Autism Spectrum Disorder: Signaling Pathways and Prospective Therapeutic Targets.

The Autism Spectrum Disorder (ASD) consists of a prevalent and heterogeneous group of neurodevelopmental diseases representing a severe burden to affected individuals and their caretakers. Despite substantial improvement towards understanding of ASD etiology and pathogenesis, as well as increased social awareness and more intensive research, no effective drugs have been successfully developed to resolve the main and most cumbersome ASD symptoms. Hence, finding better treatments, which may act as "disease-modifying" agents, and novel biomarkers for earlier ASD diagnosis and disease stage determination are needed. Diverse mutations of core components and consequent malfunctions of several cell signaling pathways have already been found in ASD by a series of experimental platforms, including genetic associations analyses and studies utilizing pre-clinical animal models and patient samples. These signaling cascades govern a broad range of neurological features such as neuronal development, neurotransmission, metabolism, and homeostasis, as well as immune regulation and inflammation. Here, we review the current knowledge on signaling pathways which are commonly disrupted in ASD and autism-related conditions. As such, we further propose ways to translate these findings into the development of genetic and biochemical clinical tests for early autism detection. Moreover, we highlight some putative druggable targets along these pathways, which, upon further research efforts, may evolve into novel therapeutic interventions for certain ASD conditions. Lastly, we also refer to the crosstalk among these major signaling cascades as well as their putative implications in therapeutics. Based on this collective information, we believe that a timely and accurate modulation of these prominent pathways may shape the neurodevelopment and neuro-immune regulation of homeostatic patterns and, hopefully, rescue some (if not all) ASD phenotypes.

Cholinergic neuroplasticity in asthma driven by TrkB signaling.

Parasympathetic neurons in the airways control bronchomotor tone. Increased activity of cholinergic neurons are mediators of airway hyperresponsiveness (AHR) in asthma, however, mechanisms are not elucidated. We describe remodeling of the cholinergic neuronal network in asthmatic airways driven by brain-derived neurotrophic factor (BDNF) and Tropomyosin receptor kinase B (TrkB). Human bronchial biopsies were stained for cholinergic marker vesicular acetylcholine transporter (VAChT). Human lung gene expression and single nucleotide polymorphisms (SNP) in neuroplasticity-related genes were compared between asthma and healthy patients. Wild-type (WT) and mutated TrkB knock-in mice (Ntrk2tm1Ddg/J) with impaired BDNF signaling were chronically exposed to ovalbumin (OVA). Neuronal VAChT staining and airway narrowing in response to electrical field stimulation in precision cut lung slices (PCLS) were assessed. Increased cholinergic fibers in asthmatic airway biopsies was found, paralleled by increased TrkB gene expression in human lung tissue, and SNPs in the NTRK2 [TrkB] and BDNF genes linked to asthma. Chronic allergen exposure in mice resulted in increased density of cholinergic nerves, which was prevented by inhibiting TrkB. Increased nerve density resulted in AHR in vivo and in increased nerve-dependent airway reactivity in lung slices mediated via TrkB. These findings show cholinergic neuroplasticity in asthma driven by TrkB signaling and suggest that the BDNF-TrkB pathway may be a potential target.

Unpuzzling COVID-19: tissue-related signaling pathways associated with SARS-CoV-2 infection and transmission.

The highly infective coronavirus disease 19 (COVID-19) is caused by a novel strain of coronaviruses - the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - discovered in December 2019 in the city of Wuhan (Hubei Province, China). Remarkably, COVID-19 has rapidly spread across all continents and turned into a public health emergency, which was ultimately declared as a pandemic by the World Health Organization (WHO) in early 2020. SARS-CoV-2 presents similar aspects to other members of the coronavirus family, mainly regarding its genome, protein structure and intracellular mechanisms, that may translate into mild (or even asymptomatic) to severe infectious conditions. Although the mechanistic features underlying the COVID-19 progression have not been fully clarified, current evidence have suggested that SARS-CoV-2 may primarily behave as other ß-coronavirus members. To better understand the development and transmission of COVID-19, unveiling the signaling pathways that may be impacted by SARS-CoV-2 infection, at the molecular and cellular levels, is of crucial importance. In this review, we present the main aspects related to the origin, classification, etiology and clinical impact of SARS-CoV-2. Specifically, here we describe the potential mechanisms of cellular interaction and signaling pathways, elicited by functional receptors, in major targeted tissues/organs from the respiratory, gastrointestinal (GI), cardiovascular, renal, and nervous systems. Furthermore, the potential involvement of these signaling pathways in evoking the onset and progression of COVID-19 symptoms in these organ systems are presently discussed. A brief description of future perspectives related to potential COVID-19 treatments is also highlighted.

High dose of dexamethasone protects against EAE-induced motor deficits but impairs learning/memory in C57BL/6 mice.

Multiple sclerosis (MS) is an autoimmune and neuroinflammatory disease characterized by demyelination of the Central Nervous System. Immune cells activation and release of pro-inflammatory cytokines play a crucial role in the disease modulation, decisively contributing to the neurodegeneration observed in MS and the experimental autoimmune encephalomyelitis (EAE), the widely used MS animal model. Synthetic glucocorticoids, commonly used to treat the MS attacks, have controversial effects on neuroinflammation and cognition. We sought to verify the influence of dexamethasone (DEX) on the EAE progression and on EAE-induced cognitive deficits. In myelin oligodendrocyte glycoprotein peptide (MOG35-55)-induced EAE female mice, treated once with DEX (50 mg/kg) or not, on the day of immunization, DEX decreased EAE-induced motor clinical scores, infiltrating cells in the spinal cord and delayed serum corticosterone peak. At the asymptomatic phase (8-day post-immunization), DEX did not protected from the EAE-induced memory consolidation deficits, which were accompanied by increased glucocorticoid receptor (GR) activity and decreased EGR-1 expression in the hippocampus. Blunting hippocampal GR genomic activation with DnGR vectors prevented DEX effects on EAE-induced memory impairment. These data suggest that, although DEX improves clinical signs, it decreases cognitive and memory capacity by diminishing neuronal activity and potentiating some aspects of neuroinflammation in EAE.

Repeated Restraint Stress Decreases Na,K-ATPase Activity via Oxidative and Nitrosative Damage in the Frontal Cortex of Rats.

Chronic psychogenic stress can increase neuronal calcium influx and generate the intracellular accumulation of oxidative (ROS) and nitrosative (RNS) reactive species, disrupting synaptic transmission in the brain. These molecules impair the Na,K-ATPase (NKA) activity, whose malfunction has been related to neuropsychiatric disorders, including anxiety, depression, schizophrenia, and neurodegenerative diseases. In this study, we assessed how 14 days of restraint stress in rats affect NKA activity via oxidative/nitrosative damage in the frontal cortex (FCx), a crucial region for emotional and cognitive control. One day after the last stress session (S14 + 1d), but not immediately after the last stress session (S14), α2,3-NKA activity was significantly reduced in the FCx, without changes in the protein levels. The S14 + 1d animals also showed increased lipid peroxidation, iNOS, and AP-1 activities, as well as TNF-α protein levels, evidencing oxidative stress and neuroinflammation. No cellular death or neurodegeneration was observed in the FCx of S14 + 1d animals. Pharmacological inhibition of iNOS or COX-2 before each stress session prevented lipid peroxidation and the α2,3-NKA activity loss. Our results show that repeated restraint exposure for 14 days decreases the activity of α2,3-NKA in FCx 24 h after the last stress, an effect associated with augmented inflammatory response and oxidative and nitrosative damage and suggest new pathophysiological roles to neuroinflammation in neuropsychiatric diseases.