Neurodegeneration is characterized by a progressive loss of neurons and their processes (axons, dendrites, synapses) in defined areas of the nervous system and a concomitant impairment of neuronal function. The most prevalent neurodegenerative diseases such as Alzheimer's disease (AD), glaucoma, age-related macular degeneration (AMD), Parkinson's disease (PD), and others, develop in selected neuroanatomical areas and in different neuron subgroups of highly specialized tissues, from the eye retina to brain regions. Despite their divergent clinical manifestations, neurodegenerative disorders are multifactorial and often share common molecular mechanisms at the basis of disease onset, such as abnormal protein aggregation, mitochondrial dysfunction, oxidative stress and inflammation (Angeloni et al., 2022; Baldassarro et al., 2022; Tarozzi and Angeloni, 2023). Over the last years, the main paradigm for the cure of neurodegeneration has been “one drug, one activity, one disease”, and a great number of preclinical and clinical treatments are currently investigated. However, most available therapeutic options are symptomatic, with approved drugs having limited clinical impact on disease progression (García and Bustos, 2018; Peña-Bautista et al., 2020). Hence, there is an urgent need of disease-modifying therapies to prevent, slow and even stop the progression of neurodegeneration. The attention of researchers is now focused on the discovery of multi-targeted compounds, in which the same molecule can exert its effects by targeting different molecular pathways. The definition of neuroprotection is wide and complex, and it refers to the mechanisms and strategies aimed at protecting the nervous system from injury and damage. Neuroprotective strategies support neuronal survival and, in the case of ongoing neurodegenerative insult, promote the maintenance of neuron structure and function, leading to a reduction in the rate of neuronal loss over time. Therefore, efficacious neuroprotective therapies are expected to gain disease modifying properties, even though, to date no directly neuroprotective therapies have been approved by regulatory agencies (Villoslada and Steinman, 2020; Yanamadala and Friedlander, 2010). (see Fig. 1, Fig. 2).

Retinal neurodegenerative diseases such as age-related macular degeneration, demyelinating and hereditary optic neuropathies, glaucoma, diabetic retinopathy and retinitis pigmentosa are the most common disorders that cause progressive and incurable loss of vision (Danesh-Meyer and Levin, 2009; Kaur and Singh, 2021). The complexity and unique architecture of retina renders it vulnerable to multiple pathological insults (Usategui-Martin and Fernandez-Bueno, 2021). Clinical manifestations and etiology, spanning from genetic mutations to various stressful conditions (i.e., high level of glucose in blood and mechanical stress due to enhancement of intraocular pressure) and aging, are quite different, depending on the single pathology. Nevertheless, they reveal some common features at cellular and molecular level, such as inflammation determined by activation of glia, oxidative stress response and progressive cell death of retinal ganglion cells (RGCs) which are the unique output neurons of the retina (Cuenca et al., 2014). RGCs cannot spontaneously regenerate axon, and, as a consequence, their loss results in permanent vision reduction and blindness (Oliveira-Valença et al., 2020). Retina neurodegeneration is usually divided into four phases: 1) the morphology of the retina appears normal, but at molecular level alterations are present; 2) stressful conditions lead to progressive cell death and activation of glia; 3) an extensive neuronal cell death and microglia activation occur; 4) retina architecture is overturned with invasion by blood vessels, hypertrophy of glia cells and RGCs death (Cuenca et al., 2014, p. 201). These progressive stages of dysfunction lead to visual blindness that becomes irreversible in later phases (Gagliardi et al., 2019). As a matter of fact, early-acting therapies are expected to change the disease course of pathology. Retinal neuroprotection represents the next frontier in ophthalmic diseases and for some pathologies (e.g., age-related macular degeneration, inherited retinal dystrophies and macular telangiectasia type 2), neuroprotective strategies are in clinical trials and an increasing number of preclinical studies are published (Levin et al., 2022; Schmetterer et al., 2023; Wubben et al., 2019). Nevertheless, key aspects that render hard to design effective neuroprotective strategies, spanning from molecular to clinical troubleshooting, include: the lack of complete understanding of molecular basis of diseases, the anatomical and tissue complexity of visual system, the time at which patients are enrolled in clinical trials, and the absence of valid endpoints (Levin et al., 2022; Weinreb and Levin, 1999). The progress of investigations to determine the primum movens of neurodegeneration and the exact mechanism leading to primary neuronal and/or glia dysfunction is crucial. Therefore, a deeper understanding of the common mechanisms among different neurodegenerative disorders is mandatory. Of note, although the pathophysiology of neurodegenerative diseases affecting eye and brain differs, they show biological commonalties, such as the activation of inflammatory and stress response, and misfolded protein accumulation (Sbardella et al., 2021; Tundo et al., 2021, 2020, p. 20,123; Usategui-Martin and Fernandez-Bueno, 2021). Additionally, in some cases, specific links have been identified, as for mild atrophy of RGCs cells in AD and mild cognitive impairment in glaucoma (Ashok et al., 2020) (see Box. 1). Hence, preclinical studies support the notion that various classes of neuroprotective therapies (i.e., antioxidants, neurotrophic factors, apoptosis and kinase inhibitors, and modulators of ubiquitin-proteasome system) could show similar efficacy in the case of brain and eye neurodegeneration (Pietrucha-Dutczak et al., 2018; Sbardella et al., 2020a; Tundo et al., 2023). A further element of complexity is represented by the fact that RGCs are highly divergent, and their precise physiology is partially unknown. In fact, there is poorly knowledge concerning which specific cell type is fundamental to preserve visual integrity and how different populations respond to the neurodegenerative insult. Moreover, animal and human visual systems differ in term of anatomy, physiology and disease manifestations, making it hard the identification of the correct animal model for testing neuroprotective strategies (Sanes and Masland, 2015; Trenholm and Krishnaswamy, 2020). Nevertheless, with the identification of novel targets and new neuroprotective agents to test, the number of clinical trials in ophthalmology has exponentially increased. However, outcomes are in general below researchers' expectations. The failure of neuroprotection trials could be related to patients’ selection issues. To be effective, by definition, neuroprotective strategies should be administrated at an early stage of disease. However, the diagnosis is often belated and patients are enrolled in later phases, when the neuronal function is compromised and the chances that a neuroprotective therapy could significatively influence disease course are few (Cummings, 2017; Wubben et al., 2019). To assess the efficacy of a therapy, the gold standard endpoint has been considered for a long time the evaluation of visual acuity, but with the improvement of knowledge, it became clear that other endpoints are required (Schmetterer et al., 2023). Meaningful endpoints should include functional, biochemical and structural parameters or any combination thereof. As a matter of fact, several potential endpoints specific for the examined pathology have been proposed, but their validation is complex and requires solid scientific evidence. Thus, the identification of combined endpoints is an urgent need to assess the ratio between risk and benefit of novel interventions (McCoy, 2018; Schmetterer et al., 2023).