scholarly journals Neurovascular Impairment and Therapeutic Strategies in Diabetic Retinopathy

2021 ◽  
Vol 19 (1) ◽  
pp. 439
Author(s):  
Toshiyuki Oshitari
Keyword(s):  
Cell Death ◽  
Diabetic Retinopathy ◽  
Glial Cells ◽  
Vision Loss ◽  
Current Knowledge ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Therapeutic Strategies ◽  
Irreversible Change ◽  
Interdependent Relationships

Diabetic retinopathy has recently been defined as a highly specific neurovascular complication of diabetes. The chronic progression of the impairment of the interdependence of neurovascular units (NVUs) is associated with the pathogenesis of diabetic retinopathy. The NVUs consist of neurons, glial cells, and vascular cells, and the interdependent relationships between these cells are disturbed under diabetic conditions. Clinicians should understand and update the current knowledge of the neurovascular impairments in diabetic retinopathy. Above all, neuronal cell death is an irreversible change, and it is directly related to vision loss in patients with diabetic retinopathy. Thus, neuroprotective and vasoprotective therapies for diabetic retinopathy must be established. Understanding the physiological and pathological interdependence of the NVUs is helpful in establishing neuroprotective and vasoprotective therapies for diabetic retinopathy. This review focuses on the pathogenesis of the neurovascular impairments and introduces possible neurovascular protective therapies for diabetic retinopathy.

scholarly journals Dpp and Hedgehog promote the glial response to neuronal apoptosis in the developing Drosophila visual system

PLoS Biology ◽  
2021 ◽  
Vol 19 (8) ◽  
pp. e3001367
Author(s):  
Sergio B. Velarde ◽  
Alvaro Quevedo ◽  
Carlos Estella ◽  
Antonio Baonza
Keyword(s):  
Cell Death ◽  
Nervous System ◽  
Glial Cell ◽  
Glial Cells ◽  
Neuronal Apoptosis ◽  
Morphological Changes ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Jnk Pathway ◽  
Glial Cell Proliferation

Damage in the nervous system induces a stereotypical response that is mediated by glial cells. Here, we use the eye disc of Drosophila melanogaster as a model to explore the mechanisms involved in promoting glial cell response after neuronal cell death induction. We demonstrate that these cells rapidly respond to neuronal apoptosis by increasing in number and undergoing morphological changes, which will ultimately grant them phagocytic abilities. We found that this glial response is controlled by the activity of Decapentaplegic (Dpp) and Hedgehog (Hh) signalling pathways. These pathways are activated after cell death induction, and their functions are necessary to induce glial cell proliferation and migration to the eye discs. The latter of these 2 processes depend on the function of the c-Jun N-terminal kinase (JNK) pathway, which is activated by Dpp signalling. We also present evidence that a similar mechanism controls glial response upon apoptosis induction in the leg discs, suggesting that our results uncover a mechanism that might be involved in controlling glial cells response to neuronal cell death in different regions of the peripheral nervous system (PNS).

scholarly journals Oncogenic BRAF V600E induces glial proliferation through ERK and neuronal death through JNK

2021 ◽  
Author(s):  
Qing Ye ◽  
Nasser Al-Kuwari ◽  
Pranay Srivast ◽  
Xiqun Chen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Glial Cells ◽  
Primary Cultures ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Braf V600e ◽  
Downstream Effectors ◽  
Mutational Activation

Abstract Background Activating V600E in BRAF is a common driver mutation in cancers of multiple tissue origins, including melanoma and glioma. BRAFV600E has also been implicated in neurodegeneration. The present study aims to characterize BRAFV600E on cell death and survival in three major cell types of the CNS: neurons, astrocytes, and microglia. Methods Multiple primary cultures and cell lines of glial cells and neurons were employed. BRAFV600E as well as BRAFWT expression was mediated by lentivirus or retrovirus. Blockage of downstream effectors were achieved by siRNA. Gene expression data from patients with Parkinson’s disease was analyzed. Results In astrocytes and microglia, BRAFV600E induces cell proliferation, and the proliferative effect in microglia is mediated by activated ERK but not JNK. Conditioned medium from BRAFV600E-expressing microglia induced neuronal cell death. In neuronal cells, BRAFV600E directly induces cell death, through JNK but not ERK. We further show that BRAF-related genes are enriched in pathways in patients with Parkinson’s disease. Conclusions Our study identifies distinct consequences mediated by distinct downstream effectors in dividing glial cells and in neurons following the same BRAF mutational activation and a causal link between BRAF-activated microglia and neuronal cell death that does not require physical proximity. It provides insight into a possibly important role of BRAF in neurodegeneration as a result of either dysregulated BRAF in neurons or its impact on glial cells.

scholarly journals The Pathogenesis and Therapeutic Approaches of Diabetic Neuropathy in the Retina

2021 ◽  
Vol 22 (16) ◽  
pp. 9050
Author(s):  
Toshiyuki Oshitari
Keyword(s):  
Cell Death ◽  
Diabetic Retinopathy ◽  
Diabetic Neuropathy ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Axon Degeneration ◽  
Diabetic Patients ◽  
Therapeutic Approaches

Diabetic retinopathy is a major retinal disease and a leading cause of blindness in the world. Diabetic retinopathy is a neurovascular disease that is associated with disturbances of the interdependent relationship of cells composed of the neurovascular units, i.e., neurons, glial cells, and vascular cells. An impairment of these neurovascular units causes both neuronal and vascular abnormalities in diabetic retinopathy. More specifically, neuronal abnormalities including neuronal cell death and axon degeneration are irreversible changes that are directly related to the vision reduction in diabetic patients. Thus, establishment of neuroprotective and regenerative therapies for diabetic neuropathy in the retina is an emergent task for preventing the blindness of patients with diabetic retinopathy. This review focuses on the pathogenesis of the neuronal abnormalities in diabetic retina including glial abnormalities, neuronal cell death, and axon degeneration. The possible molecular cell death pathways and intrinsic survival and regenerative pathways are also described. In addition, therapeutic approaches for diabetic neuropathy in the retina both in vitro and in vivo are presented. This review should be helpful for providing clues to overcome the barriers for establishing neuroprotection and regeneration of diabetic neuropathy in the retina.

scholarly journals Oncogenic BRAF V600E induces glial proliferation through ERK and neuronal death through JNK

2021 ◽  
Author(s):  
Qing Ye ◽  
Nasser Al-Kuwari ◽  
Pranay Srivast ◽  
Xiqun Chen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Glial Cells ◽  
Primary Cultures ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Braf V600e ◽  
Downstream Effectors ◽  
Mutational Activation

Abstract Background: Activating V600E in BRAF is a common driver mutation in cancers of multiple tissue origins, including melanoma and glioma. BRAF V600E has also been implicated in neurodegeneration. The present study aims to characterize BRAF V600E on cell death and survival in three major cell types of the CNS: neurons, astrocytes, and microglia. Methods : Multiple primary cultures and cell lines of glial cells and neurons were employed. BRAF V600E as well as BRAF WT expression was mediated by lentivirus or retrovirus. Blockage of downstream effectors were achieved by siRNA. Gene expression data from patients with Parkinson’s disease was analyzed. Results : In astrocytes and microglia, BRAF V600E induces cell proliferation, and the proliferative effect in microglia is mediated by activated ERK but not JNK. Conditioned medium from BRAF V600E -expressing microglia induced neuronal cell death. In neuronal cells, BRAF V600E directly induces cell death, through JNK but not ERK. We further show that BRAF-related genes are enriched in pathways in patients with Parkinson’s disease. Conclusions : Our study identifies distinct consequences mediated by distinct downstream effectors in dividing glial cells and in neurons following the same BRAF mutational activation and a causal link between BRAF-activated microglia and neuronal cell death that does not require physical proximity. It provides insight into a possibly important role of BRAF in neurodegeneration as a result of either dysregulated BRAF in neurons or its impact on glial cells.

scholarly journals Pemafibrate prevents retinal neuronal cell death in NMDA-induced excitotoxicity via inhibition of p-c-Jun expression

2020 ◽  
Author(s):  
Naoki Fujita ◽  
Kana Sase ◽  
Chihiro Tsukahara ◽  
Ibuki Arizono ◽  
Hitoshi Takagi ◽  
...  
Keyword(s):  
Cell Death ◽  
Diabetic Retinopathy ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Oral Intake ◽  
Peroxisome Proliferator ◽  
Retinal Ganglion ◽  
Peroxisome Proliferator Activated Receptor ◽  
Apoptotic Effect ◽  
Male Wistar Rats

AbstractExcitotoxicity is involved in the retinal neuronal cell death in diabetic retinopathy. Although fenofibrate has been shown to ameliorate the progression of diabetic retinopathy, the effect of pemafibrate, which is highly selective for peroxisome proliferator-activated receptor α on retinal neuronal cell death has not been documented. Here, we investigated whether pemafibrate exerts a beneficial effect against retinal ganglion cell (RGC) death induced by N-methyl-D-aspartate (NMDA) in rats. Experiments were performed on adult male Wistar rats that received an intravitreal injection of 20 nmol NMDA. Fluoro-Gold labeled RGC morphometry showed that oral intake of pemafibrate once a day for 7 days resulted in significant protection on RGC death induced by NMDA. Phosphorylated c-Jun protein, which is involved in apoptosis, was upregulated after NMDA exposure, and this increase was significantly lessened by the systemic pemafibrate treatment. Phosphorylated c-Jun immunopositive cells were colocalized with Thy-1 immunopositive cells, and the increased these cells were ameliorated by the pemafibrate treatment. An increase in TUNEL-positive cells was significantly suppressed by the pemafibrate treatment. Phosphorylated c-Jun immunopositive cells were colocalized with TUNEL-positive cells, and they were decreased by pemafibrate treatment. These results suggest that the RGC protection achieved with pemafibrate appears to be associated with inhibition of phosphorylated c-Jun and its anti-apoptotic effect.

scholarly journals GLP-1R agonist NLY01 reduces retinal inflammation, astrocyte reactivity, and retinal ganglion cell death secondary to ocular hypertension

2020 ◽  
Author(s):  
Jacob K. Sterling ◽  
Modupe Adetunji ◽  
Samyuktha Guttha ◽  
Albert Bargoud ◽  
Katherine Uyhazi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Vision Loss ◽  
Ganglion Cells ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Retinal Ganglion ◽  
Tnf Α ◽  
Glucagon Like Peptide 1

SUMMARYGlaucoma is the leading cause of irreversible blindness worldwide and is characterized by the death of retinal ganglion cells. Reduction of intraocular pressure (IOP) is the only therapeutic mechanism available to slow disease progression. However, glaucoma can continue to progress despite normalization of IOP. New treatments are needed to reduce vision loss and improve outcomes for patients who have exhausted existing therapeutic avenues. Recent studies have implicated neuroinflammation in the pathogenesis of neurodegenerative diseases of both the retina and the brain, including glaucoma and Parkinson’s disease. Pro-inflammatory A1 astrocytes contribute to neuronal cell death in multiple disease processes and have been targeted therapeutically in mouse models of Parkinson’s disease. Microglial release of pro-inflammatory cytokines C1q, IL-1α, and TNF-α is sufficient to drive the formation of A1 astrocytes. The role of A1 astrocytes in glaucoma pathogenesis has not been explored. Using a mouse model of glaucoma, we demonstrated that IOP elevation was sufficient to trigger production of C1q, IL-1α, and TNF-α by infiltrating macrophages followed by resident microglia. These three cytokines drove the formation of A1 astrocytes in the retina. Furthermore, cytokine production and A1 astrocyte transformation persisted following IOP normalization. Ablation of this pathway, by either genetic deletions of C1q, IL-1α, and TNF-α, or treatment with glucagon-like peptide-1 receptor agonist NLY01, reduced A1 astrocyte transformation and RGC death. Together, these results highlight a new neuroinflammatory mechanism behind glaucomatous neurodegeneration that can be therapeutically targeted by NLY01 administration.

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