Environmentally Induced Oxidative Stress and Disruption of Brain Thyroid Hormone Homeostasis in Autism Spectrum Disorders

In memory of my son and a budding neuroscientist, Zachary L. Sulkowski, B

A Dual-Route Perspective of SARS-CoV-2 Infection: Lung- vs. Gut-specific Effects of ACE-2 Deficiency

SARS-CoV-2, primarily considered a respiratory virus, is increasingly recognized as having gastrointestinal aspects based on its presence in the gastrointestinal (GI) tract and feces. SARS-CoV-2 uses as a receptor angiotensin-converting enzyme 2 (ACE-2), a critical member of the renin-angiotensin-aldosterone system (RAAS) involved in the regulation of blood pressure and fluid system. In addition to the systemic endocrine functions, RAAS components are also involved in intracrine and organ-specific local functions. The angiotensin-converting enzyme 2 (ACE-2) is a key component of RAAS and a receptor for SARS-CoV-2. It is expressed in many tissues with gastrointestinal (GI) tract ACE-2 levels far exceeding those in the respiratory tract. SARS-CoV-2 binding to its receptor results in a deficiency of ACE-2 activity in endocrine, intracrine, and local lung and GI tract ACE-2. The local ACE-2 has different organ-specific functions, including hypertension-independent activities; dysregulations of these functions may contribute to multiorgan COVID-19 pathology, its severity, long-term effects, and mortality. We review supporting evidence from this standpoint. Notably, COVID-19 comorbidities involving hypertension, obesity, heart disease, kidney disease, and diabetes are associated with gastrointestinal problems and display ACE-2 deficits. While RAAS inhibitors target both endocrine and intracrine ACE-2 activity, the deficit of the local ACE-2 activity in the lungs and more so in the gut have not been targeted. Consequently, the therapeutic approach to COVID-19 should be carefully reconsidered. Ongoing clinical trials testing oral probiotic bound ACE-2 delivery are promising

Otoconin-90 Deletion Leads to Imbalance but Normal Hearing: A Comparison with Other Otoconia Mutants

Our sense of gravitation and linear acceleration is mediated by stimulation of vestibular hair cells through displacement of otoconia in the utricle and saccule (the gravity receptor organ). We recently showed that otoconin-90 (Oc90) deletion led to formation of giant otoconia. In the present study, we determined the extent to which the giant otoconia affected balance and gravity receptor sensory input and compared the findings with other otoconia mutants. We employed a wide spectrum of balance behavioral tests, including reaching and air-righting reflexes, gait, swimming, beam-crossing, rotorod latencies, and a direct measure of gravity receptor input, vestibular evoked potentials (VsEPs). All tests on homozygous adult mutants consistently ranked the order of imbalance as (from worst to best) Nox3het<otopetrin 1tlt<Oc90 null<Oc90 wild type and C57Bl/6 mice using systematic statistical comparisons of the frequency of occurrence or the severity of abnormal functions. This order coincides with the degree of otoconia deficiencies and is consistent with VsEP measures. Notably, all mice (except Nox3het) showed remarkable learned adaptation to peripheral vestibular deficits by staying on the rotating rod significantly longer in each successive trial, and the rate and extent of such learned improvements ranked the same order as their initial balance ability. Despite the vestibular morbidity, Oc90 null mice had normal hearing, as measured by auditory brainstem responses (ABRs) and distortion products of otoacoustic emissions (DPOAEs). The study demonstrates that the remnant otoconia mass in Oc90 nulls does stimulate the gravity receptor organs, which was likely responsible for the improved balance performance relative to strains with absent otoconia. Furthermore, the combination of direct electrophysiological measures and a series of behavioral tests can be used to interpret the imbalance severity arising from altered inputs from the gravity receptor end organ. Originally published Neuroscience, Vol. 153, No. 1, Apr 200

A Study of Nuclear Transcription Factor-Kappa B in Childhood Autism

BACKGROUND: Several children with autism show regression in language and social development while maintaining normal motor milestones. A clear period of normal development followed by regression and subsequent improvement with treatment, suggests a multifactorial etiology. The role of inflammation in autism is now a major area of study. Viral and bacterial infections, hypoxia, or medication could affect both foetus and infant. These stressors could upregulate transcription factors like nuclear factor kappa B (NF-κB), a master switch for many genes including some implicated in autism like tumor necrosis factor (TNF). On this hypothesis, it was proposed to determine NF-κB in children with autism. METHODS: Peripheral blood samples of 67 children with autism and 29 control children were evaluated for NF-κB using electrophoretic mobility shift assay (EMSA). A phosphor imaging technique was used to quantify values. The fold increase over the control sample was calculated and statistical analysis was carried out using SPSS 15. RESULTS: We have noted significant increase in NF-κB DNA binding activity in peripheral blood samples of children with autism. When the fold increase of NF-κB in cases (n = 67) was compared with that of controls (n = 29), there was a significant difference (3.14 vs. 1.40, respectively; p<0.02). CONCLUSION: This finding has immense value in understanding many of the known biochemical changes reported in autism. As NF-κB is a response to stressors of several kinds and a master switch for many genes, autism may then arise at least in part from an NF-κB pathway gone awry

Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders

Preterm-born infants frequently suffer from an array of neurological damage, collectively termed encephalopathy of prematurity (EoP). They also have an increased risk of presenting with a neurodevelopmental disorder (e.g., autism spectrum disorder; attention deficit hyperactivity disorder) later in life. It is hypothesized that it is the gray matter injury to the cortex, in addition to white matter injury, in EoP that is responsible for the altered behavior and cognition in these individuals. However, although it is established that gray matter injury occurs in infants following preterm birth, the exact nature of these changes is not fully elucidated. Here we will review the current state of knowledge in this field, amalgamating data from both clinical and preclinical studies. This will be placed in the context of normal processes of developmental biology and the known pathophysiology of neurodevelopmental disorders. Novel diagnostic and therapeutic tactics required integration of this information so that in the future we can combine mechanism-based approaches with patient stratification to ensure the most efficacious and cost-effective clinical practice