Oxidative stress in the central nervous system mediates the increase in sympathetic tone that precedes the development of hypertension. We hypothesized that by transforming Angiotensin-II (AngII) ...into Ang-(1-7), ACE2 might reduce AngII-mediated oxidative stress in the brain and prevent autonomic dysfunction. To test this hypothesis, a relationship between ACE2 and oxidative stress was first confirmed in a mouse neuroblastoma cell line (Neuro2A cells) treated with AngII and infected with Ad-hACE2. ACE2 overexpression resulted in a reduction of reactive oxygen species (ROS) formation. In vivo, ACE2 knockout (ACE2(-/y)) mice and non-transgenic (NT) littermates were infused with AngII (10 days) and infected with Ad-hACE2 in the paraventricular nucleus (PVN). Baseline blood pressure (BP), AngII and brain ROS levels were not different between young mice (12 weeks). However, cardiac sympathetic tone, brain NADPH oxidase and SOD activities were significantly increased in ACE2(-/y). Post infusion, plasma and brain AngII levels were also significantly higher in ACE2(-/y), although BP was similarly increased in both genotypes. ROS formation in the PVN and RVLM was significantly higher in ACE2(-/y) mice following AngII infusion. Similar phenotypes, i.e. increased oxidative stress, exacerbated dysautonomia and hypertension, were also observed on baseline in mature ACE2(-/y) mice (48 weeks). ACE2 gene therapy to the PVN reduced AngII-mediated increase in NADPH oxidase activity and normalized cardiac dysautonomia in ACE2(-/y) mice. Altogether, these data indicate that ACE2 gene deletion promotes age-dependent oxidative stress, autonomic dysfunction and hypertension, while PVN-targeted ACE2 gene therapy decreases ROS formation via NADPH oxidase inhibition and improves autonomic function. Accordingly, ACE2 could represent a new target for the treatment of hypertension-associated dysautonomia and oxidative stress.
This comprehensive advanced text on the biology and pathology of glial cells--the most numerous cells in the brain and an emerging field in neuroscience--offers detailed coverage of the morphology ...and interrelationships between glial cells and neurones in different parts of the nervous system. An accompanying website offers downloadable figures and slides.
Neuropsychiatric disorders are diseases of the central nervous system (CNS) which are characterised by complex pathomechanisms that including homeostatic failure, malfunction, atrophy, pathology ...remodelling and reactivity anomaly of the neuronal system where treatment options remain challenging. β-Carboline (βC) alkaloids are scaffolds of structurally diverse tricyclic pyrido3,4-bindole alkaloid with vast occurrence in nature. Their unique structural features which favour interactions with enzymes and protein receptor targets account for their potent neuropharmacological properties. However, our current understanding of their biological mechanisms for these beneficial effects, especially for neuropsychiatric disorders is sparse. Therefore, we present a comprehensive review of the scientific progress in the last two decades on the prospective pharmacology and physiology of the βC alkaloids in the treatment of some neuropsychiatric conditions such as depression, anxiety, Alzheimer's disease, Parkinson's disease, brain tumour, essential tremor, epilepsy and seizure, licking behaviour, dystonia, agnosia, spasm, positive ingestive response as demonstrated in non-clinical models. The current evidence supports that βC alkaloids offer potential therapeutic agents against most of these disorders and amenable for further drug design.
•Neuropsychiatric disorders are diseases of the CNS with neuronal pathomechanisms.•Neurodegenerative diseases mostly account for disability-adjusted life years.•β-Carboline alkaloids possess neuropharmacological potentials.•β-Carboline alkaloids can be developed into neuropsychiatric therapeutics.•Neurotoxic β-Carboline alkaloids can be derivatised into non-toxic useable forms.
The 2016 revised fourth edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumors incorporated molecular features with histologic grading, revolutionizing ...how oncologists conceptualize primary brain and spinal cord tumors as well as providing new insights into their management and prognosis. The 2021 revised fifth edition of the WHO classification further integrates molecular alterations for CNS tumor categorization, updating current understanding of the pathophysiology of many of these disease entities. Here, the authors review changes in the new classification for the most common primary adult tumors—gliomas (including astrocytomas, oligodendrogliomas, and ependymomas) and meningiomas—highlighting the key genomic alterations for each group classification to help clinicians interpret them as they consider therapeutic options—including clinical trials and targeted therapies—and discuss the prognosis of these tumors with their patients. The revised, updated 2021 WHO classification also further integrates molecular alterations in the classification of pediatric CNS tumors, but those are not covered in the current review.
The 2021 World Health Organization classification of tumors of the central nervous system increasingly relies on molecular alterations for central nervous system tumor categorization. The new classification will help improve diagnosis, prognosis, and treatment selection (including enrollment into relevant clinical trials) for patients with brain tumors.
Treatments in Aicardi–Goutières syndrome Crow, Yanick J; Shetty, Jayakara; Livingston, John H
Developmental medicine and child neurology,
January 2020, Volume:
62, Issue:
1
Journal Article
Peer reviewed
Open access
Comprehensive reviews of the clinical characteristics and pathogenesis of Aicardi–Goutières syndrome (AGS), particularly its contextualization within a putative type I interferonopathy framework, ...already exist. However, recent reports of attempts at treatment suggest that an assessment of the field from a therapeutic perspective is warranted at this time. Here, we briefly summarize the neurological phenotypes associated with mutations in the seven genes so far associated with AGS, rehearse current knowledge of the pathology as it relates to possible treatment approaches, critically appraise the potential utility of therapies, and discuss the challenges in assessing clinical efficacy.
What this paper adds
Progress in understanding AGS disease pathogenesis has led to the first attempts at targeted treatment.
Further rational therapies are expected to become available in the short‐ to medium‐term.
What this paper adds
Progress in understanding AGS disease pathogenesis has led to the first attempts at targeted treatment.
Further rational therapies are expected to become available in the short‐ to medium‐term.
Intracellular glucose signalling pathways control the secretion of glucagon and insulin by pancreatic islet α‐ and β‐cells, respectively. However, glucose also indirectly controls the secretion of ...these hormones through regulation of the autonomic nervous system that richly innervates this endocrine organ. Both parasympathetic and sympathetic nervous systems also impact endocrine pancreas postnatal development and plasticity in adult animals. Defects in these autonomic regulations impair β‐cell mass expansion during the weaning period and β‐cell mass adaptation in adult life. Both branches of the autonomic nervous system also regulate glucagon secretion. In type 2 diabetes, impaired glucose‐dependent autonomic activity causes the loss of cephalic and first phases of insulin secretion, and impaired suppression of glucagon secretion in the postabsorptive phase; in diabetic patients treated with insulin, it causes a progressive failure of hypoglycaemia to trigger the secretion of glucagon and other counterregulatory hormones. Therefore, identification of the glucose‐sensing cells that control the autonomic innervation of the endocrine pancreatic and insulin and glucagon secretion is an important goal of research. This is required for a better understanding of the physiological control of glucose homeostasis and its deregulation in diabetes. This review will discuss recent advances in this field of investigation.
Anthocyanins, a class of water soluble flavonoids extracted from plants like berries and soybean seed, have been shown to display obvious anti-oxidative, anti-inflammatory, and anti-apoptotic ...activities. They are recommended as a supplementation for prevention and/or treatment of disorders ranging from cardiovascular disease, metabolic syndrome, and cancer. In the central nervous system (CNS), anthocyanins and its major component cyanidin-3-O-glucoside (C3G) have been reported to produce preventive and/or therapeutic activities in a wide range of disorders, such as cerebral ischemia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and glioblastoma. Both anthocyanins and C3G can also affect some important processes in aging, including neuronal apoptosis and death as well as learning and memory impairment. Further, the anthocyanins and C3G have been shown to prevent neuro-toxicities induced by different toxic factors, such as lipopolysaccharide, hydrogen peroxide, ethanol, kainic acid, acrolein, glutamate, and scopolamine. Mechanistic studies have shown that inhibition of oxidative stress and neuroinflammation are two critical mechanisms by which anthocyanins and C3G produce protective effects in CNS disorder prevention and/or treatment. Other mechanisms, including suppression of c-Jun N-terminal kinase (JNK) activation, amelioration of cellular degeneration, activation of the brain-derived neurotrophic factor (BDNF) signaling, and restoration of Ca2+ and Zn2+ homeostasis, may also mediate the neuroprotective effects of anthocyanins and C3G. In this review, we summarize the pharmacological effects of anthocyanins and C3G in CNS disorders as well as their possible mechanisms, aiming to get a clear insight into the role of anthocyanins in the CNS.
Hypomorphic mutations in the DNA repair enzyme RNase H2 cause the neuroinflammatory autoimmune disorder Aicardi-Goutières syndrome (AGS). Endogenous nucleic acids are believed to accumulate in ...patient cells and instigate pathogenic type I interferon expression. However, the underlying nucleic acid species amassing in the absence of RNase H2 has not been established yet. Here, we report that murine RNase H2 knockout cells accumulated cytosolic DNA aggregates virtually indistinguishable from micronuclei. RNase H2-dependent micronuclei were surrounded by nuclear lamina and most of them contained damaged DNA. Importantly, they induced expression of interferon-stimulated genes (ISGs) and co-localized with the nucleic acid sensor cGAS. Moreover, micronuclei associated with RNase H2 deficiency were cleared by autophagy. Consequently, induction of autophagy by pharmacological mTOR inhibition resulted in a significant reduction of cytosolic DNA and the accompanied interferon signature. Autophagy induction might therefore represent a viable therapeutic option for RNase H2-dependent disease. Endogenous retroelements have previously been proposed as a source of self-nucleic acids triggering inappropriate activation of the immune system in AGS. We used human RNase H2-knockout cells generated by CRISPR/Cas9 to investigate the impact of RNase H2 on retroelement propagation. Surprisingly, replication of LINE-1 and Alu elements was blunted in cells lacking RNase H2, establishing RNase H2 as essential host factor for the mobilisation of endogenous retrotransposons.
Among the collagen vascular diseases neurologic manifestations have been most commonly recognized and well-studied in systemic lupus erythematosus (SLE, lupus). Neurologic manifestations are less ...prevalent in other systemic inflammatory and autoimmune disorders. This review focuses on the clinical presentation, pathophysiology, and treatment strategies of neuropsychiatric lupus (NPSLE) in children and adults.
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