Abstract
Once destroyed, neurons and their axons in the mammalian central nervous system, including retinal ganglion cells (RGCs) and their axons in the eye and neurons in the thalamic and cortical brain regions involved in visual perception, cannot automatically be replaced. Intrinsic inhibitory chemicals and structural components, suppressive transcription factors, scar formation, and the sheer long distances the RGC axons have to travel to the brain prevent or reduce regenerative capacity in the visual system damaged by aging and various diseases such as glaucoma. However, non-clinical and some clinical uses of transcorneal electrical stimulation, redlight therapy, gene-therapy, and cell replacement, among other novel technologies and techniques, appear promising to help overcome some of these hurdles. Early results indicate that indeed neuronal rejuvenation; potential regeneration and ultimate replacement of the lost RGCs and their axons, such as in glaucoma; and the reestablishment of the retina-optic nerve−brain connections may be possible. Improvement and/or partial restoration of eyesight due to ocular and neurological disease-induced visual impairment in humans may thus be possible in the near future. These aspects will be discussed in this chapter.
Keywords
- glaucoma
- optic neuropathy
- degeneration
- regeneration
- retina
- electroceuticals
1. Introduction
The process of visual perception is initiated when light enters the eye and is focused on the retina at the back of the eye (Figure 1A). Simplistically, photoreceptors convert the electromagnetic energy received into chemical signals that are transmitted to the bipolar cells, which communicate with the retinal ganglion cells (RGCs), of which there are many sub-types [1, 2]. The RGCs encode the integrated information received into electrical impulses that are then transmitted down their axons, which form the optic nerve. The optic nerves carrying RGC axons from each hemi-retina cross over the optic chiasm, each half set innervates the relay station at the lateral geniculate thalamic nuclei (and other nuclei), and from there, other neuronal axons connect to various parts of the visual cortex (Figure 1B). Successive integration and processing of the information finally emerge as visual images perceived by the person or animal. This whole simplified process happens in milliseconds, and binocular color vision is achieved under normal circumstances.
Loss of visual perception due to aging and pathological factors damaging the optic nerve and the RGCs are classic structural and functional deficits observed in patients with glaucoma [3, 4, 5, 6]. Although there are many forms of glaucoma, the most prevalent types are open-angle glaucoma (OAG) and angle-closure glaucoma (ACG), followed by normotensive glaucoma (NTG) [3, 4, 5, 6, 7, 8, 9]. The two major disease-instigating and risk factors for OAG and ACG are advanced age and elevated intraocular pressure (IOP). Increased IOP results when the aqueous humor (AQH) accumulates in the anterior chamber of the eye due to blockage of the AQH drainage system, trabecular meshwork (TM), and Schlemm’s canal (SC) (Figure 1A) [7, 8, 9, 10]. Protracted IOP fluctuations and disc hemorrhage are additional risk factors of visual field deterioration and progression, especially in advanced glaucoma, even at low IOPs. Similarly, since NTG develops independent of high IOP, it is believed that local inflammation, tissue remodeling at the optic nerve head (ONH) and lamina cribosa (LC) in the retina (Figures 1A and 2), and subsequent loss of RGCs and their axons that are supersensitive to injurious conditions are responsible for the pathogenesis of the disease. Many molecular and cellular elements conspire to cause this glaucomatous optic neuropathy (GON). Close to 80 million people worldwide suffer from OAG and ACG alone with projected numbers to increase to >112 million by 2040 [9]. Even though IOP-lowering drugs, devices, and surgical treatments slow down the disease progression [10, 11, 12], there remains a high unmet medical need to help protect, preserve, and restore visual field/visual perception in the OAG/ACG/NTG-afflicted patients and hence the need to discover and develop novel treatment modalities and technologies to mitigate these ocular diseases at various intervention points and through diverse receptor/enzyme/ion-channel targets [6, 11, 12].
2. Basic anatomy and pathology of GON
Multifaceted research into GON has revealed that one of the weakest structural components of the visual system is the retinal region known as the ONH and LC at the back of the eye (Figures 1A–3). The high IOP associated with OAG exerts physical compressive pressure and damages the latter tissues through mechanical forces [13, 14] and the ensuing microglial activation, infiltration of immune cells into the retina, aberrant activation of the complement system, and release of inflammatory cytokines (e.g., interleukins), vasoconstrictor (endothelin) and neurotoxic (glutamate; ATP) agents, and destructive proteases (matrix metalloproteinases [MMPs]) [15, 16, 17, 18, 19, 20, 21, 22, 23, 24]. The most susceptible RGC axons and cell bodies are injured, and over time, their terminals retract away from the brain neurons, thereby reducing the delivery of mitochondria and neurotrophins to the RGC somas due to impaired retrograde axonal flow [19, 24]. The ischemia/hypoxia [25, 26] induced by vasoconstriction of retinal blood vessels that travel along with the RGC axons also causes immense oxidative stress on the whole visual system with resultant atrophic consequences [27, 28, 29, 30, 31, 32].
Even though these events and this chronic disease progress slowly over decades, ultimately many RGCs and their axons wither and die, thus causing visual impairment, which, if it is not diagnosed and treatment administered, can lead to irreversible loss of eyesight. The asymptomatic nature of OAG and NTG means that the patients are totally oblivious to the damage being inflicted on their visual system and only notice vision defects when significant vision loss has occurred. Not only are the RGCs and the optic nerve damaged in OAG and NTG, but due to reduced retina−brain communication activity, many neurons in the thalamus, superior colliculus, suprachiasmatic nucleus, and visual cortex are also destroyed and cannot be replaced [27, 28, 29, 30, 31, 32].
Due to the aging process, coupled with the pathological events described above, the autophagic clearance of dead or dying neurons and axonal debris in the retina and brain is impaired. The toxicity, oxidative insults, and glial proliferation caused by the pathological condition and milieu [2, 5, 6, 17, 18, 19, 20] further slow down the intrinsic reparative mechanisms, and more cells and axons are destroyed. The patient now begins to notice blind-spots in the visual images, reduced contrast sensitivity, and an overall loss of visual acuity and loss of peripheral vision [14, 32]. At such time, it is imperative to lower and control the IOP in the patient’s eyes and thus preserve the remaining RGCs and their axons and maintain good health of the brain’s gray and white matter associated with vision. As mentioned above, lowering and controlling IOP in glaucoma patients is no longer a huge issue [5, 6, 10], although patient compliance in administering prescribed eyedrops presents continued problems, and of course, more efficacious treatments with a longer duration of action and less side effects are still needed. However, what remains a major healthcare concern is the ways and means to directly protect the remaining visual infrastructure, to implement novel methods to rejuvenate and potentially regenerate or replace the lost RGCs and their axons, and to re-establish lost retina-optic nerve–brain connections, thereby restoring some lost visual function.
3. Concept and progress in neuroprotection for GON
Because GON is a multifactorial disease, it requires a multi-pronged therapeutic approach. Unfortunately, much of the reported research data published thus far has utilized a strategy involving a single insult (whether it is a neurotoxin, hypoxia, aglycemia, or neurotrophic factor deprivation or optic nerve crush) and a single test agent to protect the neurons and their axons. However, while not fully representing the
4. Gene therapies for glaucoma treatment
With the success of gene therapy for a specific form of retinitis pigmentosa, Leber’s congenital amaurosis [37], there has been a surge in genetic manipulation studies directed toward glaucoma treatment. Although such studies have so far been pre-clinical using animal models of disease, there is hope that some will enter clinical trials soon. Early studies focused on the use of adeno-associated viral (AAV) vectors delivering genes to the ANC cells and were aimed at opening up the TM drainage system to promote AQH outflow to lower IOP and thus reduce the mechanical pressure on the ONH/LC and thus indirectly protect the optic nerve. Indeed, insertion of AAV-mediated genes enhancing expression of MMP-1 in sheep [38] and MMP-3 in mice [39], to remodel the TM tissue, resulted in reduction of IOP. In a different way, genetic manipulation of the mouse ciliary body aquaporin-1 [40] and the silencing of the β-adrenoceptors in the same tissue [41], to reduce AQH production, also yielded significant IOP decreases. In an effort to promote AQH outflow via the uveoscleral pathway to decrease feline IOP, cells of the ANC were transduced with the gene for cyclooxygenase-2 (in order to produce endogenous prostaglandins) and a gene for an optimized FP-receptor protein [42].
Gene therapies specifically directed at protecting RGCs and other retinal neurons have also found some success in pre-clinical studies. Thus, transduction of gene encoding a form of erythropoietin in the eyes of mice with pigmentary glaucoma (DBA/2 J) suppressed infiltration of peripheral immune cells into their retinas, modulated microglial reactivity, reduced oxidative stress, and preserved their visual perception [43]. RGCs and their axons in DBA/2 J mice and other mice with micro-bead-induced ocular hypertension (OHT) could be protected by genetic expression of the anti-apoptotic soluble Fas-ligand [44], by over-expression of the complement C3 inhibitor CR2-Crry [45], and by retinal expression of scAAV2-C3 (exoenzyme C3 transferase), which significantly reduced the number of apoptotic RGCs and decreased cell loss in the ganglion cell layer after ischemia/reperfusion injury [46]. Additional examples of gene therapies for RGC preservation in the face of death signals after GON induction in various animal models have involved delivering X-linked inhibitor of apoptosis (XIAP; potent caspase inhibitor) [47], transduction of RGCs with the protective transcription factors BCL2L1 [48], and Myc-associated protein X (MAX) [49] and over-expression of NMNAT1, the key enzyme in the NAD+ biosynthetic pathway to enhance RGC rejuvenation through increased intrinsic energy production [50]. A most advanced form of gene therapy that proved successful in animals has been the co-delivery of the neurotrophin BDNF and its receptor to impart neuroprotection to RGCs [51]. However, despite such non-clinical successes, the multifactorial nature of GON will most likely still require use of a combination of gene therapies to achieve clinically relevant efficacy. Furthermore, translation to the clinical management of various forms of glaucoma will remain rather challenging, but hopefully, this will become a reality in the near future.
5. Cell-replacement therapies for glaucoma treatment
Delivering missing genes or modifying genetic expression of certain gene products has its complexities and difficulties. However, replacing injured or dead cells as a form of treatment for ocular hypertension and GON is an even more daunting task. Nevertheless, several pre-clinical studies have demonstrated the effectiveness of such an approach. Due to cell senescence caused by aging or pathological conditions as in glaucoma, the TM region could benefit from enhanced cellularity to filter and drain AQH and maintain IOP within normal ranges. Hence, stem cells isolated from human TM and expanded
Unlike the TM cell replacement, the challenge of replacing lost RGCs in the retina of glaucomatous animals (and humans), due to physical barriers such as the inner and outer limiting membranes, fibrotic scarring, and the growth-inhibitory microenvironment, is much greater. However, some successes, at least in animals, are noteworthy. Firstly, a multitude of cell sources have been identified for potential in vitro differentiation, proliferation, and characterization before being considered for transplantation purposes. Additionally, techniques have been developed that permit re-programming [62, 63] or conversion of cells to specific desired cell types. Sources of cells include the following: allogenic cadaveric human cells, human fetal retinal stem cells, human CNS stem cells, adult hippocampal neural stem cells, ciliary pigmented epithelial cells, limbal stem cells, retinal progenitor cells (RPCs), mesenchymal stem cells (MSCs), human pluripotent stem cells (PSCs) [including both human embryonic stem cells (ESCs) and human-induced pluripotent stem cells (iPSCs)], and retinal organoids themselves. Regarding glaucoma treatment via cell replacement technologies, successful transfer of embryonic retinal progenitor cells labeled with green fluorescent protein into mouse eyes depleted of RGCs and their movement to the RGC layer and establishment of appropriate connections was demonstrated [64]. The transplanted cells began to express key RGC-related genes and extended bundled axons, although their numbers were not so high [64]. Subsequently, chemically induced conversion of human embryonic stem cells and iPSCs into functional RGCs was achieved using a Notch inhibitor [65], where >30% of the cells expressed key RGC markers, which generated action potentials. Such techniques have been further refined that included reprograming fibroblasts into RGC-like neurons via transcription factors
6. Electroceutical technologies for improving vision
Activity-dependent maturation and maintenance of synaptic connectivity, long-term potentiation for memory consolidation, and axonal regrowth and connectivity are essential for CNS homeostasis and normal functions of neural networks [72]. Action potential transmission keeps neural circuits healthy and functioning [73]. Based on these findings, electrotherapies have been shown to promote tissue and bone healing whether administered via acupuncture, electroacupuncture, or electrical stimulation via electrodes. Indeed, electroshock treatment for anxiety and depression is well known as is deep brain stimulation to help deal with motor dysfunctions as in Parkinson’s disease and as beneficial paradigms for other neurological diseases.
As a continuum of the above application, electrical stimulation (ES) and transcorneal electrical stimulation (TCES) have been utilized for visual perception improvement. Indeed, ES and TCES protected and preserved RGCs of rats in which optic nerve lesions had been introduced and where endogenously secreted insulin-like growth factor-1 (IGF-1) was demonstrated to be the neuroprotective agent [74, 75]. Interestingly, repetitive ES promoted axonal regeneration in a rat optic nerve crush model of glaucoma [76] and afforded retinal neuroprotection in a retinal ischemia injury model [77, 78]. Inhibition of inflammatory cell migration and release of their inflammatory cytokines coupled with concomitant release of endogenous neurotrophic factors were observed following ES procedures [77, 78, 79]. Furthermore, TCES helped preserve and aided the recovery of retinal cells and their function following various external insults through reductions in microglial activation and suppression of cytokine secretion in the retina [80, 81, 82]. Similarly, in an animal model of pigmentary glaucoma (DBA2/J mice), TCES treatment suppressed infiltration and activation of inflammatory cells and microglia through improved energy utilization/homeostasis and by reducing cellular apoptosis [81]. The theme of neurotrophins release and suppression of inflammation, among other beneficial elements, induced by TCES in promoting RGC neuroprotection and their axonal growth is illustrated in Figure 4.
ES
Even though ethical considerations and regulatory issues have thus far hampered translation of such studies to the glaucoma patients or to others afflicted with major retinal dystrophies, a few encouraging studies have been reported. Some improvement in vision was observed in patients with nonarteritic ischemic optic neuropathy and traumatic optic neuropathy administered TCES [85]. Likewise, patients with optic nerve lesions subjected to transorbital stimulation experienced improvement in their visual field size and visual acuity or increased detection ability within the visual field [86, 87]. Furthermore, transorbital alternating current stimulation of patients with optic neuropathy yielded increased thresholds in static perimetry tests and led to improved visual fields [87]. Investigations dealing with use of electrical stimulation to improve retinal circulation or to combat retinal vein occlusion issues demonstrated positive findings [88, 89, 90] and an improvement in retinal function after such treatment in patients who had retinal artery occlusions [90]. Transpalpebral stimulation using 10 Hz nonrectangular current pulses (100 μA) constant current in primary OAG (POAG) patients reduced their IOP down to 14.41–15.29 mmHg starting with baseline IOPs of 19.25–20.38 mmHg [91]. Similarly, transorbital AC current (30 min/day for 10 days at 10 Hz) given to patients with visual field defects resulted in significant improvement in their visual fields due to local activation of their visual cortex and increased retinal blood flow [88, 89, 90]. Furthermore, a very recent study employing optic nerve stimulation (ONS) demonstrated highly significant improvements in visual fields (2 weeks to 1 year of daily treatment) in 101 eyes of 70 patients (composed of mainly POAG and NTG) and decreased the mean defects in their retinas (Figures 6 and 7) [92]. An Eyetronic® device (Neuromodtronic GmbH, Potsdam, Germany) that applied electrical stimulation via goggles with embedded supraorbital and infraorbital electrodes and recorded EEG signals via an electrode cap was used to deliver the stimulation. All four electrodes, two on each side, in the stimulation goggles were controlled by four separate constant-current stimulators with the following stimulation parameters: Pulse shape: biphasic, symmetric rectangular; pulse amplitude: up to 1.2 mA; pulse duration: 14 to 20 ms; and repetition frequency in pulse trains: 5 to 34 Hz. The daily duration of the stimulation treatment was less than 40 min but varied slightly from one treatment day to another. While the results are impressive, we await confirmation of these types of studies in the near future.
Despite some successes described above, the use of electrical stimulation to tackle ocular diseases is still being refined, and many challenges remain. For instance, the choice of type of electrical stimulator, the type of electrical current to use (AC or DC), the strength of the current (50–800 μA), and the frequency and duration of each treatment session for OAG, ACG, and NTG patients need defining. Nevertheless, the electroceutical therapeutics may prove useful in the future and may be adopted for clinical use on a routine basis.
7. Photobiomodulation for glaucoma treatment
Use of nonthermal, non-ionizing light sources (lasers, light emitting diodes, and/or broadband light) using visible and near-infrared light is now recognized as helpful treatment modalities to aid healing (muscles and joints) and for reducing pain. Furthermore, by generating CO, redlight (650 nm wavelength) has been shown to destroy certain viruses, to activate neurite outgrowth after blue-light-induced retraction, and to aid corneal epithelial healing through rejuvenation of cellular mitochondria [93, 94]. The principal MOA of photo biomodulation involves the activation of the respiratory chain of the Krebs cycle within the mitochondria of cells to enhance ATP production and cause the release of NO and free radicals. The beneficial effects of redlight resulting from these activities help increase local circulation and metabolism. Whilst blue light damaged retina cell mitochondria via oxidative stress, redlight prevented the injury and protected Muller glial and RGCs [94, 95]. Mice with autosomal optic atrophy subjected to redlight exposure for 5 days exhibited less RGC dendritic atrophy than control mice that did not receive redlight [96, 97, 98]. Thus, benefits of redlight exposure may benefit OAG/ACG/NTG patients and need to be investigated in the future.
8. Conclusions
Multifaceted research in ophthalmology and neuroscience has greatly contributed to our understanding of the pathogenesis of neurodegenerative diseases. Accumulated evidence points to several local microenvironmental deleterious events and factors conspiring to cause death of RGCs and brain nuclei neurons and axonal damage within the optic nerve. Inflammation and reduced ocular perfusion at the ONH/LC retinal region caused by elevated IOP appears to trigger the initial damage in the eyes of glaucoma patients, leading to weakening of the LC structure. The contusion, bending, and overall increased tortuosity of the injured RGCs axons and retinal blood vessels then cause oxidative damage, reduced axonal flow of neurotrophins and mitochondria to the RGC cell somas, and retraction of the axonal terminals in the thalamic and other parts of the brain. Decreased overall input from RGCs eventually leads to the death of brain neurons involved in visual image processing and loss of peripheral vision. Such detrimental events appear to be also responsible for decreased visual acuity, contrast sensitivity, and visual impairment in patients where the IOPs are within normal ranges (NTG), indicating involvement of genetic, environmental, and other factors in their RGC, axonal, and CNS atrophy.
While lowering and controlling IOP by pharmaceutical, surgical, and microshunt implantation procedures slows down the progression of GON, other direct and indirect means are needed to protect and preserve the retinal and visual center architecture and functions. The neuroprotective paradigm is now well accepted, and many drugs and food-derived agents have shown efficacy in cell-based and animal model-based systems. Likewise, gene- [51, 99] and cell-therapy [70, 100, 101, 102] and controlled electrical stimulation [92] and photobiomodulation [97, 102] have beneficial effects and a place in tackling degenerative maladies. The latter alone, or coupled with optogenetic [102], photoswitch [103], electromagnetic, and ultrasound-based technologies [104, 105], is also beginning to show promise in promoting cytoprotection and even potential axonal regeneration. Though many challenges remain, we look forward to further progress in translating these to help patients with GON and other related neurodegenerative eye and brain diseases in the near future.
Acknowledgments
The inspiration to compile literature information and to write this book chapter was provided by my family members and many colleagues and collaborators who are working tirelessly to find suitable remedial solutions for glaucoma patients. My appointments to several universities and interactions with faculty and students at these research institutions and at the Glaucoma Foundation have further infused energy and enthusiasm toward this goal. I am also grateful to Santen for allowing me to pursue such scholarly activities.
Conflict of interest
The author declares no conflict of interest and simply wishes to advance sharing of knowledge to help in the discovery and development of methods and compositions to help patients suffering from neurodegenerative eye and brain disorders.
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