Neurodegenerative diseases are caused by the loss of neurons, myelin sheaths, and synapses. Neurodegenerative diseases can be caused by aging and genetic mutations, and the condition of the diseases worsens over time, leading to functional impairment [79]. Common pathogenic mechanisms of neurodegenerative diseases include: (1) abnormal protein dynamics (protein misfolding and aggregation); (2) oxidative stress (formation of reactive oxygen species and free radicals); (3) dysfunction of neurotrophic factors; (4) mitochondrial dysfunction; (5) neuroimmune inflammation; (6) neuronal Golgi breakdown; (7) disruption of cell/axon transport; and (8) altered cell signaling. Altogether, the diversity of multiple pathogenic factors leads to multifaceted neuronal death [80].

The main research areas of neurodegenerative diseases include: (1) tau protein disease—Alzheimer’s disease (AD); (2) extrapyramidal disorder: Parkinson’s disease (PD), Huntington’s disease (HD); (3) spinocerebellar degeneration: multiple system atrophy (MSA); (4) autonomic disorders: Shy-Drager syndrome (SDS); and (5) motor neuron disorders: amyotrophic lateral sclerosis (ALS), Werdnig–Hoffmann disease. Ophthalmological neurodegenerative diseases mainly include retinitis pigmentosa (RP).

The main drugs for neurodegenerative diseases include: galantamine, rivastigmine, and donepezil for Alzheimer’s disease [81,82,83]; levodopa, monoamine oxidase-B inhibitors, and dopamine agonists for Parkinson’s disease [84]; tetrabenazine (Xenazine) and deutetrabenazine (Austedo) for Huntington’s disease [85]; fingolimod (Gilenya), dimethyl fumarate (Tecfidera), and teriflunomide (Aubagio) for multiple sclerosis (MS) [86]; and Radicava, rilutek, exservan, nuedexta, and tiglutik for amyotrophic lateral sclerosis [87]. As a therapeutic drug for retinitis pigmentosa, Luxturna^® (voretigene neparvovec) is the only Food and Drug Administration (FDA)-approved retinitis pigmentosa therapy, designated for a small subset of patients with RPE65 mutations [88].

On 23 June 2022, the FDA published a 5-year action plan for drugs of neurodegenerative diseases, focusing on ALS [89,90]. Therefore, with the deepening of neurodegenerative disease research, multi-pathway and multi-target therapeutic drugs urgently need to be developed.

In a report, besides the neurotrophic and neurogenesis activity of NK-4 observed in a transgenic mouse model of Alzheimer’s disease (Tg 2576), the effect of NK-4, which was better than acetylcholinesterase inhibitors (AChEIs), was also observed in the early stages of mouse dementia (6 months old). NK-4 may be a new drug for the treatment of early- to late-stage Alzheimer’s disease [91]. Another study showed that NK-4 had neurotrophin-like activity and exhibited neuroprotective effects in vitro and in vivo. In vitro, NK-4 significantly enhanced nerve growth factor (NGF)-induced neurite outgrowth in PC12HS cells. In vivo, NK-4 effectively prevented injury in a rat stroke model (middle cerebral artery occlusion (MCAO) Rats) through neurotrophin-like activity and antioxidative activity [75]. In vitro, NK-4 was shown to dose-dependently protect PC12 cells from oxidative stress-induced toxicity by 6-hydroxydopamine (6-OHDA) or hydrogen peroxide (H₂O₂). In an ataxia animal model (Syrian hamster marked by Purkinje cell degeneration, PCD model) of neurodegeneration, the studies showed that the neuroprotective effects of NK-4 are mediated by the PI3K-Akt signaling pathway [92]. NK-4 can also reduce the accumulation of Aβ in the brain, inhibit Aβ aggregation, scavenge free radicals, and produce neuroprotective effects by its intraperitoneal injection in Alzheimer’s disease model AβPP transgenic mice (Tg2576). It is thus suggested that NK-4 can also be used to treat Alzheimer’s disease [77,93].

In a recent study, researchers administered NK-4 into the eyes of RCS rats via intravitreal injection; the researchers found that NK-4 could inhibit the apoptosis of photoreceptor cells. Hmox1, Mt1, Atf5, Slc7a11, and Bdh2 genes were up-regulated by the RNA-seq analysis and confirmed by the RT-PCR analysis. Functional and pathway enrichment analyses of up-regulated genes in that study suggest that the neuroprotective effect of NK-4 in RCS rat retina might be related to the retinal pigment epithelial metabolic process, transition metal ion homeostasis, and negative regulation of neurons’ apoptosis by Metascape analysis. They also uploaded five genes (Hmox1, Mt1, Slc7a11, Bdh2, and Atf5) to the DAVID database for the functional annotation clustering of bioinformatics resources. Based on the gene function distributed by DAVID, it was divided into the following categories: response to oxidative stress, negative regulation of neuron apoptotic process, and iron ion homeostasis [78]. All of these results revealed the molecular mechanism by which NK-4 inhibits the apoptosis of photoreceptor cells, indicating that NK-4 upregulates genes involved in anti-oxidative stress and anti-apoptotic pathways.

The synthetic route for NK-4 is shown in Figure 4 [94,95]. 1-Ethyl-4-methylquinolin-1-ium iodide was treated with Vilsmeier reagent generated in situ from P(O)Cl₃ and N,N-dimethylformamide, affording the desired NK-4 at a 41% yield (Figure 4A). A different C1 unit protocol was also reported (Figure 4B). However, these routes could be used for the same three-quinoline moiety, but not for hetero-quinoline moieties. In the future, the development of a new synthetic methodology is highly required to supply various derivatives which have different quinoline cores (Figure 4C).