Insulin-like growth factor-1 (IGF-1) is widely recognized as a multifaceted peptide crucial for fundamental growth and developmental processes. Its structural resemblance to insulin further underscores its significance, playing a key role in growth and development by activating both the MAP kinase and PI3K signaling pathways across nearly all tissues [1, 2]. Through its transmembrane ligand-activated tyrosine kinase receptor (IGF-1R), similar to the insulin receptor, IGF-1 drives anabolic processes that promote growth and maturation with widespread biological effects [3].

In early life, IGF-1 supports brain development by facilitating neurogenesis, synaptogenesis, neurite growth, myelination, and cellular survival [4]. Along with growth hormone (GH), it forms the somatotropic axis, essential for regulating aging [5]. However, GH/IGF-1 signaling diminishes significantly by the third decade of life, leading to a complex role for IGF-1 in the aging brain due to its mixed beneficial and detrimental effects [5, 6]. Consequently, the role of IGF-1 in the aging brain is complex and debated, due to its conflicting positive and negative effects.

IGF-1R signaling in neurons triggers intracellular processes vital for synaptic function and neuronal health. It enhances calcium influx via phosphorylation of voltage-gated calcium channels, inhibits tau hyperphosphorylation, and facilitates glutamate receptor trafficking into dendritic spines, contributing to synaptic remodeling [7].

IGF-1 also influences microglial and astrocytic activity. In microglia, it promotes an anti-inflammatory phenotype via the TLR4/NF-kB pathway [8]. In astrocytes, IGF-1 signaling is essential for maintaining neurovascular unit integrity, with its disruption impairing neurovascular coupling [9] a key process in cerebral blood flow regulation. Additionally, IGF-1 modulates mitochondrial metabolism, enhances glucose uptake, and increases the availability of glutamate transporters, preventing excitotoxicity [10–12]. It also regulates astrocytic phagocytosis and inflammation through PI3K signaling [13].

IGF-1 is known to modulate the expression and activity of several key antioxidant enzymes, contributing to the defense against oxidative stress (OS). Enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and thioredoxin reductase play essential roles in neutralizing reactive oxygen species (ROS), which are harmful byproducts of cellular metabolism. IGF-1 enhances the activity of SOD, which catalyzes the conversion of superoxide radicals into less harmful molecules such as hydrogen peroxide, while catalase and GPx further reduce hydrogen peroxide to water, preventing oxidative damage and consequently, ROS production [14]. Similarly, thioredoxin reductase helps maintain the reduced state of thioredoxin, a crucial molecule in redox regulation [15]. By enhancing both the expression and the activity of these enzymes, IGF-1 contributes significantly to cellular antioxidative capacity, reinforcing its role in protecting cells from oxidative damage.

In certain contexts, reduced IGF-1 signaling can enhance survival in various experimental models by limiting the production of ROS, reducing autophagy and stress responses, and thereby decreasing the likelihood of age-related neurodegenerative disorders (NDs) [16–18]. Conversely, a deficiency in IGF-1 has been linked to cognitive impairments and a higher risk of poor cognitive performance in humans. Increasing IGF-1 levels in the bloodstream can mitigate these problems, aiding in neural tissue repair, enhancing cellular resilience, and reducing the buildup of age-related cellular debris [17, 19–21]. IGF-1’s multifaceted effects on neurodegenerative and neuroinflammatory disorders may lie in its role in addressing OS.

NDs encompass a cluster of incapacitating diseases characterized by progressive neuronal loss. Prominent examples include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and multiple sclerosis (MS). While the precise etiology of these largely protein-misfolding diseases remains elusive, they often arise from a complex interplay of genetic predisposition, environmental triggers, aging, and neuroinflammation. The latter pertains to the immune response within nervous tissue, involving neurons, astrocytes, oligodendrocytes, and microglia [22]. Nonetheless, a skewed redox system equilibrium may be a common denominator in the progression of these acute and chronic disorders, regulating their advancement rather than being the primary cause [23]. Biomarkers—naturally occurring molecules indicative of distinct physiological or pathological processes—play a critical role in this context [24]. Within this realm, an intricate interplay between elevated OS biomarker concentrations and diminished antioxidative biomarker levels, along with the interaction of ROS and biomolecules such as proteins and neurotrophic factors, emerges as a heterogeneous modulator. The literature suggests that both diminished and elevated IGF-1 signaling might significantly influence OS regulation in these diseases—contributing to the deposition of abnormal proteins or metabolites and cell death via ROS. Acknowledging these dualistic attributes, the aim of this study is to delve into the existing literature regarding the interplay between the IGF-1 signaling pathway and its implications for OS regulation in the context of NDs (Figure 1).

AD stands as an age-associated neurodegenerative ailment and holds the grim distinction of being the primary cause of mortality and debilitation among the elderly across the globe [25]. Central to the identification of this neuropathology is the detection of misfolded proteins: Aβ peptides that aggregate into amyloid plaques and the tau protein that assembles into neurofibrillary tangles (NFTs) [26, 27]. The “amyloid cascade hypothesis” posits that Aβ peptides are produced in normally aging brains when the amyloid precursor protein (APP) undergoes proteolytic cleavage by β- and γ-secretases [28, 29]. Dysfunctional autophagy leading to impaired control over APP metabolism results in the accumulation of Aβ protein 42 (Aβ42) and Aβ protein 40 (Aβ40) as senile plaques (SPs) [30]. Numerous therapeutic avenues are now focusing on targetable factors that could alleviate the so-called ‘amyloid burden’ characteristic of AD brains and their distinct tissue attributes. Given that cognitive impairment is the predominant clinical hallmark of AD, several investigations propose a connection between IGF-1 and memory processes, with this neurotrophic factor playing a crucial role in specific forms of associative learning within neural circuits [31–33]. Altered levels of circulating IGF-1 have been identified as prognostic indicators in AD patients [34, 35] and animal models involving rodents [36, 37]. Significantly enriched expression of IGF-1 is particularly observed in the hippocampus, contributing to the regulation of the excitatory/inhibitory equilibrium pivotal for cognition and synaptic plasticity processes [7].

Among the central hypotheses underpinning Aβ neurotoxicity in AD etiology is OS [38]. SPs contribute to the peroxidation of lipid membranes and modify products involved in protein transformation, such as 4-hydroxynonenal (4-HNE). Additionally, they impede the dephosphorylation of the microtubule-associated protein tau. Beyond this, oxidative modification of proteins leads to a surge in carbonyl group numbers due to the oxidation of vulnerable amino acids in neurons and glia of individuals with AD. The interaction between superoxide radical (O₂^•−) and nitric oxide (NO) with proteins yields a potent oxidizing agent called peroxynitrite, the damaging effects of which extend beyond the conventional brain regions affected by AD, implying widespread oxidative damage in the brain [39]. In addition to protein oxidative damage, cytoplasmic RNA, as well as nuclear and mitochondrial DNA, are susceptible to oxidative modification, a consequence of hydroxylated products impacting their bases and the disruption of repair mechanisms [40].

PD is the second most common ND after AD, with an unclear etiology [39]. The hallmark of PD is the progressive loss and dysfunction of dopaminergic (DA) neurons in the nigrostriatal pathway [46]. Clinical manifestations of PD include motor symptoms such as rigidity, bradykinesia, and tremor, as well as a wide range of non-motor symptoms that appear in the premotor stage and progress throughout the disease [47]. The primary underlying cause of cellular dysfunction and death in PD is believed to be OS [48]. DA neurons are particularly susceptible to OS and mitochondrial dysfunction due to the presence of ROS-generating enzymes like tyrosine hydroxylase (TH) and monoamine oxidase (MAO) [39]. These neurons, located in the substantia nigra (SN), contain iron, which catalyzes the Fenton reaction and exacerbates OS [49]. This OS can initiate a cascade of events leading to protein aggregation, apoptosis, and neuroinflammation. Castilla-Cortázar et al. [50] identified parallels between the cellular and molecular mechanisms in the pathogenesis of PD and IGF-1 deficiency. Consequently, the age-related decline in serum IGF-1 levels may be a risk factor for PD development, where partial IGF-1 deficiency exacerbates brain oxidative damage, inflammation, blood-brain barrier (BBB) integrity issues, and behavioral impairments. Replacement therapy could potentially mitigate these alterations [32, 50–53]. Moreover, Bhalla et al. [54], review the pharmacological actions of IGF-1 and GLP-1 receptor activators indicating that IGF-1R analogues bind to their receptor, restoring the PI3K/AKT/mTOR signaling pathway, inhibiting neuronal apoptosis and ROS production, and thus ameliorating the pathological condition of neurodegenerative processes among them, PD.

Among protein misfolding diseases we find HD, which results from the nucleotide sequence CAG repeat expansion in the HD gene, increasing the polyglutamine tail at the N-terminal of huntingtin (Htt). Mutant Htt causes the neurodegeneration of striatal and cortical pathway and leads to the characteristic cascade of events described earlier: excitotoxicity, proteasomal dysfunction, transcriptional deregulation, mitochondrial dysfunction, impaired energy metabolism, and OS [64]. Furthermore, amyotrophic lateral sclerosis (ALS) is another ND characterized by the presence of protein misfolding inclusions and, as a consequence, the loss of motor neurons in the motor cortex, brainstem, and spinal cord [65, 66]. In these inclusions, the main protein detected is TAR DNA binding protein of 43 kDa (TDP-43) and its insoluble, ubiquitinated, and cleaved C-terminal fragments. One of these latter is the ∼25 kDa C-terminal fragment (TDP-25), identified as a key player in the pathogenesis of this disease, which interacts with multiple factors—ubiquitinated aggregates, OS, mitochondria dysfunction, apoptosis-that contribute to the injury of motoneurons [67].

In addition to these ND, a group of animal and human brain diseases, characterized by neuronal loss, has been named prion diseases. Prion diseases are peculiar since they are caused by an infectious agent, prion, whose main component is an abnormal isoform (PrPSc) of prion protein (PrP) [68]. A specific sequence of PrP (106–126) has been targeted as the underlying cause of apoptosis, mitochondrial dysfunction and associated OS in the neurodegenerative mechanisms of prion disorders [69]. About cell loss and degeneration, we found that OS along with the inflammatory response constitute the primary event leading to the loss of functional neurons and demyelination in spinal cord injury (SCI) [70], axonal degeneration [71] and in aging progression [72]. Moreover, Siddiqui et al. [73], summarizes the potential role of IGF-1/GLP-1 signaling activation in intracerebral hemorrhage, concluding that the disease could be aggravated by the downregulation of IGF-1 and GLP-1 receptors and can lead related neurodegeneration disorders.

As we mentioned above, IGF-1 is well-known growth factor to exert trophic effects on neuronal regeneration and stimulate neurons and glia protein synthesis, and favor neuronal survival, inhibiting apoptosis key events of OS response [74] and being considering as a mitochondrial protector in several experimental models [75].

There is a direct and consequent relationship between neurodegeneration and neuroinflammation, with OS as an intrinsic mechanism of these pathological processes. In this context, glia and immune cells are crucial players in regulating inflammatory responses in the nervous system. The cascade of events, already mentioned, of neurodegeneration may facilitate immunocyte infiltrations and mediate neuroinflammation [83] or vice versa playing synergistic roles. Moreover, it is settling a self-toxic feedback loop between inflammatory cytokines, mitochondrial dysfunction and the production of ROS [84], since under pathological conditions mitochondrial membranes and DNA are damaged, and the release of mitochondrial components is induced. These mitochondrial components are recognized by pattern recognition receptors (PRRs) as DAMPs, indicating that cells are damaged, which trigger the innate immune response [85, 86]. This situation activates the NLRP3 inflammasome complex acting as a sensor of mitochondrial dysfunction, and activation of this complex leads to the production of IL-1β [84]. Among therapeutic approaches to modulate this loop, IGF-1 properties allow it to exert anti-inflammatory actions by the reduction of brain cytokine expression via the downregulating of glia activation [52]. Moreover, our group recently demonstrated that IGF-1 gene therapy resulted in significant changes in several parameters related to microglia and astrocyte phenotypes (particularly in the CPu and dorsal hippocampal areas), supporting the use of IGF-1 as a therapeutic molecule for neuroinflammatory processes [87].

Throughout this review, it is evident that inflammation is a common factor in various central nervous system (CNS) neurodegenerative pathologies, often exacerbated by a decrease in IGF-1 pathway activity.

The brain produces natural antioxidants, including growth factors like IGF-1, which may have regenerative and neuroprotective actions partly through antioxidant mechanisms. Alterations in IGF-1 signaling may lead to free radical generation and adverse outcomes in both animal models and humans. Consequently, modulating the IGF-1 signaling pathway presents a promising therapeutic strategy to alleviate the harmful effects of OS, aging, and neuroinflammation.

Neurotrophic peptides, while promising for promoting neuronal survival and regeneration in the CNS, are constrained by several limitations. A major challenge is their poor ability to cross the BBB, which hinders their delivery to the CNS in therapeutically relevant concentrations. As other insulin-like peptides, IGF-1 is described to cross through the BBB by transcytosis [94]. In any case, as some therapeutic approaches may involve delivery systems such as nanoparticles or viral vectors, these should also be able to cross the BBB.

Another concern is the potential for off-target effects, as trophic peptides can act on multiple receptor types, leading to unintended biological responses. Thus, it is important to restrict IGF-1 overexpression to the SNC cells, since IGF-1 could have negative effects such as tumorigenic effects in obesity and endocrine-related cancer [95]. Moreover, the risk of inducing aberrant neuronal growth or hyperactivation further complicates their therapeutic use, necessitating precise control over their activity. Consequently, a deeper understanding of IGF-1’s role in the CNS is required. By characterizing the interaction between OS and IGF-1, we can identify specific downstream molecules in the IGF-1 signaling pathway that may serve as novel and effective therapeutic targets.

This review consolidates evidence showing that IGF-1 has antioxidant and anti-inflammatory effects that can improve and reduce alterations associated with NDs. Thus, we suggest that disruptions in IGF-1 signaling could induce free radical production and cellular damage. Therefore, modulating IGF-1 signaling offers a new therapeutic avenue in neurodegeneration, potentially mitigating the detrimental effects of OS, aging, and inflammation in the brain. However, this neurotrophic factor exhibits pleiotropic activity that varies depending on the specific cell type it acts upon. Even within the same cell type, its effects can differ based on peptide levels. Therefore, further research is essential to obtain more conclusive and promising results.