Neuroprotection, Growth Factors and BDNF-TrkB Signalling in Retinal Degeneration

Kimura, Atsuko; Namekata, Kazuhiko; Guo, Xiaoli; Harada, Chikako; Harada, Takayuki

doi:10.3390/ijms17091584

Cited by 158 publications

(136 citation statements)

References 148 publications

(174 reference statements)

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“…These included, besides CDKN2A and CDKN2B , developmentally relevant genes, CDKN1B , FGF2 , SOX11 , FOS , JUNB , STAT1 , STAT3 , VEGF , BDNF , SCNG, and ATF3 . Of these, the majority is involved in RGC development/survival/regeneration such as FGF2 , SOX11 , SNCG , STAT3 , VEGF , BDNF , and ATF3 . Other common genes included CEBPB , CP , FAS , EDNRB , ANXA1 , NEFL , TP53 , TXN , TXN2 , TBK1 , SOD1 , and OPTN .…”

Section: Resultsmentioning

confidence: 99%

Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities

et al. 2017

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Glaucoma represents a group of multifactorial diseases with a unifying pathology of progressive retinal ganglion cell (RGC) degeneration, causing irreversible vision loss. To test the hypothesis that RGCs are intrinsically vulnerable in glaucoma, we have developed an in vitro model using the SIX6 risk allele carrying glaucoma patient-specific induced pluripotent stem cells (iPSCs) for generating functional RGCs. Here, we demonstrate that the efficiency of RGC generation by SIX6 risk allele iPSCs is significantly lower than iPSCs-derived from healthy, age- and sex-matched controls. The decrease in the number of RGC generation is accompanied by repressed developmental expression of RGC regulatory genes. The SIX6 risk allele RGCs display short and simple neurites, reduced expression of guidance molecules, and immature electrophysiological signature. In addition, these cells have higher expression of glaucoma-associated genes, CDKN2A and CDKN2B, suggesting an early onset of the disease phenotype. Consistent with the developmental abnormalities, the SIX6 risk allele RGCs display global dysregulation of genes which map on developmentally relevant biological processes for RGC differentiation and signaling pathways such as mammalian target of rapamycin that integrate diverse functions for differentiation, metabolism, and survival. The results suggest that SIX6 influences different stages of RGC differentiation and their survival; therefore, alteration in SIX6 function due to the risk allele may lead to cellular and molecular abnormalities. These abnormalities, if carried into adulthood, may make RGCs vulnerable in glaucoma. Stem Cells 2017;35:2239-2252.

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Section: Resultsmentioning

confidence: 99%

Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities

et al. 2017

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“…For example, neurotrophins, such as brain-derived neurotrophic factor and ciliary neurotrophic factor, protect retinal RGCs in an ONI model. [4][5][6] Also, inhibitors of glutamate receptors, tumor necrosis factor receptors, and nitric oxide synthase may be effective for RGC protection. …”

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confidence: 99%

Edaravone Prevents Retinal Degeneration in Adult Mice Following Optic Nerve Injury

Akiyama

Azuchi

Guo

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.To assess the therapeutic potential of edaravone, a free radical scavenger that is used for the treatment of acute brain infarction and amyotrophic lateral sclerosis, in a mouse model of optic nerve injury (ONI).METHODS. Two microliters of edaravone (7.2 mM) or vehicle were injected intraocularly 3 minutes after ONI. Optical coherence tomography, retrograde labeling of retinal ganglion cells (RGCs), histopathology, and immunohistochemical analyses of phosphorylated apoptosis signal-regulating kinase-1 (ASK1) and p38 mitogen-activated protein kinase (MAPK) in the retina were performed after ONI. Reactive oxygen species (ROS) levels were assessed with a CellROX Green Reagent.RESULTS. Edaravone ameliorated ONI-induced ROS production, RGC death, and inner retinal degeneration. Also, activation of the ASK1-p38 MAPK pathway that induces RGC death following ONI was suppressed with edaravone treatment. CONCLUSIONS.The results of this study suggest that intraocular administration of edaravone may be a useful treatment for posttraumatic complications.Keywords: edaravone, oxidative stress, neuroprotection, ASK1, retinal ganglion cell T raumatic optic neuropathy is a common clinical problem that occurs in 0.5% to 5% of patients with closed head injury.1 Damage to the optic nerve induces secondary swelling within the optic canal, accompanied by subsequent retinal ganglion cell (RGC) loss and optic nerve atrophy.2 Although no large natural history or randomized controlled trials have been published, corticosteroid therapy and optic canal decompression surgery are not considered to be effective for patients with traumatic optic neuropathy.3 Research into finding therapeutic targets for treatment of traumatic optic neuropathy indicated that neuroprotection might be an effective strategy and studies using an optic nerve injury (ONI) model in rodents have provided useful information. For example, neurotrophins, such as brain-derived neurotrophic factor and ciliary neurotrophic factor, protect retinal RGCs in an ONI model. [4][5][6] Also, inhibitors of glutamate receptors, tumor necrosis factor receptors, and nitric oxide synthase may be effective for RGC protection. 7-11The ONI model mimics some aspects of glaucoma, including RGC death induced by oxidative stress, and therefore, it is also a useful animal model for glaucoma.Edaravone is a free radical scavenger that has been used clinically to treat acute brain infarction and amyotrophic lateral sclerosis (ALS). Edaravone quenches hydroxyl radicals ( Á OH) and inhibits lipid peroxidation dependent and independent of Á OH. 12,13 In an in vitro cell culture study using the RGC-5 to study the neurobiology of RGCs, edaravone scavenged the intracellular Á OH, superoxide anion (O 2 ÀÁ ), and hydrogen peroxide (H 2 O 2 ) while demonstrating the strongest scavenging activity against14 Recent studies have shown that oxidative stress plays an important role in many ocular diseases including glaucoma. [15][16][17][18] Interestingly, edaravone attenuates retinal ischemia/reperfusion ...

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“…Brain‐derived neurotrophic factor (BDNF) is a neurotrophic factor and exists widely in the central nervous system (CNS), such as the hippocampus and cortex . BDNF plays crucial roles in survival, development, differentiation, and proliferation of brain neurons and repairs of injured nerve cells, which is mediated by the high‐affinity tropomysin‐related kinase B (TrkB) receptor . It has been reported that serum BDNF level is significantly low in depressed and diabetic patients and negatively correlated with the risk of depression .…”

Section: Introductionmentioning

confidence: 99%

“…development, differentiation, and proliferation of brain neurons and repairs of injured nerve cells, 7,8 which is mediated by the high-affinity tropomysin-related kinase B (TrkB) receptor. 9 It has been reported that serum BDNF level is significantly low in depressed and diabetic patients and negatively correlated with the risk of depression.…”

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confidence: 99%

BDNF‐TrkB pathway mediates antidepressant‐like roles of H₂S in diabetic rats via promoting hippocampal autophagy

Liu

Wei

et al. 2019

Clin Exp Pharma Physio

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Hydrogen sulfide (H2S) plays antidepressant‐like roles in diabetic rats. However, the underlying mechanisms remain unclear. Brain‐derived neurotropic factor (BDNF), a neurotrophic factor, plays important regulatory roles in depression by its high‐affinity tropomysin‐related kinase B (TrkB) receptor. Autophagy also is implicated in modulation of depression. Previous work confirmed the modulatory roles of H2S in BDNF protein expression and autophagy. Thus, in this study, we explored whether the BDNF‐TrkB pathway mediates the antidepressant‐like effects of H2S in diabetic rats and whether this process is achieved via promoting hippocampal autophagy. We demonstrated that H2S upregulated the expressions of BDNF and p‐TrkB proteins in the hippocampus of streptozotocin (STZ)‐induced diabetic rats. K252a (an inhibitor of BDNF‐TrkB pathway) reversed the antidepressant‐like roles of H2S, as evidenced by the tail suspension, forced swimming, novelty suppressed feeding, and elevated plus‐maze tests. Furthermore, K252a abolished H2S‐promoted hippocampal autophagy in diabetic rats, as evidenced by a decrease in the number of autolysosome, downregulation of Beclin‐1 (a regulator of autophagy in the early stage of the formation of autophagosomal membranes and its level is positively correlated with autophagic activity) expression, and upregulation of P62 (a substrate of autophagic degradation and its level is inversely correlated with autophagic activity) expression, in the hippocampus of rats co‐treated with NaHS and STZ. Taken together, these data indicated that the BDNF‐TrkB pathway mediates the antidepressant‐like roles of H2S in diabetic rats by enhancing hippocampal autophagy.

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Neuroprotection, Growth Factors and BDNF-TrkB Signalling in Retinal Degeneration

Cited by 158 publications

References 148 publications

Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities

Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities

Edaravone Prevents Retinal Degeneration in Adult Mice Following Optic Nerve Injury

BDNF‐TrkB pathway mediates antidepressant‐like roles of H₂S in diabetic rats via promoting hippocampal autophagy

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Neuroprotection, Growth Factors and BDNF-TrkB Signalling in Retinal Degeneration

Cited by 158 publications

References 148 publications

Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities

Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities

Edaravone Prevents Retinal Degeneration in Adult Mice Following Optic Nerve Injury

BDNF‐TrkB pathway mediates antidepressant‐like roles of H2S in diabetic rats via promoting hippocampal autophagy

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BDNF‐TrkB pathway mediates antidepressant‐like roles of H₂S in diabetic rats via promoting hippocampal autophagy