Memantine/Aripiprazole Combination Alleviates Cognitive Dysfunction in Valproic Acid Rat Model of Autism: Hippocampal CREB/BDNF Signaling and Glutamate Homeostasis.

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.

Harmine prevents 3-nitropropionic acid-induced neurotoxicity in rats via enhancing NRF2-mediated signaling: Involvement of p21 and AMPK.

Oxidative stress induced neurotoxicity is increasingly perceived as an important neuropathologic mechanism underlying the motor and behavioral phenotypes associated with Huntington's disease (HD). Repeated exposure to 3-nitropropionic acid (3-NP) induces neurotoxic changes which closely simulate the neuropathological and behavioral characteristics of HD. This study aimed at evaluating the prophylactic effects of the dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) inhibitor "harmine" against 3-NP-indued neurotoxicity and HD-like symptoms. The potential prophylactic effect of harmine (10 mg/kg/day; intraperitoneal) was investigated on 3-NP-induced motor and cognitive HD-like deficits, nuclear factor erythroid 2 like 2 (NRF2), AMP kinase (AMPK) and p21 protein levels and the gene expression of haem oxygenase-1 (Ho-1), NAD(P)H: quinone oxidoreductase-1 (Nqo-1) and p62 in addition to redox imbalance and histological neurotoxic changes in the striatum, prefrontal cortex, and hippocampus of male Wistar rats. Harmine successfully increased the protein levels of NRF2, AMPK and p21 and the gene expression of Ho-1, Nqo-1 and p62, restored redox homeostasis, and reduced CASPASE-3 level. This was reflected in attenuation of 3-NP-induced neurodegenerative changes and improvement of rats' motor and cognitive performance. This study draws attention to the protective role of harmine against 3-NP-induced motor and cognitive dysfunction that could be mediated via enhancing NRF2-mediated signaling with subsequent amelioration of oxidative stress injury via NRF2 activators, p21 and AMPK, in the striatum, prefrontal cortex, and hippocampus which could offer a promising therapeutic tool to slow the progression of HD.

Novel role of peroxisome proliferator activated receptor-α in valproic acid rat model of autism: Mechanistic study of risperidone and metformin monotherapy versus combination.

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.

Pterostilbene ameliorates the disrupted Adars expression and improves liver fibrosis in DEN-induced liver injury in Wistar rats: A novel potential effect.

The knowledge of RNA editing modifications and its subsequent proteomic diversity in is still limited and represents only the tip of the iceberg. Adenosine to inosine (A-to-I) RNA editing is the most prevalent in RNA editome with a rising role for ADARgene family as a major regulator of the dynamic landscape of RNA editing. This study aimed at evaluating the potential chemopreventive effects of the epigenetic regulator "pterostilbene" in diethylnitrosamine (DEN)-exposedrat model. Consequently, the hepatic Adars expression was investigated as a possible mechanism for mediation of the putative pterostilbene-induced chemopreventive effect. The effects of administration of pterostilbene were investigated on the structural changes, immunohistochemical staining, liver function test, serum alpha feto-protein (AFP), IL-6, and hepatic Adar1 and Adar2 relative gene expression at the beginning and at the 6th week of the study. Pterostilbene attenuated DEN-induced liver injury, improves hepatocyte parrafin-1 (Hep Par-1), decreases heat shock protein 70 (HSP70), improved AFP, serum albumin, transaminases, IL-6 with alleviation of disturbed hepatic Adar1 and Adar2 expression. This study spotlights the role of pterostilbene in attenuation of DEN-induced liver injury which could be mediated, at least partially, through the alleviation of the aberrant expression of Adar enzymes. Yet, more in-depth studies are needed to further elucidate the molecular mechanisms underlying the effects of pterostilbene on RNA editing enzymes.

Validation of prenatal versus postnatal valproic acid rat models of autism: A behavioral and neurobiological study.

Despite the increasing prevalence of autism spectrum disorder (ASD), there is still a deficiency in understanding its exact pathophysiology and treatment, therefore validation of translational ASD animal model is warranted. Although strong evidences support the valproic acid (VPA) model of autism, yet a controversy exists regarding the best timing of exposure whether prenatal or postnatal. Accordingly, this study was designed to compare the time dependent effects of VPA exposure as regard its ability to induce autistic like changes in male Wistar rats. In this study, two different protocols of VPA exposure (prenatal and postnatal) were compared at different levels (behavioral, neurochemical and histopathological). Results of this study revealed that both prenatal and postnatal VPA exposures induced autistic-like behaviors manifested by reduced social interaction, increased repetitive stereotyped behavior and anxiety, cognitive dysfunction, lowered sensitivity to pain, and neurodevelopmental delay. Furthermore, inflammatory cytokines and oxidative/nitrosative stress markers were elevated in prefrontal cortex and hippocampal homogenates. Likewise, histopathological and immunohistochemical assessment confirmed the neurodegenerative and the apoptotic changes in prefrontal cortex, hippocampus and cerebellum exhibited by decreased viable cells number and Nissl's granules optical density, and increased caspase-3 immunoreactivity respectively. Interestingly, ASD core symptoms and histopathological changes were significantly (P < 0.05) altered in prenatal VPA model compared to postnatal VPA model. Additionally, postnatal mortality in prenatal model (4.3%) was much lower compared to the postnatal model (22.7%). In conclusion, our study overweighs the ability of prenatal VPA model over postnatal VPA model to induce behavioral and neuropathological alterations that simulate those observed in autistic individuals with a lower postnatal animal mortality, highlighting the privilege of prenatal over postnatal VPA exposure as a translational model for understanding pathophysiology and developing novel targets for management of ASD.

The Effect of Vitamin D Supplementation on Glycemic Control and Lipid Profile in Patients with Type 2 Diabetes Mellitus.

AIM: The aim of this study was to evaluate the effect of vitamin D supplementation in patients with type 2 diabetes mellitus (T2DM) with regard to their glycemic control and lipid profile. METHODS: One hundred subjects with T2DM were recruited and given 4500 IU/day of vitamin D for 2 months. 25-Hydroxyvitamin D [25(OH)D], fasting blood glucose (FBG), glycosylated hemoglobin A1c (HbA1c), and lipid profile were measured pre- and postsupplementation. RESULTS: There was a significant increase in the mean value of 25(OH)D level after supplementation (baseline level 16 ± 5.3 ng/ml vs. after supplement level 49.2 ± 17.7 ng/ml, p < 0.05). Both FBG and HbA1c but not lipid profile were significantly decreased after supplementation. However, the univariate general linear model between 25(OH)D percentiles and lipid profile levels showed that diabetic subjects with high 25(OH)D levels (>61 ng/ml) had significantly lower levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) in comparison to those in the low or middle percentiles. Furthermore, participants in a higher percentile had a significantly higher level of high-density lipoprotein cholesterol (HDL-C) than those in the middle percentile. Lipid profile levels were not affected by the supplement except for triglycerides (TG) levels in females, which were significantly decreased. CONCLUSIONS: Vitamin D supplementation may be beneficial to diabetic subjects because it improved glycemic control. Diabetic subjects with high 25(OH)D levels (>61 ng/ml) had better lipid profiles.

Evaluation of insulin like growth factor-1 (IGF-1) level and its impact on muscle and bone mineral density in frail elderly male.

Decrease in IGF-1 level is a major endocrine dysregulation that has been implicated in frailty, disability, and mortality in older adults. Our aim was to clarify the effect of IGF-1 on muscle and bone mineral density (BMD) in frail males. One hundred elderly males were included and divided into frail group (n=50) and robust group (n=50) based on the study of osteoporotic fractures (SOF) frailty index. Anthropometric measures, femoral BMD, and serum IGF-1 level were measured. Our results showed that the IGF-1 level was significantly lower in the frail males in comparison to the robust with mean value 37.1±24.2 versus 68.5±18.4ng/ml (P<0.05). Receiver operating curve (ROC) analysis of the IGF-1 level revealed that sensitivity was 88.5%, specificity was 100%, cutoff value was 46.5ng/ml and area under the curve (AUC) was 0.897 (P<0.05). Participants with low IGF-1 percentile had significantly higher odds ratio of being frail compared to those with high IGF-1 percentile (odds ratio=12.8, 95% CI: 4.2-38.8, P-value<0.05). Subjects with low IGF-1 percentile had 13.5 times the odds of having an abnormal BMD than those with middle IGF-1 percentile (95% CI: 3.4-53.3, P<0.05). In multivariate analysis BMD, mid arm circumference (MAC), mid calf circumference (MCC), and handgrip strength were significantly affected by IGF-1 percentiles with age and co-morbid diseases adjustment. Male subjects with a low IGF-1 level may be at risk of being frail and having abnormal BMD. 16.8% and 15% of variability in MCC and BMD may be attributed to IGF-1 level respectively.

Histone deacetylases enzyme, copper, and IL-8 levels in patients with Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive loss of cognitive abilities. Epigenetic modification, oxidative stress, and inflammation play an important role in the pathogenesis of the disease. We aimed to detect noninvasive peripheral biomarkers with a high degree of sensitivity and specificity in diagnosis and progression of AD. METHODS: A total of 25 elderly patients with AD and 25 healthy control participants were selected and subjected to cognitive assessment and laboratory measures including histone deacetylases (HDACs), copper, and interleukin 8 (IL-8) levels. RESULTS: The levels of HDACs, copper, and IL-8 were significantly higher in patients with AD (P < .001) and had a significant negative effect on all cognitive assessment tests. Receiver-operating curve (ROC) analysis revealed that HDACs and copper levels had higher sensitivity and specificity. CONCLUSIONS: Plasma levels of HDACs and copper may be used as peripheral biomarkers in diagnosis of AD, while IL-8 level could be a useful biomarker in following AD progression.