Hypophagia induced by intracerebroventricular injection of apelin-13 is mediated via CRF1/CRF2 and MC3/MC4 receptors in neonatal broiler chicken.

Previous studies have shown the role of apelin and its receptors in the regulation of food intake. In the present study, we investigate the mediating role of melanocortin, corticotropin, and neuropeptide Y systems in apelin-13- induced food intake in broilers. Eight trials were run in the current investigation to ascertain the relationships between the aforementioned systems and apelin-13 on food intake and behavioral changes after apelin-13 administration. In experiment 1, hens were given an intracerebroventricular administration of a solution for control in addition to apelin-13 (0.25, 0.5, and 1 µg). Astressin-B (a CRF1/CRF2 receptor antagonist, 30 µg), apelin-13 (1 µg), and administration of astressin-B and apelin-13 concurrently, were all injected into the birds in experiment 2. Experiments 3 through 8 were quite similar to experiment 2, with the exception of astressin2-B (CRF2 receptor antagonist, 30 µg), SHU9119 (MC3/MC4 receptor antagonist, 0.5 nmol), MCL0020 (MC4 receptor antagonist, 0.5 nmol), BIBP-3226 (NPY1 receptor antagonist, 1.25 nmol), BIIE 0246 (NPY2 receptor antagonist, 1.25 nmol), and CGP71683A (NPY5 receptor antagonist, 1.25 nmol) were injected instead of astressin-B. After then, total food consumption was monitored for 6 h. Apelin-13 injections of 0.5 and 1 µg decreased feeding (P < 0.05). The hypophagic effects of apelin were attenuated following the simultaneous administration of Astressin-B and Astressin2-B with apelin-13 (P > 0.05). Co-infusion of SHU9119 and apelin-13 reduced the appetite-decreasing effects of apelin-13 (P > 0.05). When MCL0020 and apelin-13 were injected at the same time, the hypophagia that apelin-13 induced was eliminated (P > 0.05). BIBP-3226, BIIE 0246, and CGP71683A had no effect on the hypophagia brought on by apelin-13 (P > 0.05). Also, apelin-13 significantly increased number of steps, jumps, exploratory food, pecks and standing time while decreased siting time (P < 0.05). These findings suggest that apelin-13-induced hypophagia in hens may involve the CRF1/CRF2 and MC3/MC4 receptors.

Molecular mechanisms highlighting the potential role of COVID-19 in the development of neurodegenerative diseases.

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to the pulmonary manifestations, COVID-19 patients may present a wide range of neurological disorders as extrapulmonary presentations. In this view, several studies have recently documented the worsening of neurological symptoms within COVID-19 morbidity in patients previously diagnosed with neurodegenerative diseases (NDs). Moreover, several cases have also been reported in which the patients presented parkinsonian features after initial COVID-19 symptoms. These data raise a major concern about the possibility of communication between SARS-CoV-2 infection and the initiation and/or worsening of NDs. In this review, we have collected compelling evidence suggesting SARS-CoV-2, as an environmental factor, may be capable of developing NDs. In this respect, the possible links between SARS-CoV-2 infection and molecular pathways related to most NDs and the pathophysiological mechanisms of the NDs such as Alzheimer's disease, vascular dementia, frontotemporal dementia, Parkinson's disease, and amyotrophic lateral sclerosis will be explained.

Central dopaminergic, serotoninergic, as well as GABAergic systems mediate NMU-induced hypophagia in newborn chicken.

AIM: Dopaminergic, serotoninergic, and GABAergic systems influence feeding; however, it is unknown how these chemicals interact with neuromedin U (NMU)-induced feeding in birds. In the current study, ten trials were conducted to determine the links between the above-mentioned systems and NMU. MATERIALS AND METHODS: In the foremost experimentation, chickens were given intracerebroventricularly injections of NMU (0.1, 1, and 10 µg). NMU (10 µg), SCH23390 (5 nmol), a D1 receptor antagonist, and NMU + SCH23390 were administered in the second experiment. In subsequent experiments, instead of SCH23390, were applied AMI-193 (5 nmol D2 receptor antagonist), NGB2904 (6.4 nmol D3 receptor antagonist), L-741,742 (6 nmol D4 receptor antagonist), 6-OHDA (2.5 nmol dopamine inhibitor), SB242084 (5-HT2c receptor antagonist, 1.5 µg), 8-OH-DPAT (5-HT1A receptor agonist, 15.25 nmol), picrotoxin (GABAA receptor antagonist, 0.5 µg), and CGP54626 (GABAB receptor antagonist, 20 ng). Then, cumulative intake of food was recorded for 2 h. RESULTS: According to the results, NMU reduced feeding when compared to the control group (p < 0.05). The NMU-induced hypophagia was reduced with co-injection of NMU and SCH23390 (p < 0.05). Hypophagia was diminished with NMU and AMI-193 (p < 0.05). NMU + NGB2904 and NMU + L-741,742 co-injections had no influence (p > 0.05). 6-OHDA reduced the hypophagia (p < 0.05). NMU and SB242084 decreased the hypophagia (p < 0.05), whereas NMU and 8-OH-DPAT had no effect (p > 0.05). The effects were amplified with picrotoxin (p < 0.05). NMU with CGP54626 had no influence on the hypophagia (p > 0.05). CONCLUSION: Thus, NMU-induced hypophagia is probably mediated by D1/D2, 5-HT2c, and GABAA receptors in neonatal chicks.

Opioid receptor µ, not δ and κ, modulate food intake induced by ghrelin in laying chickens.

Evidence from animal studies suggests that the opioidergic system and ghrelin have a regulatory role in food intake, but their interaction(s) have not been studied in laying chickens. So in this study, four experiments (each included four groups) were designed. The first experiment was performed to evaluate the effect of ghrelin on the cumulative food intake. Experiments 2-4 were designed to investigate the possibility of µ, δ, or κ opioid receptors mediating ghrelin-induced hypophagia. All drugs were injected intracerebroventricularly (ICV) at 5 days of age. The results of this study showed that the ICV injection of 1.5 nmol ghrelin did not affect cumulative food intake. However, ICV injection of ghrelin with doses of 3 and 6 nmol significantly reduced the cumulative food intake (p < 0.05). However, co-injection of ghrelin with naltrindole and norbinaltorphimine did not show a significant change in decreased food intake compared with ghrelin. Also, opioid µ receptor gene expression significantly increased (p < 0.05), but δ and κ opioid receptors' gene expression did not significantly change. These results indicated that the opioidergic system is involved in developing ghrelin-induced hypophagic effects in laying chickens. Accordingly, this effect of ghrelin to modify the nutritional behavior is possibly mediated by opioid µ receptor.

A novel nonsense mutation in WNK1/HSN2 associated with sensory neuropathy and limb destruction in four siblings of a large Iranian pedigree.

BACKGROUND: Hereditary sensory and autonomic neuropathy type 2 (HSAN2) is an autosomal recessive disorder with predominant sensory dysfunction and severe complications such as limb destruction. There are different subtypes of HSAN2, including HSAN2A, which is caused by mutations in WNK1/HSN2 gene. METHODS: An Iranian family with four siblings and autosomal recessive inheritance pattern whom initially diagnosed with HSAN2 underwent whole exome sequencing (WES) followed by segregation analysis. RESULTS: According to the filtering criteria of the WES data, a novel candidate variation, c.3718C > A in WNK1/HSN2 gene that causes p.Tyr1025* was identified. This variation results in a truncated protein with 1025 amino acids instead of the wild-type product with 2645 amino acids. Sanger sequencing revealed that the mutation segregates with disease status in the pedigree. CONCLUSIONS: The identified novel nonsense mutation in WNK1/HSN2 in an Iranian HSAN2 pedigree presents allelic heterogeneity of this gene in different populations. The result of current study expands the spectrum of mutations of the HSN2 gene as the genetic background of HSAN2A as well as further supports the hypothesis that HSN2 is a causative gene for HSAN2A. However, it seems that more research is required to determine the exact effects of this product in the nervous system.

Exploring yale-brown obsessive-compulsive scale symptom structure in Iranian OCD patients using item-based factor analysis.

Obsessive compulsive disorder (OCD) is a heterogeneous psychiatric disorder. This study aimed to reach a comprehensive perspective of OCD symptoms in Iranian patients. Item-based factor analysis of Y-BOCS checklist from 216 outpatients resulted in five factors including aggression/checking, contamination/cleaning, symmetry/ordering/repeating/counting/hoarding, sexual and somatic. Regression analyses showed that miscellaneous items can be predicted by these factors. Results showed that OCD subtypes in Iranian patients resemble to those of other nations except the aggressive, sexual and religious obsessions; demonstrating the influence of the culture on obsession manifestation. The correlation analyses of factors and clinical characteristics demonstrated that aggression/checking was associated with high obsession scores and more avoidance. Contamination/cleaning was correlated with higher compulsion score. Patients with higher scores on symmetry/ordering/counting/repeating/hoarding had familial OCD pattern with earlier age of onset, lower age at assessment, higher obsession and more avoidance. Sexual factor was associated with less compulsion scores and somatic factor was associated with higher obsessions and compulsions as well as less familial history and more avoidance. These findings provide a comprehensive view of OCD symptom structure in Iranian OCD patients and will be of value to studies using symptom factor to lead investigation of its causes, correlates and treatment strategies considering cross-cultural differences.

Neurosteroids; potential underpinning roles in maintaining homeostasis.

The neuroactive steroids which are synthesized in the brain and nervous system are known as "Neurosteroids". These steroids have crucial functions such as contributing to the myelination and organization of the brain connectivity. Under the stressful circumstances, the concentrations of neurosteroid products such as allopregnanolone (ALLO) and allotetrahydrodeoxycorticosterone (THDOC) alter. It has been suggested that these stress-derived neurosteroids modulate the physiological response to stress. Moreover, it has been demonstrated that the hypothalamic-pituitary-adrenal (HPA) axis mediates the physiological adaptation following stress in order to maintain homeostasis. Although several regulatory pathways have been introduced, the exact role of neurosteroids in controlling HPA axis is not clear to date. In this review, we intend to discern specific pathways associated with regulation of HPA axis in which neuroactive steroids have the main role. In this respect, we propose pathways that may be initiated after neurosteroidogenesis in different brain subregions following acute stress which are potentially capable of activating or inhibiting the HPA axis.

Glycogen synthase kinase-3 beta (GSK-3ß) signaling: Implications for Parkinson's disease.

Glycogen synthase kinase 3 (GSK-3) dysregulation plays an important role in the pathogenesis of numerous disorders, affecting the central nervous system (CNS) encompassing both neuroinflammation and neurodegenerative diseases. Several lines of evidence have illustrated a key role of the GSK-3 and its cellular and molecular signaling cascades in the control of neuroinflammation. Glycogen synthase kinase 3 beta (GSK-3ß), one of the GSK-3 isomers, plays a major role in neuronal apoptosis and its inhibition decreases expression of alpha-Synuclein (α-Synuclein), which make this kinase an attractive therapeutic target for neurodegenerative disorders. Parkinson's disease (PD) is a chronic neurodegenerative movement disorder characterized by the progressive and massive loss of dopaminergic neurons by neuronal apoptosis in the substantia nigra pars compacta and depletion of dopamine in the striatum, which lead to pathological and clinical abnormalities. Thus, understanding the role of GSK-3ß in PD will enhance our knowledge of the basic mechanisms underlying the pathogenesis of this disorder and facilitate the identification of new therapeutic avenues. In recent years, GSK-3ß has been shown to play essential roles in modulating a variety of cellular functions, which have prompted efforts to develop GSK-3ß inhibitors as therapeutics. In this review, we summarize GSK-3 signaling pathways and its association with neuroinflammation. Moreover, we highlight the interaction between GSK-3ß and several cellular processes involved in the pathogenesis of PD, including the accumulation of α-Synuclein aggregates, oxidative stress and mitochondrial dysfunction. Finally, we discuss about GSK-3ß inhibitors as a potential therapeutic strategy in PD.

Preconditioning as a potential strategy for the prevention of Parkinson's disease.

Parkinson's disease (PD) is a chronic neurodegenerative movement disorder characterized by the progressive and massive loss of dopaminergic neurons by neuronal apoptosis in the substantia nigra pars compacta and depletion of dopamine in the striatum, which lead to pathological and clinical abnormalities. A numerous of cellular processes including oxidative stress, mitochondrial dysfunction, and accumulation of α-synuclein aggregates are considered to contribute to the pathogenesis of Parkinson's disease. A further understanding of the cellular and molecular mechanisms involved in the pathophysiology of PD is crucial for developing effective diagnostic, preventative, and therapeutic strategies to cure this devastating disorder. Preconditioning (PC) is assumed as a natural adaptive process whereby a subthreshold stimulus can promote protection against a subsequent lethal stimulus in the brain as well as in other tissues that affords robust brain tolerance facing neurodegenerative insults. Multiple lines of evidence have demonstrated that preconditioning as a possible neuroprotective technique may reduce the neural deficits associated with neurodegenerative diseases such as PD. Throughout the last few decades, a lot of efforts have been made to discover the molecular determinants involved in preconditioning-induced protective responses; although, the accurate mechanisms underlying this "tolerance" phenomenon are not fully understood in PD. In this review, we will summarize pathophysiology and current therapeutic approaches in PD and discuss about preconditioning in PD as a potential neuroprotective strategy. Also the role of gene reprogramming and mitochondrial biogenesis involved in the preconditioning-mediated neuroprotective events will be highlighted. Preconditioning may represent a promising therapeutic weapon to combat neurodegeneration.

Gemfibrozil pretreatment resulted in a sexually dimorphic outcome in the rat models of global cerebral ischemia-reperfusion via modulation of mitochondrial pro-survival and apoptotic cell death factors as well as MAPKs.

Inducers of mitochondrial biogenesis are widely under investigation for use in a novel therapeutic approach in neurodegenerative disorders. The ability of Gemfibrozil, a fibrate, is investigated for the first time to modulate mitochondrial pro-survival factors involved in the mitochondrial biogenesis signaling pathway, including peroxisome proliferator-activated receptor coactivator-1α (PGC-1α), nuclear respiratory factor (NRF-1), and mitochondrial transcription factor A (TFAM) in the brain. Gemfibozil is clinically administered to control hyperlipidemia. It secondarily prevents cardiovascular events such as cardiac arrest in susceptible patients. In this study, pretreatment of animals with gemfibrozil prior to ischemia-reperfusion (I/R) resulted in a sexually dimorphic outcome. While the expression of NRF-1 and TFAM were induced in gemfibrozil-pretreated met-estrous females, they were suppressed in males. Gemfibrozil also proved to be neuroprotective in met-estrous females, as it inhibited caspase-dependent apoptosis while in males it led to hippocampal neurodegeneration via activation of both the caspase-dependent and caspase-independent apoptosis. In the mitogen-activated protein kinase (MAPKs) pathway, gemfibrozil pretreatment induced the expression of extracellular signal-regulated kinases (ERK1/2) in met-estrous females and reduced it in males. These findings correlatively point to the sexual-dimorphic effects of gemfibrozil in global cerebral I/R context by affecting important factors involved in the mitochondrial biogenesis, MAPKs, and apoptotic cell death pathways.

Gemfibrozil pretreatment affecting antioxidant defense system and inflammatory, but not Nrf-2 signaling pathways resulted in female neuroprotection and male neurotoxicity in the rat models of global cerebral ischemia-reperfusion.

Two important pathophysiological mechanisms involved during cerebral ischemia are oxidative stress and inflammation. In pathological conditions such as brain ischemia the ability of free radicals production is greater than that of elimination by endogenous antioxidative systems, so brain is highly injured due to oxidation and neuroinflammation. Fibrates as peroxisome proliferator-activated receptor (PPAR)-α ligands, are reported to have antioxidant and anti-inflammatory actions. In this study, gemfibrozil, a fibrate is investigated for its therapeutic potential against global cerebral ischemia-reperfusion (I/R) injury of male and female rats. This study particularly has focused on inflammatory and antioxidant signaling pathways, such as nuclear factor erythroid-related factor (Nrf)-2, as well as the activity of some endogenous antioxidant agents. It was found that pretreatment of animals with gemfibrozil prior to I/R resulted in a sexually dimorphic outcome. Within females it proved to be protective, modulating inflammatory factors and inducing antioxidant defense system including superoxide dismutase (SOD), catalase, as well as glutathione level. However, Nrf-2 signaling pathway was not affected. It also decreased malondialdehyde level as an index of lipid peroxidation. In contrast, gemfibrozil pretreatment was toxic to males, enhancing the expression of inflammatory factors such as tumor necrosis factor-α, nuclear factor-κB, and cyclooxygenase-2, and decreasing Nrf-2 expression and SOD activity, leading to hippocampal neurodegeneration. Considering that gemfibrozil is a commonly used anti-hyperlipidemic agent in clinic, undoubtedly more investigations are crucial to exactly unravel its sex-dependent neuroprotective/neurodegenerative potential.