scholarly journals Diabetes Accelerates Retinal neuronal cell Death in A Mouse Model of endogenous Hyperhomocysteinemia

2009 ◽  
Vol 1 ◽  
pp. OED.S2855 ◽  
Author(s):  
Preethi S. Ganapathy ◽  
Penny Roon ◽  
Tracy K.V.E. Moister ◽  
Barbara Mysona ◽  
Sylvia B. Smith
Keyword(s):  
Neuronal Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Plasma Homocysteine ◽  
Retinal Ganglion ◽  
Neuronal Cell Loss ◽  
Onset Of Diabetes ◽  
Plexiform Layers ◽  
Post Onset

Hyperhomocysteinemia has been implicated in visual dysfunction. We reported recently that mice with endogenous hyperhomocysteinemia, due to mutation of the cystathionine-β-synthase ( cbs) gene, demonstrate loss of neurons in the retinal ganglion cell (RGC) layer and other retinal layers as homocysteine levels increase. Some clinical studies implicate hyperhomocysteinemia in the pathogenesis of diabetic retinopathy, which is also characterized by RGC loss. The present study used cbs+/– mice to determine whether modest elevation of plasma homocysteine, in the presence of diabetes, accelerates neuronal cell loss. Diabetes (DB) was induced in 3 wk old cbs+/– and wildtype mice using streptozotocin; four groups of mice were studied: DB cbs+/– non-DB cbs+/– DB cbs+/+; non-DB cbs+/+. One group of diabetic cbs+/– mice was maintained on a high methionine diet (HMD, 0.5% methionine drinking water) to increase plasma homocysteine slightly. Eyes were harvested at 5, 10 and 15 weeks post-onset of diabetes; retinal cryosections were examined by light microscopy and subjected to systematic morphometric analysis. Diabetic cbs+/– had significantly fewer RGCs at 5 weeks compared to age-matched, non-diabetic cbs+/– and wildtype controls (10.0 ± 0.5 versus 14.9 ± 0.5 and 15.8 ± 0.6 cells/100 μm retina length, respectively). Significant differences in retinas of DB/high homocysteine versus controls were obtained 15 wks post-onset of diabetes including fewer RGCS and decreased thickness of inner nuclear and plexiform layers. Moderate increases in plasma homocysteine coupled with diabetes cause a more dramatic alteration of retinal phenotype than elevated homocysteine or diabetes alone and suggest that diabetes accelerates the retinal neuronal death in hyperhomocysteinemic mice.

scholarly journals Numb reduces Tau levels and prevents neurodegeneration in mouse models of tauopathy in an isoform-specific manner

2021 ◽  
Author(s):  
Marine Lacomme ◽  
Sarah C. Hales ◽  
Katarina Stevanovic ◽  
Christine Jolicoeur ◽  
Therence Bois ◽  
...  
Keyword(s):  
Mouse Models ◽  
Ganglion Cells ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Adaptor Protein ◽  
Cell Loss ◽  
Retinal Ganglion ◽  
Extracellular Release ◽  
Health And Disease

ABSTRACTAccumulation of the microtubule-associated protein Tau is linked to neuronal cell death in tauopathies, but how exactly intraneuronal Tau levels are regulated in health and disease remains unclear. Here we identify the trafficking adaptor protein Numb as an essential regulator of Tau homeostasis. Conditional inactivation of Numb in retinal ganglion cells (RGCs) increases monomeric and oligomeric Tau levels, leading to axonal blebbing followed by neuronal cell loss in aged mice. Moreover, in a mouse model of tauopathy, inactivation of Numb in RGCs and spinal motoneurons accelerates neurodegeneration, and leads to precocious hindlimb paralysis. Conversely, overexpression of the long isoform of Numb (Numb-72), but not other isoforms, decreases intracellular Tau levels by promoting the extracellular release of monomeric Tau, and AAV-mediated delivery of Numb-72 in RGCs in vivo prevents neurodegeneration in two different mouse models of tauopathy. Taken together, these results uncover Numb as a modulator of intracellular Tau levels and identify Numb-72 as a novel therapeutic factor for tauopathies.

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 Effects of Transient Receptor Potential Cation 5 (TRPC5) Inhibitor, NU6027, on Hippocampal Neuronal Death after Traumatic Brain Injury

2020 ◽  
Vol 21 (21) ◽  
pp. 8256 ◽  
Author(s):  
Min Kyu Park ◽  
Bo Young Choi ◽  
A Ra Kho ◽  
Song Hee Lee ◽  
Dae Ki Hong ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neuronal Death ◽  
Transient Receptor Potential ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Treated Group ◽  
Therapeutic Window ◽  
Permanent Disability ◽  
Fluoro Jade B

Traumatic brain injury (TBI) can cause physical, cognitive, social, and behavioral changes that can lead to permanent disability or death. After primary brain injury, translocated free zinc can accumulate in neurons and lead to secondary events such as oxidative stress, inflammation, edema, swelling, and cognitive impairment. Under pathological conditions, such as ischemia and TBI, excessive zinc release, and accumulation occurs in neurons. Based on previous research, it hypothesized that calcium as well as zinc would be influx into the TRPC5 channel. Therefore, we hypothesized that the suppression of TRPC5 would prevent neuronal cell death by reducing the influx of zinc and calcium. To test our hypothesis, we used a TBI animal model. After the TBI, we immediately injected NU6027 (1 mg/kg, intraperitoneal), TRPC5 inhibitor, and then sacrificed animals 24 h later. We conducted Fluoro-Jade B (FJB) staining to confirm the presence of degenerating neurons in the hippocampal cornus ammonis 3 (CA3). After the TBI, the degenerating neuronal cell count was decreased in the NU6027-treated group compared with the vehicle-treated group. Our findings suggest that the suppression of TRPC5 can open a new therapeutic window for a reduction of the neuronal death that may occur after TBI.

scholarly journals Overexpression of Mitochondrial Calcium Uniporter Causes Neuronal Death

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Veronica Granatiero ◽  
Marco Pacifici ◽  
Anna Raffaello ◽  
Diego De Stefani ◽  
Rosario Rizzuto
Keyword(s):  
Cell Fate ◽  
Neuronal Death ◽  
Cortical Neurons ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Neuronal Loss ◽  
Calcium Uniporter ◽  
Organelle Morphology

Neurodegenerative diseases are a large and heterogeneous group of disorders characterized by selective and progressive death of specific neuronal subtypes. In most of the cases, the pathophysiology is still poorly understood, although a number of hypotheses have been proposed. Among these, dysregulation of Ca2+ homeostasis and mitochondrial dysfunction represent two broadly recognized early events associated with neurodegeneration. However, a direct link between these two hypotheses can be drawn. Mitochondria actively participate to global Ca2+ signaling, and increases of [Ca2+] inside organelle matrix are known to sustain energy production to modulate apoptosis and remodel cytosolic Ca2+ waves. Most importantly, while mitochondrial Ca2+ overload has been proposed as the no-return signal, triggering apoptotic or necrotic neuronal death, until now direct evidences supporting this hypothesis, especially in vivo, are limited. Here, we took advantage of the identification of the mitochondrial Ca2+ uniporter (MCU) and tested whether mitochondrial Ca2+ signaling controls neuronal cell fate. We overexpressed MCU both in vitro, in mouse primary cortical neurons, and in vivo, through stereotaxic injection of MCU-coding adenoviral particles in the brain cortex. We first measured mitochondrial Ca2+ uptake using quantitative genetically encoded Ca2+ probes, and we observed that the overexpression of MCU causes a dramatic increase of mitochondrial Ca2+ uptake both at resting and after membrane depolarization. MCU-mediated mitochondrial Ca2+ overload causes alteration of organelle morphology and dysregulation of global Ca2+ homeostasis. Most importantly, MCU overexpression in vivo is sufficient to trigger gliosis and neuronal loss. Overall, we demonstrated that mitochondrial Ca2+ overload is per se sufficient to cause neuronal cell death both in vitro and in vivo, thus highlighting a potential key step in neurodegeneration.

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.

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