Retinal neurons are considered to be a part of the central nervous system (CNS). As a consequence, they share several properties with CNS neurons, including the inability to undergo spontaneous regeneration in response to damage. Since there is no possibility to replace cells that become non-functional due to damage or aging, these long-living cells are likely endowed with specific mechanisms to protect them from both intracellular and environmental stress (Hayashi and Takagi, 2015). Retinal neurons, including retinal ganglion cells (RGCs), are exposed to similar stressors as observed in other cell types, i.e., UV radiation, high temperature, ischemia, hypo- or hyperoxic conditions, harmful microbes, allergens and environmental pollutants, all factors able to induce reactive oxygen species (ROS) production and/or release (Bouayed and Bohn, 2010). In addition, retinal neurons are exposed to the glutamate, which in excess concentration is a neuron-specific toxin. Subsequently, ROS production results in genes expression alteration, protein misfolding and other events leading to cell stress with apoptosis as the terminal process. Since the technologies allowing CNS repair by cell replacement are still under development, the efficiency of the endogenous cellular protective systems is a key factor for neuronal apoptotic susceptibility and survival (Bakalash et al., 2002; Wei Y. et al., 2011). As a consequence of this, the neurodegeneration can be described as an imbalance between protective and damaging factors affecting RGCs (Figure 1).
FIGURE 1. Schematic diagram illustrating the impact of endogenous neuroprotective mechanisms on RGC rescue after injury. ∗If factors representing the endogenous rescue-mechanisms are sufficiently activated they can allow functional recovery of RGCs; however, if these mechanisms are not efficient enough, irreversible cell death may occur.
Retinal ganglion cells projections form the optic nerve (ON) and conduct the visual signal from the retina to visual centers in the brain (i.e., lateral geniculate nuclei). RGCs are the site of numerous primary retinal and optic nerve pathologies among which glaucoma, ischemic optic neuropathy and Leber’s hereditary optic neuropathy (LHON) are the most common. Moreover, there are pathologies with ocular signs, such as diabetes (Gerber et al., 2015; Wan et al., 2017), Alzheimer’s disease (AD) (Hart et al., 2016) and brain tumors (Tieger et al., 2017). Damage to RGCs or the ON results in impairment of visual signal propagation and subsequent progressive visual field defects. Since the retina represents a highly organized structure, with neighboring cells closely interacting with each other, death of a single RGC can induce self-perpetuating processes affecting survival of surrounding cells; these detrimental events are related mostly to the release of intracellular glutamate from the dying cells that triggers an excitotoxic cascade (Chang and Goldberg, 2012). Therefore, impairment of RGC endogenous neuroprotective mechanisms and increased RGC apoptosis can participate in spreading of pro-death signals resulting in progressive damage to the retinal cells.
Endogenous neuroprotective mechanisms in neurons, including RGCs, can be classified in various categories. Neurotrophic factors and both enzymatic and non-enzymatic mechanisms of ROS scavenging are well-known players in RGC homeostasis. In addition, systems of misfolded protein degradation (i.e., autophagy) and mechanisms controlling gene expression are gaining increasing attention and represent potentially interesting targets for therapy and/or prevention of neurodegeneration. Here, we summarize and describe the most recently studied endogenous neuroprotective factors involved in RGC survival, which include (a) neurotrophic/growth factors (neuronal, vascular, or both), (b) processes regulating the redox status, and (c) other factors, including pathways regulating apoptosis/cell death and neuroinflammation modulators (Figure 1).
Neurotrophic factors regulate the development and survival of neurons. They seem to be involved in the endogenous neuroprotection of RGCs. A variety of studies have reported that neurotrophic factors, particularly nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), glial cell-derived neurotrophic factor (GDNF), and ciliary neurotrophic factor (CNTF), protect RGCs in various models of ON injuries (Johnson et al., 2011; Domenici et al., 2014; Gupta et al., 2014; Table 1). In agreement with their well-known role in maintaining neuronal homeostasis, neurotrophic factors have been proposed as novel therapies for various neurodegenerative diseases, however, outcomes of known clinical trials were not satisfactory, presenting only partial or no expected effects (Greenberg et al., 2009; Allen et al., 2013; Shruthi et al., 2016). Interestingly, some CNS pathologies, such as AD, Parkinson disease and Huntington disease, display ocular signs and alterations within RGCs (Batcha et al., 2012; Ramirez et al., 2017); thus, for these neurodegenerative diseases, neurotrophic factors promoting the survival of neurons may be of beneficial at both the central and ocular levels.
TABLE 1. Expression of neurotrophins and their receptors in different RGC degeneration models and human glaucoma (↑ upregulation; ↓ downregulation).
Neurotrophins can bind to different receptors and transduce diverse intracellular signals, finally leading to opposite outcomes – death or survival. For instance, the binding of a neurotrophin to the tyrosine-receptor kinase (Trk) promotes cell survival, whereas interaction with p75 NT receptors (p75NTR) induces apoptosis (Kimura et al., 2016; Figure 2).
FIGURE 2. Neurotrophic factor (NTFs) signaling pathways. Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5) bind to two families of receptors. Tropomyosin kinase (Trk) receptor binds with high affinity to promote cell survival via phospholipase C-γ (PLC-γ), phosphoinositide-3 kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways (light blue arrows). Binding of NTFs to low affinity p75 receptor activates cell death through the JNK pathway (light blue and red arrows). Ciliary neurotrophic factor (CNTF) binding to CNTFRα receptor and two subunits – gp130 and leukemia inhibitory factor (LIFRβ) activate the Janus kinase/signal transducer and activator of transcription (JAK/STAT) (blue-violet arrows), MAPK and PI3K pathways (dark blue arrows). Binding of glial cell line-derived neurotrophic factor (GDNF) to the GDNFα receptor and tyrosine kinase RET receptor stimulates PLC-γ, MAPK and PI3K pathways (green arrows). Akt controls the activities of several proteins important in promoting cell survival, including substrates that directly regulate the caspase cascade, such as BAD. Phosphorylated BAD prevents its proapoptotic actions (Skaper, 2008) (red arrows). The pathway illustration was based on Reactome (https://www.frankenthalerfoundation.org PMID: 29145629, PMID: 29077811). Represents the pathways responsible for endogenous cell-rescue mechanisms in glaucoma; these pathways were significantly activated when IOP was elevated, but decreased to baseline levels when IOP was lowered (Levkovitch-Verbin et al., 2007; Levkovitch-Verbin, 2015).
Neurotrophin deprivation, mainly BDNF, is considered as one of the leading causes of RGC death in glaucoma. BDNF is synthesized in the superior colliculus and the lateral geniculate nucleus and retrogradely transported to the RGC bodies. Moreover, this neurotrophic factor is produced locally in RGCs (Herzog and von Bartheld, 1998). Exposure to high IOP induces a two-phase response (a decrease followed by an increase) in BDNF and NT4/5 expression in RGCs and in the ON head glia, suggesting the participation of these neurotrophins in endogenous neuroprotective responses of RGCs (Vecino et al., 1999; Johnson et al., 2000; Table 1). It is widely accepted that BDNF upregulation is an early response in RGCs that undergo axonal injury (Kimura et al., 2016). Several studies indicated that the therapeutic effects of different neuroprotective agents in promoting RGC survival are related to their induction of retinal BDNF expression (Bai et al., 2010; Pietrucha-Dutczak et al., 2017; Chou et al., 2018). Our previous studies also confirm these results. Application of extracts from pre-degenerated peripheral nerves stimulate RGC survival through induction of endogenous retinal BDNF expression in glaucoma (Pietrucha-Dutczak et al., 2017). It is important to note that BDNF levels in the serum and tears of glaucoma patients are significantly lower than in control subjects, suggesting that deficits in this neurotrophin may participate in RGC death in glaucoma (Ghaffariyeh et al., 2009, 2011; Oddone et al., 2017). Furthermore, BDNF inhibits the osmotic swelling of Müller cells and bipolar cells (Berk et al., 2015) and upregulates the glutamate/aspartate transporter (GLAST) and Glutamine Synthetase (GS) expression in Müller cells in the mouse retina, increasing glutamate uptake during hypoxia (Dai et al., 2012). To our knowledge, no clinical trials evaluating the potential therapeutic effects of BDNF in glaucoma have been conducted so far, however, there have been many attempts and future plans in developing BDNF-based therapies.
Nerve growth factor is another important growth factor affecting the survival of nerve cells. NGF deprivation can lead to apoptosis preceded by impairment of glucose uptake, an increase in ROS production, activation of c-Jun N-terminal kinase (JNK) and its downstream target c-Jun, and caspase activation (Freeman et al., 2004; Lomb et al., 2009
