＊Correspondence to:Najam A. Sharif, Ph.D.,FARVO, FBPhS,najam.sharif@santen.com.

orcid:0000-0002-4432-730X(Najam A. Sharif)

doi: 10.4103/1673-5374.235017

Accepted: 2018-04-28

Introduction to Glaucoma and Ocular Hypertension

The blinding diseases known as “glaucoma” comprise several different forms of optic neuropathies with diverse and complex etiologies. Primary open-angle glaucoma (POAG)is the most common type and is estimated to affect ＞ 80 million people by 2020 (Tham et al. 2014). As with most forms of glaucoma, including normotensive glaucoma (NTG) and pseudo-exfoliation glaucoma (PEXG), POAG is painless and can remain undetected and undiagnosed for decades.POAG, PEXG and NTG develop slowly and their pathology involves defects at multiple locations within the eye-brain visual axes (Figure 1; Weinreb et al., 2014). Whilst the disease-initiating factor(s) remains elusive, it has been chronicled that damage to the retinal ganglion cell (RGC) axons that form the optic nerve causes retrograde and anterograde demise of the corresponding RGC bodies. It is possible that the RGCs themselves are simultaneously and deleteriously impacted by their environment that may contain low oxygen, depleted energy sources, and high levels of damaging neurotoxins and in fl ammatory cytokines (Ito and Di Polo,2017). Over time, the RGC axons dissociate from the brain lateral geniculate nucleus (LGN) and superior colliculus (SC)(Yucel et al., 2000). Since the outermost layer of RGCs in the retina are initially the most susceptible to the damaging effects of various mechanical and chemical insults, they die fi rst. Thus, initially the patient’s peripheral vision is diminished followed by gradual but progressive loss of central vision, culminating in total irreversible blindness (Weinreb et al., 2014). Early diagnosis and initiation of treatment are therefore pivotal to preserving vision in POAG and to reduce the harmful effects of this glaucomatous optic neuropathy (GON) on the patient’s quality of life. Unfortunately,since the disease is asymptomatic, the earliest manifestation of visual impairment for the POAG patient occurs when almost half of the total 1 million RGCs have died and the patient begins to notice visual disturbances such as patchy dark visual images, distorted and incomplete images and/or“tunnel vision” (Crabb, 2016). Therapeutic intervention now becomes critical to delay and prevent the loss of additional RGCs and preserve the remaining visual apparatus, thereby preserving the RGC axons and thus reducing the impact on the structure and function of the optic nerve (Figure 2).

Years of basic and clinical research have finally yielded some clues as to what may be happening in the eyes of the POAG patients. Intraocular pressure (IOP) is determined by the drainage of aqueous humor (AQH) from the anterior chamber of the eye via the trabecular meshwork (TM), and in POAG patients, the TM cells can become dysfunctional and congested, interfering with proper fl ow of AQH through the TM. This can cause an increase in (IOP), which epidemiological and pathological studies have shown to be the most damaging risk factor associated with POAG. However, poor ocular blood perfusion (Pasquale, 2016), low inter-cranial and cerebrospinal fl uid pressure (CSF) (Jonas et al., 2015), advancing age, and genetics (Aung and Khor, 2016; Danford et al., 2017) also play a part in the disease process. The sequence of these destructive events, that also include heightened TM and RGC apoptosis, and the relative severity of their impact may be patient-dependent, but it is clear that a multitude of factors conspire to undermine the RGCs and their axons leading to their degeneration, dysfunction and demise (Weinreb et al., 2014; Sharif, 2018).

The elevated IOP causes mechanical distortion and stretching of the unmyelinated RGC axons at the lamina cribosa (LC), where they exit the globe to form the optic nerve(Figure 2; Danford et al., 2017). This appears to involve release of matrix metalloproteinases (MMPs) that digest and weaken the LC tissue leading to further bending and stretching of the optic nerve and the associated retinal blood vessels at the back of the eye (Hollander et al., 1995; Xu et al., 2014).The spaces previously occupied by neurons are invaded by glial cells that form a fibrotic scar over time. The ensuing ischemia and local hypoxia causes production of reactive oxygen species, aglycemia, activation of complement system(Tezel et al., 2010), inflammasome activation (Chi et al.,2014), and reduced axonal flow of mitochondria and neurotrophic factors to-and-from the brain LGN/SC and RGC somas (Quigley et al., 2000). As the mitochondrial energy stores diminish (Thomas et al., 2000; Osborne et al., 2014;Li et al., 2015), the LC and RGC cellular machinery maintaining homeostasis becomes dysfunctional (McElnea et al., 2011) and the somal and axonal demise begins. The net effect of these events is the death of some of the RGCs and their neighboring retinal neurons, resulting in the release of their cytoplasmic contents into the extracellular space. Consequently, large amounts of glutamate, ATP, endothelin, and preformed inflammatory cytokines such a tumor necrosis factor-α and numerous interleukins begin bathing the retinal neurons. The ensuing in fl ammation, excitotoxicity and the prevalent oxidative stress conditions induce senescence of even more RGCs and interneurons, and the vicious cycle continues unabated unless the patient receives suitable treatment(s). The various mechanical, chemical, bioenergetic and local environmental conditions/insults that appear involved in the etiology of POAG/ocular hypertension (OHT)-induced GON are pictorially depicted in Figures 1 and 2 (Nickells et al., 2012) Fortuitously, these areas provide suitable points of therapeutic intervention in order to preserve sight and prevent, or at least slow down, visual impairment in OHT/POAG patients (Jonas et al., 2017; Sharif, 2018).

Drug Treatment Options for OHT and Glaucoma

What constitutes the current and future treatment options for the patients afflicted with POAG and OHT, and how may damage to the optic nerve and its components be prevented to help preserve vision? This is a complex problem since many elements are involved in the pathophysiology of the disease process. As elevated (IOP) appears most intimately associated with POAG, clinical medicine has focused on lowering IOP as the fi rst step. Unfortunately, since even normalizing IOP doesn’t stop the ravages of GON, and as ocular normotensive patients’ vision still continues to deteriorate, it has become abundantly clear that direct protection of the RGCs and their axons is also necessary in addition to reducing the OHT. Nevertheless, since every 1 mm Hg IOP-lowering results in 10-13% reduction in progression of POAG, it is important to address elevated IOP in the context of glaucoma optic nerve changes immediately. Pharmacotherapy to treat and lower elevated IOP has constituted drugs to reduce the production of AQH (e.g., carbonic anhydrase inhibitors [CAIs: dorzolamide; brinzolamide]; beta-blockers [e.g., timolol; betaxolol]; α2-adrenergic agonists[e.g., apraclonidine and brimonidine]), and agents that stimulate AQH out fl ow through the trabecular meshwork (TM)[conventional out fl ow] (e.g., pilocarpine; brimonidine), and the mainstay fi rst-line uveoscleral out fl ow stimulator drugs(e.g., FP-receptor agonists latanoprost; travoprost; ta fl uprost)(Sharif, 2017). Unfortunately, all these drugs have signi fi cant ocular and/or systemic side-effects (e.g., stinging, burning,ocular allergy, hyperemia, iris color changes, lethargy, pulmonary and cardiovascular insufficiency, and/or short duration of action) that lead to signi fi cant patient non-compliance in administering their eye-drop medicines (Weinreb et al., 2014;Jonas et al., 2017; Sharif, 2017). Whilst certain long-term drug delivery approaches and microsurgeries coupled with AQH drainage shunts may help address the compliance issues,novel drugs that offer longer duration of action, higher potency and efficacy, perhaps involving multiple mechanisms of action, are thus urgently needed. Certain IOP-lowering combination products (e.g., a CAI + a β-blocker + an α2-agonist;Hollo et al., 2014) have partially filled this gap temporarily,but since ocular hypotensive agents alone may be insufficient to combat GON, multi-pharmacophoric drugs with poly-pharmacological properties (including cyto-axon-protective agents) will ultimately be needed to stem the tide of GON damage and to preserve the optic nerve and vision.

Some of the latter features (dual pharmacophoric activities) appear to be present in two recently FDA-approved novel drugs, namely netarsudil 0.02% (Rhopressa®; Serle et al., 2018) and latanoprostene bunod 0.024% (Vyzulta®;Weinreb et al., 2018). Thus, netarsudil inhibits rho kinase and norepinephrine transporter--it relaxes the TM and Schlemm’s canal (SC) cells (thereby helping AQH to drain via the conventional pathway), and it inhibits Na+/K+-ATPase in the ciliary epithelial cells thereby inhibiting AQH production and lowering IOP. In a similar vein, latanoprostene bunod releases latanoprost free acid (LFA) and nitric oxide (NO)--the FP-receptors in ciliary muscle and TM are activated by LFA to cause local release of MMPs that digest extracellular matrix (ECM) to create/enlarge the UVS outflow pathway and promote AQH drainage from both the UVS and TM/SC pathways, while the NO activates soluble guanylate cyclase in TM/SC cells (Dismuke et al., 2009,2010) that produces cGMP that relaxes TM/SC cells and enhances conventional out fl ow of AQH. Netarsudil also offers the possibility of adjunctive therapy to further enhance the IOP-lowering activity by combining it with FP-receptor prostaglandin agonist analogs (PGAs) such as latanoprost(Lewis et al., 2016). Indeed, such studies have been conducted in POAG/OHT patients and the results are encouraging for this novel formulation containing both netarsudil and latanoprost (Roclatan™) (Lewis et al., 2016).

Devices and Novel Approaches to Combat OHT and Glaucoma

Since some patients do not respond well to PGAs, in particular to latanoprost, and to other drugs and their IOPs remain higher than desired, such glaucoma patients may be good candidates to receive the AQH drainage devices implanted in the anterior chambers of their eyes. These drainage implants extrude excess AQH down the conventional outflow pathway, into the suprachoroidal space or subconjunctival or into sub-tenon space. Indeed, such novel AQH drainage devices(e.g., iStent; XEN Gel Stent; CyPass Microshunt; Hydrus Microshunt; InnFocus Microshunt) (Batlle et al. 2016; Pillunat et al., 2018) represent some of the most innovative advances in treating OHT/POAG. These devices are already making a big difference in the clinical setting in the management of these disorders by providing long-term ocular hypotensive activity and control of IOP. Some of these novel tools are able to bring the IOP down to 10–13 mmHg and keep it lowered over a 3-year period, which is remarkable efficacy (Batlle et al. 2016; Pillunat et al., 2018). Similarly, the ability of corneal endothelial cells transfected with vectors that continuously release small amounts of endogenous MMPs to digest away ECM accumulated in the TM/SC cells to enhance out fl ow of AQH appears very exciting (O’Callagan et al., 2017). At any rate, based on the currently reported efficacy of the drainage devices in POAG/OHT patients, lowering IOP down to 10–14 mmHg and maintaining this for multiple years, there may come a time when anti-glaucoma eyedrop medications may be replaced by AQH microshunts and gene therapy in the Western world. Revolutionary as this may appear, patients’continued poor compliance with topically delivered IOP-decreasing drugs may necessitate these advances.

Poor translation of laboratory-based efficacy studies of GON to the clinical setting occurs for numerous reasons.First and most importantly, in the animal models the RGC/optic nerve head (ONH)/RGC axon-damaging insult (e.g.,high IOP or cytokine or neurotoxic agent injection) used to recapitulate the human disease processes is singular in nature and often an acute one, whereas in the human disease progression at multiple retinal and axonal dysfunctions occur simultaneously and in a chronic manner. Secondly,only a single presumed therapeutic agent is tested against a single ocular insult, and it is administered prior to or during the induced damage, whereas in the human situation the damage has been ongoing for a protracted period of time.Thirdly, in POAG patients with chronically elevated IOP, a signi fi cant number of retinal neurons have died, and other RGC bodies and axons may be beyond rescue. Other reasons of clinical failure of neuroprotective agents that show efficacy in vitro and in animals encompass issues of metabolic and or chemical instability of the drugs when administered over long periods of time, drug formulation/delivery/bioavailability, lack of attainment of therapeutic concentration of the drug at target tissues/cells, and unacceptable systemic,central and local ocular side-effects. Obviously, the multifactorial aspects and chronic nature of GON/POAG/OHT disease (Figure 1) also makes it difficult to mitigate the disease processes. Consequently, only a combinatorial amalgam of numerous different classes of drugs targeting different intervention points of the pathological cascade may be necessary to combat the symptoms associated with the optic and brain neuropathies.

Con fl icts of interest: None declared.

Drugs, Electroceuticals, Cell and GeneTherapy as Soma-Axonal Rescue Strategies

降水天气多或降水强度大的地区应注意及时排涝，避免或减轻农田渍涝和作物倒伏对产量形成的不利影响;青海东部、河套地区、内蒙古东部、东北地区西部等地因地制宜做好蓄水保水工作。

Another paradigm shift on the horizon for lowering and controlling IOP involves ability of sustained drug delivery platforms (Barar et al., 2016; Hartman and Kompella, 2018).Included amongst the technologies to enhance patient adherence are: drug-coated contact lenses, PGA-containing silicone insert that encircles the eyeball (Brandt et al., 2017), intracameral injection of a biodegradable poly-lactic-co-glycolic acid-containing PGA implant, poly-ethylene-glycol(PEG)-containing- and PEG-hydrogel-containing-ocular hypotensive drug implant, drugs placed inside bioerodable microspheres(Bertram et al., 2009), dendrimer-(synthetic polymeric nanoparticles)-containing drug, punctal plugs containing IOP-lowering drug (Perera et al., 2016), and a polycaprolactone-device containing a novel non-PG EP2-receptor agonist(DE-117; Omidenepag Isopropyl) that can be intracamrally injected affording months of continued ocular hypotensive treatment due to the extended release characteristics of the delivery technologies (e.g., Barar et al. 2016; Kim et al. 2016).Lastly, transscleral (Nagai et al., 2018), juxtrascleral (Robin et al., 2009) and suprachoroidal (Hartman and Kompella, 2018)drug delivery via speci fi cally designed and fabricated devices and injections could prove extremely useful for providing extended release of IOP-lowering and/or neuroprotective drugs.

Figure 1 Key vulnerable regions of the ocular-cerebral axis involved in glaucomatous optic neuropathy (GON).

ONH: Optic nerve head; ECM: extracellular matrix; AQH: aqueous humor; LGN: lateral geniculate nucleus; SC: superior colliculus; GF:growth factor.

Financial support: None.

Figure 2 Magni fi ed region of the optic nerve head depicting components of the retina, lamina cribosa, retinal ganglion cell axons(optic nerve) and retinal vasculature that are impacted by ocular hypertension and glaucomatous optic neuropathy.

Copyright license agreement: The Copyright License Agreement has been signed by all authors before publication.

在本次试验中，同一区组的标准地内毛竹密度不同，使得产量在进行方差分析时F值减小，相对较难以检验出处理的差异显著性。因此，将标准地的总产量平均到每径阶(1 cm)水平，即为相对增产量。在低密度林分中3种施肥处理尿素、生物有机肥、钢渣肥相对增加产量分别为：2.63、2.60、2.72 kg；在高密度林分中相应的相对增加产量则分别为：2.18、2.57、2.52 kg。可见，在3种肥料处理下，毛竹林随着密度的增加相对增加产量均呈现下降趋势。

解得：Q=n（e）×NA×1.6×10-19=9.6/64×2×6.02×10-23×1.6×10-19=2.89×104C

Conclusions

In conclusion, there are still many challenges that need to be overcome in the arena of optic nerve protection in order to preserve vision. The value of sight requires an enhanced public awareness of the insidious nature of glaucoma so that regular eye exams become routine. Such habits will certainly increase the probability of timely diagnosis of OHT/POAG. The availability of Food and Drug Administration(FDA)-approved Icare HOME tonometer (Icare, Raleigh,NC, USA) and future utility of both temporary contactlens-based (Sensimed’s “TriggerFish”) IOP detector and implantable IOP-sensor (Implandata’s “Eyemate”) should allow more frequent and remote 24-hour monitoring of IOP possible for patients and their ophthalmologists. With such advances it is hoped that OHT/POAG patients can quickly receive appropriate topical ocular hypotensive drug (or a combination product), or AQH drainage device, and/or low responders with fast progressing visual fields can receive suitable gene therapy, and/or receive suitable neuroprotective therapeutic agent(s) without delay. A combination of the above-mentioned treatment paradigms may be necessary to achieve a successful outcome for the patient. In particular, slowing down the progression of the disease processes associated with POAG/OHT/GON and thus limiting further loss of RGCs and their axons should be the primary goal. As is evident from the above discourse, the neurobiology of the disease processes has advanced greatly in recent years such that full restoration of partial blindness or visual impairment due to OHT/POAG/GON may be feasible. The possible linkage of the disease processes in POAG to genetic targets(Aung and Khor, 2016; Danford et al., 2017), metabolomics(Williamson et al., 2018) and other diagnostic/prognostic biomarkers (Cordeiro et al., 2017) can also enhance our understanding of disease pathology and lead to discovery of better medicines to revitalize sick and dying RGCs and optic nerve components (Williams et al., 2017; Ota et al., 2018).Of course, this will eventually depend on how well treatment modalities unearthed by laboratory science can be applied to the human condition, including deployment of gene therapy(Hines-Beard et al., 2016) and perhaps stem cell therapies(Venugopalan et al., 2016; Daliri et al., 2017). This may be a bridge too far at present, but we should not surrender to the threat of burgeoning GONs. The pathways to preserving vision should not be allowed to be obscured or abandoned,and the hope and promise of achieving such audacious goals need to be kept alive as we strive to fi nd solutions for those patients afflicted by these blinding diseases.

It is evident that despite maximum lowering of IOP in POAG/OHT patients, many millions of these patients continue to experience progressive visual impairment and still go blind, as do patients whose long-term ambient IOPs are considered in the normal range and who are classified as“ocular normotensive” glaucoma patients. These facts and observations have led to the conclusion that direct protection of RGC cell bodies and associated axons are paramount,in addition to lowering and controlling IOP. This concept of neuroprotection or soma-axon-protection is now well recognized and accepted in neurodegenerative brain and spinal diseases, and now also in ocular diseases including in POAG.Despite discovery of numerous classes of neuroprotective agents using isolated primary brain neurons, surrogate neuronal cells (neuroblastoma cells), and RGCs subjected to metabolic, excitotoxic, inflammatory and oxidative insults, and con fi rmation of efficacy in animal models of various diseases(e.g., stroke, Parkinson’s/Alzheimer’s/Huntington’s disease,amyotrophic lateral sclerosis, chronic OHT/glaucoma; Ito and Di Polo, 2017; Jonas et al., 2017; Sharif et al., 2018), we still lack bona fi de translation of such neuroprotection in human subjects suffering from these diseases.

Author contributions: The author is solely responsible for researching and writing the review article.

要从生活和思想两个方面服务好老同志，管理的加强是一个基础。笔者考虑的管理的加强，指的是对退休职工党员教育管理工作长效机制进行探索

Thus, one can envision scenarios where “soft” multiple conjugates or suitable and compatible mixtures of efficacious health-authority-approved drugs [e.g., anti-oxidants:edaravone and resveratrol; Ca2+-channel blockers: lamotrogine and nimodepine; rho kinase (ROCK) inhibitors:netarsudil and ripasudil; PGAs like latanoprost, and other IOP-lowering agents; and marketed drugs that have shown neuroprotective activity in animal models (e.g., α2-agonists:brimonidine; β-blockers: betaxolol; anti-epileptics: valproate, phenytoin; anti-inflammatory agents like ibudilast,aspirin and meloxicam)] could be synthesized, formulated and delivered intravitreally to slow down the death of RGCs and their axons. Perhaps the above approach coupled with gene-therapy (Hines-Beard et al. 2016) to deliver neurotrophins such as brain-derived neurotrophic factor (BDNF),ciliary neurotrophic factor (CNTF), nerve-growth factor(NGF) and/or erythropoietin to RGC bodies and axons may be successful. Another approach that may help prevent RCG loss is using immortalized human neural stem cells that can differentiate into neurons and oligodendrocytes to form a“physical platform/substratum/bridge” in vivo to repair and support the optic nerve components in GON/POAG patients(Kador et al., 2013; Kashani et al., 2018; O’Rourke et al., 2018)may be necessary. Physical grafting of human optic nerve components such a delivery of Schwann cells that form myelin (Guo et al., 2014; Smedowski et al., 2016; Auricchio et al.,2017) to the weakened optic nerve could also become a reality in the near future. Likewise, stem cells to replace dying or dead RGCs is another possibility (Venugopalan et al., 2016;Daliri et al., 2017). However, the latter will be ineffective if we cannot fi rst overcome the growth-inhibiting effects of the local chemical environment around the damaged axons and RGC somas. Thus, it is imperative to fi nd ways to induce the phagocytosis, degradation, active uptake and elimination of some or all of these culprits that inhibit axonal/dendritic growth including excess zinc, myelin-associated glycoprotein,Nogo, oligodendrocyte-myelin glycoprotein, chondroitin sulfate proteoglycans and the physical barrier represented by glial scar tissue.

本书对企业管理体系作了全景式的扫描，为体系建设提供了路线图和方案参照。主要内容包括：价值创造活动分类，流程体系架构（从一级流程到三级流程），基于流程分解的组织设计，以及组织单元之间的协同机制。以上各部分的顺序即为管理体系构建的逻辑。本书借鉴了美的等优秀企业的管理经验，吸纳了管理领域的最新成果，整合性、实用性强，内容扎实，干货丰富。读懂本书，基本可以理解整个企业。作者施炜，管理学博士，知名战略管理专家。

Electrotherapy that can release endogenous neurotrophins, enhance ocular blood-flow and resuscitate energy-depleted mitochondria of the RGCs (Fujikado et al., 2006;Kurimoto et al., 2010; Morimoto et al., 2011; Ota et al.,2018), coupled with delivery of exogenous re-energizing agents like vitamin B3 (Williams et al., 2017) could be used to rescue failing retinal cellular and axonal components (Ito and Di Polo, 2017). Additional contributors to this cause could include drugs that inhibit formation and deposition of amyloid/tau proteins and complement, and agents that can abrogate the actions of damaging cyto-/chemo-kines, and anti-apoptotic drugs. Likewise, inhibiting p38-MAP kinase,ROCK, dual leucine zipper kinase, Janus kinase, mammalian target of rapamycin (mTOR), phosphoinositide-3 kinase,and suppression of various transcription factors that can induce apoptosis, or generate cytokines or elicit fi brosis [by up-regulating thromospondin-1, periostin and collagen-1A1](e.g., Bax, PTEN, Klf-4, SOC3, NFκB, NFAT) (He et al., 2018;Sharif, 2018), have the potential to enhance regrowth of damaged RGC axons (Morgan-Warren et al., 2016). Similarly,activation of certain transcription factors and proteins (e.g.,Bcl; oncomodulin, Mmnat1, tropomyosin regulated kinase-B)represent beneficial survival elements that could be exploited to elicit regeneration of RGCs and their axons (He et al., 2018;Sharif, 2018). Since Ca2+-overloading of cells due to excitotoxicity underlies cellular demise (Irnaten et al., 2018), mitochondrial targeting of specific Ca2+-channel blockers appears worthy of pursuit to combat RGC/LC cell death (Cheung et al., 2017). Despite all this effort, however, all of the above may still be unsatisfactory and prove non-efficacious because what is really needed are disease-modifying therapeutics and most likely a combination product approach. However, irrespective of the hurdles, all this multifaceted research is helping build the neuroprotectant armamentarium necessary to deal with different aspects of POAG/GON pathology (He et al., 2018; Sharif, 2018).

Plagiarism check: Checked twice by iThenticate.

Peer review: Externally peer reviewed.

Open access statement: This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

Open peer reviewer: Jiaxing Wang, Emory University, USA.

Additional fi le: Open peer review report 1.

中国工程机械工业协会会长祁俊在致辞中说，山重建机在继2011年北京工程机械展会上推出节能环保的混合动力挖掘机和电动挖掘机后，今年在上海宝马展上又隆重推出了燃气动力挖掘机等多款创新产品，这充分体现了山重建机在技能环保等方面的研发实力，零排放、零污染的技术变革正改变着工程机械行业发展的格局，进一步拓宽了市场需求。

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