration of follow up was 38.4 +/- 16.9 months. At the end of the study, 6 patients (16.2%) had one episode, 23 (62.1%) had multiple episodes and 8 (21.6%) continuous course. Nineteen patients (51.4%) achieved full remission, and only 11 (29.7%) achieved their average educational level for their age. Twenty seven percent of the sample had good outcome and 24.3% had poor outcome. Factors associated with non remission and poor outcome included gradual onset, low IQ, poor premorbid adjustment, negative symptoms at onset of the illness and poor adherence to drugs. Moreover, there was tendency of negative symptoms at illness start to predict poor outcome. CONCLUSION: Some patients with early onset non affective psychosis can behave and function properly after few years from the start of the illness. Although remission is a difficult target in childhood psychosis, it is still achievable.