The damage, degeneration, or death of neurons depending on different areas of the brain causes a variety of incurable and irreversible neurodegenerative diseases. Progressively, a decrease in cognitive functions has been associated with reduced necessary movement, compromised well-being, and lower life satisfaction (Davenport et al., 2023). Arginine as a semi-essential amino acid is an important player in a biological process that is expected to be strongly related to health and disease. Arginine serves as a biological substrate for some neuronal enzymes in the brain, including nitric oxide synthase (nNOS), arginase, arginine decarboxylase (ADC), and arginine-glycine aminotransferase (AGAT). These enzymes are responsible for metabolizing this small molecule to produce vital metabolites including nitric oxide (NO), urea, ornithine, agmatine, and creatine respectively (Rath et al., 2014). Arginine and their endogenous metabolites directly or indirectly participated in a broad range of physiological functions, including cerebral blood flow, cell hemostasis, cell proliferation, neurogenesis, neuroplasticity, regeneration, modulation of neurotransmitters, energy production, immune response, and extracellular matrix remodeling. Arginine metabolites are known as cellular messengers, especially NO which serves as a retrograde/multimodal brain transmitter (Garthwaite, 2019). Moreover, agmatine and creatine have neuroprotective effects and act like a neurotransmitter to modulate the release of GABA, glutamate, and dopamine (Béard and Braissant, 2010; Xu et al., 2018). Arginine is a building block for protein synthesis and is involved in the structure of the neuropeptide of vasopressin that is produced in specific neurons in the hypothalamus to release from the neurohypophysis. Vasopressin is responsible for cardiovascular regulation and neuropsychiatric conditions. Arginine participates in the body structure of cell-penetrating peptides (CPPs) such as arginine-rich peptides (ARPs).

ARPs can represent a powerful delivery system for different types of agents such as DNA, RNA, miRNA, siRNA, PNA, peptides, small molecules, liposomes, and nanoparticles, which fulfil various applications such as gene vaccines, gene editing, neuroprotective drugs, and imaging (Geng et al., 2022). ARPs have also been developed as therapeutics for Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) in previous experimental in vitro and in vivo studies (Table 1). The neuroprotective properties of ARPs are associated with their ability to transport diverse cargoes across the blood-brain barrier (BBB), their mechanism of action, and modulating immune responses (Macdougall et al., 2020h). This review provides an overview of the unique biochemical features of arginine and describes how ARPs and ARP-derived peptides, due to their arginine residues provide potential therapeutics to target a range of neurodegenerative diseases.