scholarly journals Comprehensive phenotyping revealed transient startle response reduction and histopathological gadolinium localization to perineuronal nets after gadodiamide administration in rats

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Johanna Habermeyer ◽  
Janina Boyken ◽  
Julia Harrer ◽  
Fabio Canneva ◽  
Veronika Ratz ◽  
...  
Keyword(s):  
Neuronal Cell ◽  
Cell Loss ◽  
Repeated Administration ◽  
Perineuronal Net ◽  
Treatment Groups ◽  
Long Time ◽  
Clinical Consequences ◽  
Molecular Weight Fractions ◽  
Clinical Mri ◽  
Pathway Deregulation

AbstractGadolinium based contrast agents (GBCAs) are widely used in clinical MRI since the mid-1980s. Recently, concerns have been raised that trace amounts of Gadolinium (Gd), detected in brains even long time after GBCA application, may cause yet unrecognized clinical consequences. We therefore assessed the behavioral phenotype, neuro-histopathology, and Gd localization after repeated administration of linear (gadodiamide) or macrocyclic (gadobutrol) GBCA in rats. While most behavioral tests revealed no difference between treatment groups, we observed a transient and reversible decrease of the startle reflex after gadodiamide application. Residual Gd in the lateral cerebellar nucleus was neither associated with a general gene expression pathway deregulation nor with neuronal cell loss, but in gadodiamide-treated rats Gd was associated with the perineuronal net protein aggrecan and segregated to high molecular weight fractions. Our behavioral finding together with Gd distribution and speciation support a substance class difference for Gd presence in the brain after GBCA application.

scholarly journals Impact of Gba2 on neuronopathic Gaucher’s disease and α-synuclein accumulation in medaka (Oryzias latipes)

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Etsuro Nakanishi ◽  
Norihito Uemura ◽  
Hisako Akiyama ◽  
Masato Kinoshita ◽  
Sawamura Masanori ◽  
...  
Keyword(s):  
Microglial Activation ◽  
Biochemical Analysis ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Pathological Changes ◽  
Gaucher's Disease ◽  
Gaucher’S Disease ◽  
Short Lifespan ◽  
Behavioral Abnormalities ◽  
Glucocerebrosidase Gene

AbstractHomozygous mutations in the lysosomal glucocerebrosidase gene, GBA1, cause Gaucher’s disease (GD), while heterozygous mutations in GBA1 are a strong risk factor for Parkinson’s disease (PD), whose pathological hallmark is intraneuronal α-synuclein (asyn) aggregates. We previously reported that gba1 knockout (KO) medaka exhibited glucosylceramide accumulation and neuronopathic GD phenotypes, including short lifespan, the dopaminergic and noradrenergic neuronal cell loss, microglial activation, and swimming abnormality, with asyn accumulation in the brains. A recent study reported that deletion of GBA2, non-lysosomal glucocerebrosidase, in a non-neuronopathic GD mouse model rescued its phenotypes. In the present study, we generated gba2 KO medaka and examined the effect of Gba2 deletion on the phenotypes of gba1 KO medaka. The Gba2 deletion in gba1 KO medaka resulted in the exacerbation of glucosylceramide accumulation and no improvement in neuronopathic GD pathological changes, asyn accumulation, or swimming abnormalities. Meanwhile, though gba2 KO medaka did not show any apparent phenotypes, biochemical analysis revealed asyn accumulation in the brains. gba2 KO medaka showed a trend towards an increase in sphingolipids in the brains, which is one of the possible causes of asyn accumulation. In conclusion, this study demonstrated that the deletion of Gba2 does not rescue the pathological changes or behavioral abnormalities of gba1 KO medaka, and GBA2 represents a novel factor affecting asyn accumulation in the brains.

scholarly journals Multidisciplinary Interventions in Motor Neuron Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
U. E. Williams ◽  
E. E. Philip-Ephraim ◽  
S. K. Oparah
Keyword(s):  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Motor Neurons ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Cellular Processes ◽  
Team Care ◽  
Respiratory Management ◽  
Care Approach ◽  
Management Of Dysphagia

Motor neuron disease is a neurodegenerative disease characterized by loss of upper motor neuron in the motor cortex and lower motor neurons in the brain stem and spinal cord. Death occurs 2–4 years after the onset of the disease. A complex interplay of cellular processes such as mitochondrial dysfunction, oxidative stress, excitotoxicity, and impaired axonal transport are proposed pathogenetic processes underlying neuronal cell loss. Currently evidence exists for the use of riluzole as a disease modifying drug; multidisciplinary team care approach to patient management; noninvasive ventilation for respiratory management; botulinum toxin B for sialorrhoea treatment; palliative care throughout the course of the disease; and Modafinil use for fatigue treatment. Further research is needed in management of dysphagia, bronchial secretion, pseudobulbar affect, spasticity, cramps, insomnia, cognitive impairment, and communication in motor neuron disease.

Neuronal Cell Loss in the CA3 Subfield of the Hippocampus Following Cortical Contusion Utilizing the Optical Disector Method for Cell Counting

1997 ◽  
Vol 14 (6) ◽  
pp. 385-398 ◽  
Author(s):  
STANLEY A. BALDWIN ◽  
TONYA GIBSON ◽  
C. TODD CALLIHAN ◽  
PATRICK G. SULLIVAN ◽  
ERICK PALMER ◽  
...  
Keyword(s):  
Neuronal Cell ◽  
Cell Loss ◽  
Cell Counting ◽  
Optical Disector ◽  
Neuronal Cell Loss ◽  
Cortical Contusion

scholarly journals NADPH Oxidase Mediates Membrane Androgen Receptor–Induced Neurodegeneration

Endocrinology ◽  
2019 ◽  
Vol 160 (4) ◽  
pp. 947-963 ◽  
Author(s):  
Mavis A A Tenkorang ◽  
Phong Duong ◽  
Rebecca L Cunningham
Keyword(s):  
Androgen Receptor ◽  
Nadph Oxidase ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Receptor Activation ◽  
Reduced Form ◽  
Negative Effects ◽  
Protein Activation ◽  
Trisphosphate Receptor

Abstract Oxidative stress (OS) is a common characteristic of several neurodegenerative disorders, including Parkinson disease (PD). PD is more prevalent in men than in women, indicating the possible involvement of androgens. Androgens can have either neuroprotective or neurodamaging effects, depending on the presence of OS. Specifically, in an OS environment, androgens via a membrane-associated androgen receptor (mAR) exacerbate OS-induced damage. To investigate the role of androgens on OS signaling and neurodegeneration, the effects of testosterone and androgen receptor activation on the major OS signaling cascades, the reduced form of NAD phosphate (NADPH) oxidase (NOX)1 and NOX2 and the Gαq/inositol trisphosphate receptor (InsP3R), were examined. To create an OS environment, an immortalized neuronal cell line was exposed to H2O2 prior to cell-permeable/cell-impermeable androgens. Different inhibitors were used to examine the role of G proteins, mAR, InsP3R, and NOX1/2 on OS generation and cell viability. Both testosterone and DHT/3-O-carboxymethyloxime (DHT)–BSA increased H2O2-induced OS and cell death, indicating the involvement of an mAR. Furthermore, classical AR antagonists did not block testosterone’s negative effects in an OS environment. Because there are no known antagonists specific for mARs, an AR protein degrader, ASC-J9, was used to block mAR action. ASC-J9 blocked testosterone’s negative effects. To determine OS-related signaling mediated by mAR, this study examined NOX1, NOX2, Gαq. NOX1, NOX2, and the Gαq complex with mAR. Only NOX inhibition blocked testosterone-induced cell loss and OS. No effects of blocking either Gαq or G protein activation were observed on testosterone’s negative effects. These results indicate that androgen-induced OS is via the mAR–NOX complex and not the mAR–Gαq complex.

scholarly journals The Neuroprotective Effect of Zingiber cassumunar Roxb. Extract on LPS-Induced Neuronal Cell Loss and Astroglial Activation within the Hippocampus

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Ratchaniporn Kongsui ◽  
Napatr Sriraksa ◽  
Sitthisak Thongrong
Keyword(s):  
Proinflammatory Cytokine ◽  
Wistar Rats ◽  
Single Injection ◽  
Neuroprotective Effect ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Neuronal Cell Loss ◽  
Male Wistar Rats ◽  
Astroglial Activation ◽  
Zingiber Cassumunar

The systemic administration of lipopolysaccharide (LPS) has been recognized to induce neuroinflammation which plays a significant role in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. In this study, we aimed to determine the protective effect of Zingiber cassumunar (Z. cassumunar) or Phlai (in Thai) against LPS-induced neuronal cell loss and the upregulation of glial fibrillary acidic protein (GFAP) of astrocytes in the hippocampus. Adult male Wistar rats were orally administered with Z. cassumunar extract at various doses (50, 100, and 200 mg/kg body weight) for 14 days before a single injection of LPS (250 μg/kg/i.p.). The results indicated that LPS-treated animals exhibited neuronal cell loss and the activation of astrocytes and also increased proinflammatory cytokine interleukin- (IL-) 1β in the hippocampus. Pretreatment with Z. cassumunar markedly reduced neuronal cell loss in the hippocampus. In addition, Z. cassumunar extract at a dose of 200 mg/kg BW significantly suppressed the inflammatory response by reducing the expression of GFAP and IL-1ß in the hippocampus. Therefore, the results suggested that Z. cassumunar extract might be valuable as a neuroprotective agent in neuroinflammation-induced brain damage. However, further investigations are essential to validate the possible active ingredients and mechanisms of its neuroprotective effect.

A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson’s disease

2020 ◽  
Vol 12 (560) ◽  
pp. eaau3960
Author(s):  
Ibrahim Boussaad ◽  
Carolin D. Obermaier ◽  
Zoé Hanss ◽  
Dheeraj R. Bobbili ◽  
Silvia Bolognin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disorder ◽  
Neuronal Cell ◽  
Exon Skipping ◽  
Cell Loss ◽  
Genetically Engineered ◽  
Neuronal Precursor Cells

Parkinson’s disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic forms of the disease. Using a patient-based in vitro model of PARK7-linked PD, we identified a U1-dependent splicing defect causing a drastic reduction in DJ-1 protein and, consequently, mitochondrial dysfunction. Targeting defective exon skipping with genetically engineered U1-snRNA recovered DJ-1 protein expression in neuronal precursor cells and differentiated neurons. After prioritization of candidate drugs, we identified and validated a combinatorial treatment with the small-molecule compounds rectifier of aberrant splicing (RECTAS) and phenylbutyric acid, which restored DJ-1 protein and mitochondrial dysfunction in patient-derived fibroblasts as well as dopaminergic neuronal cell loss in mutant midbrain organoids. Our analysis of a large number of exomes revealed that U1 splice-site mutations were enriched in sporadic PD patients. Therefore, our study suggests an alternative strategy to restore cellular abnormalities in in vitro models of PD and provides a proof of concept for neuroprotection based on precision medicine strategies in PD.

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