Acute NMDA toxicity in cultured rat cerebellar granule neurons is accompanied by autophagy induction and late onset autophagic cell death phenotype

<p>Abstract</p> <p>Background</p> <p>Autophagy, an intracellular response to stress, is characterized by double membrane cytosolic vesicles called autophagosomes. Prolonged autophagy is known to result in autophagic (Type II) cell death. This study examined the potential role of an autophagic response in cultured cerebellar granule neurons challenged with excitotoxin N-methyl-D-aspartate (NMDA).</p> <p>Results</p> <p>NMDA exposure induced light chain-3 (LC-3)-immunopositive and monodansylcadaverine (MDC) fluorescent dye-labeled autophagosome formation in both cell bodies and neurites as early as 3 hours post-treatment. Elevated levels of Beclin-1 and the autophagosome-targeting LC3-II were also observed following NMDA exposure. Prolonged exposure of the cultures to NMDA (8-24 h) generated MDC-, LC3-positive autophagosomal bodies, concomitant with the neurodegenerative phase of NMDA challenge. Lysosomal inhibition studies also suggest that NMDA-treatment diverted the autophagosome-associated LC3-II from the normal lysosomal degradation pathway. Autophagy inhibitor 3-methyladenine significantly reduced NMDA-induced LC3-II/LC3-I ratio increase, accumulation of autophagosomes, and suppressed NMDA-mediated neuronal death. ATG7 siRNA studies also showed neuroprotective effects following NMDA treatment.</p> <p>Conclusions</p> <p>Collectively, this study shows that autophagy machinery is robustly induced in cultured neurons subjected to prolonged exposure to excitotoxin, while autophagosome clearance by lysosomal pathway might be impaired. Our data further show that prolonged autophagy contributes to cell death in NMDA-mediated excitotoxicity.</p

Pediatric traumatic brain injury in the Middle East and North Africa region: a systematic review and meta-analysis to assess characteristics, mechanisms, and risk factors

Pediatric traumatic brain injury (pTBI) represents a major cause of child injuries in the Middle East and North Africa (MENA) region. This review aims to assess pTBIs in the MENA region and reports their clinical severity and outcomes. A search was conducted using major electronic databases, including Medline/Ovid, PubMed, EMBASE, Web of Science, and SCOPUS. Abstracts were screened independently and in duplicate to detect original research. The objective and study findings for each article were recorded, along with the mechanism of pTBI, patient age and sex, injury assessment tool(s) used, and outcome. A total of 1345 articles were retrieved, of which 152 met the criteria for full-text review, and 32 were included in this review. Males predominantly suffered from pTBIs (78%). Motor vehicle accidents, followed by child abuse, were the leading causes of pTBI. Overall, 0.39% of cases were mild, 0.58% moderate, 16.25% severe, and 82.27% unclassified. The mortality rate was 13.11%. Most studies used the computed tomography scan, Glasgow Coma Scale, Abbreviated Injury Scale, and Injury Severity Score as investigation methods. This review reports on the alarming rate of child-abuse-related pTBI and offers further understanding of pTBI-associated risk factors and insight into the development of strategies to reduce their occurrence, as well as policies to promote child well-being

Can, Want and Try: Parents' Viewpoints Regarding the Participation of Their Child with an Acquired Brain Injury

BACKGROUND: Acquired brain injury (ABI) is a leading cause of permanent disability, currently affecting 20,000 Australian children. Community participation is essential for childhood development and enjoyment, yet children with ABI can often experience barriers to participation. The factors which act as barriers and facilitators to community participation for children with an ABI are not well understood. AIM: To identify the viewpoints of parents of children with an ABI, regarding the barriers and facilitators most pertinent to community participation for their child. METHODS: Using Q-method, 41 parents of children with moderate/severe ABI sorted 37 statements regarding barriers and facilitators to community participation. Factor analysis identified three viewpoints. RESULTS: This study identified three distinct viewpoints, with the perceived ability to participate decreasing with a stepwise trend from parents who felt their child and family "can" participate in viewpoint one, to "want" in viewpoint two and "try" in viewpoint three. CONCLUSIONS: Findings indicated good participation outcomes for most children and families, however some families who were motivated to participate experienced significant barriers. The most significant facilitators included child motivation, supportive relationships from immediate family and friends, and supportive community attitudes. The lack of supportive relationships and attitudes was perceived as a fundamental barrier to community participation. SIGNIFICANCE: This research begins to address the paucity of information regarding those factors that impact upon the participation of children with an ABI in Australia. Findings have implications for therapists, service providers and community organisations

Insomnia in hospitalized psychiatric patients: prevalence and associated factors

Farid Talih,1 Jean Ajaltouni,1 Hiba Ghandour,2 Ahmad Subhi Abu-Mohammad,2 Firas Kobeissy2,3 1Department of Psychiatry, American University of Beirut Medical Center, Beirut, Lebanon; 2Faculty of Medicine, American University of Beirut, Beirut, Lebanon; 3Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon Objectives: To quantify and describe the prevalence of insomnia in hospitalized psychiatric patients and to investigate the associations between insomnia and demographic and clinical factors in hospitalized psychiatric patients.Methods: The participants included 203 individuals hospitalized for psychiatric treatment at an academic medical center. Demographic information, psychiatric diagnoses, current psychotropic medication use, and history of substance use were collected. Insomnia screening was performed using the Insomnia Severity Index. Depressive and anxiety symptoms were also evaluated using the Generalized Anxiety Disorder questionnaire and the Patient Health Questionnaire. Restless legs syndrome (RLS) symptoms were evaluated using the Restless Legs Syndrome Rating Scale (RLSRS). Statistical analysis was conducted to detect the prevalence of insomnia among the participants and to examine possible associations among psychiatric disorders, psychotropic medications, and RLS.Results: Out of the 203 participants that completed the survey, 67.4% were found to have insomnia and 14.3% were found to have RLS. The severity of insomnia was found to be associated with the presence of RLS, depressive and anxious symptomatology, suicidal ideation, use of selective serotonin reuptake inhibitors, and use of benzodiazepines. Keywords: insomnia, depression, anxiety, restless legs syndrom

Culture of PC12 neuronal cells in GelMA hydrogel for brain tissue engineering

Restoration of brain functions following trauma or degenerative neural diseases is considered among the greatest challenges in neurology due to the fact that the central nervous system (CNS) does not regenerate on its own. Tissue engineering offers a potential solution in developing artificial neural/brain tissues. Numerous hydrogel based biomaterials have been investigated in the field of neural tissue engineering. However, the lack of the optimum combination of mechanical and biological properties in commonly available hydrogels represents a major bottle neck in growing artificial neural tissues. In this study, 3 dimensional cell culture of PC12 neuronal cells have been investigated in methacrylated Gelatin (GelMA) hydrogel for brain tissue engineering. The cell viability and propagation of PC12 neural cell lines on GelMA-based hydrogel was tested revealing its positive effects on these cells. In addition, cytotoxicity was assessed in vivo showing that implantation of GelMA did not show any acute neurotoxic effects in mice exposed to experimental brain injury.Scopu

Dysregulation of angiotensin converting enzyme 2 expression and function in comorbid disease conditions possibly contributes to coronavirus infectious disease 2019 complication severity

ACE2 has emerged as a double agent in the COVID-19 ordeal, as it is both physiologically protective and virally conducive. The identification of ACE2 in as many as 72 tissues suggests that extrapulmonary invasion and damage is likely, which indeed has already been demonstrated by cardiovascular and gastrointestinal symptoms. On the other hand, identifying ACE2 dysregulation in patients with comorbidities may offer insight as to why COVID-19 symptoms are often more severe in these individuals. This may be attributed to a pre-existing proinflammatory state that is further propelled with the cytokine storm induced by SARS-CoV-2 infection or the loss of functional ACE2 expression as a result of viral internalization. Here, we aim to characterize the distribution and role of ACE2 in various organs to highlight the scope of damage that may arise upon SARSCoV- 2 invasion. Furthermore, by examining the disruption of ACE2 in several comorbid diseases, we offer insight into potential causes of increased severity of COVID-19 symptoms in certain individuals.This work was supported by the Medical Practice Plan Grants from the Faculty of Medicine at the American University of Beirut [320148] to A.F.E.-Y. and the Medical Practice Plan Grants from the Faculty of Medicine at the American University of Beirut [320133] to A.H.E. 1S.H. and Z.W. contributed equally to this work. https://doi.org/10.1124/molpharm.120.000119.Scopu

Biofluid proteomics and biomarkers in traumatic brain injury

Traumatic brain injury (TBI) is an injury to the brain caused by an external mechanical force, affecting millions of people worldwide. The disease course and prognosis are often unpredictable, and it can be challenging to determine an early diagnosis in case of mild injury as well as to accurately phenotype the injury. There is currently no cure for TBI?drugs having failed repeatedly in clinical trials?but an intense effort has been put to identify effective neuroprotective treatment. The detection of novel biomarkers, to understand more of the disease mechanism, facilitates early diagnosis, predicts disease progression, and develops molecularly targeted therapies that would be of high clinical interest. Over the last decade, there has been an increasing effort and initiative toward finding TBI-specific biomarker candidates. One promising strategy has been to use state-ofthe- art neuroproteomics approaches to assess clinical biofluids and compare the cerebrospinal fluid (CSF) and blood proteome between TBI and control patients or between different subgroups of TBI. In this chapter, we summarize and discuss the status of biofluid proteomics in TBI, with a particular focus on the latest findings.Scopu

Early metabolic impairment as a contributor to neurodegenerative disease: Mechanisms and potential pharmacological intervention

The metabolic syndrome comprises a family of clinical and laboratory findings, including insulin resistance, hyperglycemia, hypertriglyceridemia, low high-density lipoprotein cholesterol levels, and hypertension, in addition to central obesity. The syndrome confers a high risk of cardiovascular mortality. Indeed, metabolic dysfunction has been shown to cause a direct insult to smooth muscle and endothelial components of the vasculature, which leads to vascular dysfunction and hyperreactivity. This, in turn, causes cerebral vasoconstriction and hypoperfusion, eventually contributing to cognitive deficits. Moreover, the metabolic syndrome disrupts key homeostatic processes in the brain, including apoptosis, autophagy, and neurogenesis. Impairment of such processes in the context of metabolic dysfunction has been implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer, Parkinson, and Huntington diseases. The aim of this review is to elucidate the role that the metabolic syndrome plays in the pathogenesis of the latter disorders, with a focus on the role of perivascular adipose inflammation in the peripheral-to-central transduction of the inflammatory insult. This review delineates common signaling pathways that contribute to these pathologies. Moreover, the role of therapeutic agents aimed at treating the metabolic syndrome, as well as their risk factors that interfere with the aforementioned pathways, are discussed as potential interventions for neurodegenerative diseases