Neuroprotective Strategies in Glaucoma

Gossman, Cynthia A.; Christie, John D.; Webster, Mark K.; Linn, David M.; Linn, Cindy L.

doi:10.2174/1381612822666160128144747

Cited by 16 publications

(11 citation statements)

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“…1 Therefore, glaucoma treatment remains open to genetic and pharmacological neuroprotective therapies, in addition to IOPlowering strategies, to further prevent retinal neuronal loss or delay the disease progression. 2,3 Several studies have implicated neurotrophins and their receptors, particularly the brain-derived neurotrophin factor-tropomyosin receptor kinase B (BDNF/TrkB) signaling pathway, to play a protective role in the RGCs in glaucoma. [4][5][6][7] BDNF is a high-affinity ligand for TrkB, and its ligand-receptor interaction induces TrkB autophosphorylation while promoting phosphatidyl inositol 3 kinase, phospholipase C-g1, and Erk/mitogen-activated protein kinase (MAPK) pathways.…”

Section: Introductionmentioning

confidence: 99%

Loss of Shp2 Rescues BDNF/TrkB Signaling and Contributes to Improved Retinal Ganglion Cell Neuroprotection

et al. 2019

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Glaucoma is characterized by the loss of retinal ganglion cells (RGC), and accordingly the preservation of RGCs and their axons has recently attracted significant attention to improve therapeutic outcomes in the disease. Here, we report that Src homology region 2-containing protein tyrosine phosphatase 2 (Shp2) undergoes activation in the RGCs, in animal model of glaucoma as well as in the human glaucoma tissues and that Shp2 dephosphorylates tropomyosin receptor kinase B (TrkB) receptor, leading to reduced BDNF/TrkB neuroprotective survival signaling. This was elucidated by specifically modulating Shp2 expression in the RGCs in vivo, using adeno-associated virus serotype 2 (AAV2) constructs. Shp2 upregulation promoted endoplasmic reticulum (ER) stress and apoptosis, along with functional and structural deficits in the inner retina. In contrast, loss of Shp2 decelerated the loss of RGCs, preserved their function, and suppressed ER stress and apoptosis in glaucoma. This report constitutes the first identification of Shp2-mediated TrkB regulatory mechanisms in the RGCs that can become a potential therapeutic target in both glaucoma and other neurodegenerative disorders.

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Section: Introductionmentioning

confidence: 99%

Loss of Shp2 Rescues BDNF/TrkB Signaling and Contributes to Improved Retinal Ganglion Cell Neuroprotection

et al. 2019

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“…Neuroprotective treatments were conducted and explored with drugs targeting to inhibit neuroexcitation, reduce oxidative stress, decrease extrinsic or intrinsic apoptosis and deprive of internal neurotrophic factors. Other treatments including stem cell, gene therapy and viral research were also in the process of exploration (24,25). These drugs were unsuccessful in the clinical trials or still in pre-clinical research stage.…”

Section: Discussionmentioning

confidence: 99%

Huperzine A lowers intraocular pressure via the M3 mAChR and provides retinal neuroprotection via the M1 mAChR: a promising agent for the treatment of glaucoma

Yu¹,

Dong²,

Tang³

et al. 2021

Ann Transl Med

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Background: Glaucoma is a neurodegenerative disease that shares similar pathological mechanisms with Alzheimer's disease (AD). Drug treatments for glaucoma increasingly rely upon both lowering of intraocular pressure (IOP) and optic nerve protection, as lowering of IOP alone has been unsatisfactory. Huperzine A (HupA) is an acetylcholinesterase inhibitor (AChEI) used for AD. This study investigated the potential of HupA as a treatment for glaucoma. Methods:The ability of HupA to lower IOP via causing pupil constriction was assessed using New Zealand rabbits. The retinal neuroprotective effects of HupA were assessed in vivo using rat retinas subjected to ischemia-reperfusion (I/R) and in vitro using primary retinal neurons (PRNs) suffering from oxygen-glucose deprivation (OGD).Results: HupA caused pupil constriction in a dose-time dependent manner which was reversed by the nonselective muscarinic acetylcholine receptor (mAChR) antagonist atropine and the selective M3 mAChR antagonist 4-DAMP. However, HupA had no effect on isolated iris muscle tension and calcium flow indicating an indirect M3 mAChR mediated effect. HupA exerted a neuroprotective effect against I/R and OGD to attenuate the retinal pathological lesion, improve retinal neuronal cell viability, reverse oxidative stress injury by increasing GSH levels and SOD activity, and decreasing MDA content and reduce the retinal neuronal apoptosis by decreasing Bax/Bcl-2 ratio and caspase-3 expression with no effect on the calcium flow tests. The effects were abolished by atropine and the selective M1 mAChR antagonist pirenzepine in OGDinduced PRNs suggesting an indirect M1 mAChR-mediated effect via inhibiting AChE activity to increase endogenous ACh level. Furthermore, HupA increased phosphorylated AKT level and decreased the levels of phosphorylated JNK, P38 MAPK and ERK via M1 mAChR antagonists indicating an involvement of activating the M1 mAChR and the downstream AKT/MAPK signaling pathway in the protective effects of HupA.Conclusions: HupA could significantly decrease IOP via activating M3 mAChR indirectly and produce retinal neuroprotective effect through M1 mAChR/AKT/MAPK by increasing endogenous ACh level. These investigations demonstrated that HupA was an effective drug in glaucoma treatment and the clinical

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“…This drug belongs to a new class of Alzheimer's disease medications that inhibits NMDA receptors to counteract the toxic effect of L-glutamate accumulation into the nervous system. It has been shown to strongly reduce RGCs loss in various animal species [79]. Unfortunately, Memantine failed to demonstrate any protective properties in glaucoma patients [80].…”

Section: Neuroprotective Drugsmentioning

confidence: 99%

“…Increased levels of reactive oxygen species (ROS) and associated DNA damage have been reported in glaucoma patients [86]. Numerous pre-clinical studies in glaucoma animal models have shown a neuroprotective benefit for a large variety of anti-oxidant such as Vitamin E, Coenzyme Q10, Ginkgo biloba extract and other Chinese medicines [79]. One clinical trial previously addressed the impact of oral versatile anti-oxidants on glaucoma progression, comparing Ginkgo biloba and α-tocopherol for 3…”

Section: Neuroprotective Drugsmentioning

confidence: 99%

Managing Intraocular Pressure: Innovation in Glaucoma Management

Bleau¹,

Vargas²,

Jiménez³

et al. 2016

Glaucoma - Intraocular Pressure and Aqueous Dynamics

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Primary open-angle glaucoma is a progressive ocular neuropathy that if left untreated may lead to blindness. The main risk factor for developing glaucoma is increased intraocular pressure. Intraocular pressure is regulated by the balance of aqueous humour synthesis and secretion into the eye and outflow from the eye; therefore, most therapies for glaucoma seek lowering intraocular pressure to avoid disease progression. There are several types of drugs in the market for the treatment of glaucoma, but there are still unmet needs to be overcome; therefore, significant effort has been put in the last few years to develop new medicines with innovative mechanisms of action as well as devices to improve quality of life in glaucoma patients. The present review offers a thorough revision of the latest advances in the glaucoma therapy field, focusing on innovative approaches, new targets and new mechanisms of action.

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Neuroprotective Strategies in Glaucoma

Abstract: It is likely that future development for glaucoma treatment will include a combination of these treatments to prevent the pathophysiology of glaucoma.

Cited by 16 publications

References 0 publications

Loss of Shp2 Rescues BDNF/TrkB Signaling and Contributes to Improved Retinal Ganglion Cell Neuroprotection

Loss of Shp2 Rescues BDNF/TrkB Signaling and Contributes to Improved Retinal Ganglion Cell Neuroprotection

Huperzine A lowers intraocular pressure via the M3 mAChR and provides retinal neuroprotection via the M1 mAChR: a promising agent for the treatment of glaucoma

Managing Intraocular Pressure: Innovation in Glaucoma Management

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