OS is caused by free radicals, atoms or groups with unpaired electrons, such as hydroxyl, superoxide and nitric monoxide (35). OS may cause damage to the cells and tissues of the body, such as the DNA, RNA, protein and lipid bilayer of nerve cells (36-38). Oxidative damage to nerve tissue has been found in NDs, such as AD, PD and amyotrophic lateral sclerosis. Studies have indicated a close association between Aβ, Tau protein and OS in neurons. For instance, Aβ aggregation may damage the mitochondria, leading to mitochondrial dysfunction and the release of numerous reactive oxygen species (ROS) and OS; the generation of ROS may also increase the production of Aβ (39,40). Free radicals, such as oxidized Fe³⁺, may promote the phosphorylation and aggregation of Tau (41). Furthermore, hyperphosphorylation and accumulation of Tau may also damage mitochondrial function, thereby generating a substantial amount of ROS. Chronic OS and the resultant peroxides, such as 4-hydroxynonenal, may also provoke Tau hyperphosphorylation, causing conformational changes and Tau aggregation (42). Aβ aggregation and Tau hyperphosphorylation have crucial roles in the pathogenesis of AD (43-46). In addition, OS is also associated with the free iron content of cells and elevated levels of iron ions may be found in the brains of patients with PD or AD (47). Therefore, it may be concluded that OS is intertwined with ND.

One of the main pathological features of AD is the formation of senile plaques by the accumulating Aβ outside the brain nerve cells. CR, the major active component of saffron, has been indicated to increase the tightness of a cell-based blood-brain barrier model, increase recombinant low-density lipoprotein receptor-related protein 1 and P-glycoprotein expression, improve Aβ clearance, reduce Aβ aggregation and inhibit the formation of senile plaques (48). Both CR and the extract of saffron (water/methanol, 50:50 v/v) was reported to inhibit the accumulation of Aβ in the human brain through antioxidant effects (49). Furthermore, saffron extract was able to antagonize aluminum oxide-induced neurotoxicity by elevating the activity of antioxidant enzymes, such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-Px) (50). Streptozotocin (STZ) may cause OS by increasing the production of oxygen-free radicals, thereby inducing cognitive impairment (51). In addition, CR may elevate GSH-Px activity and the total thiol content and reduce malondialdehyde (MDA) levels and OS damage, producing an antagonistic effect on STZ-induced cognitive impairment in rats (52-54). CR may also significantly decrease the Bax/Bcl-2 ratio and cleaved caspase-3 levels by reducing ROS production and inhibiting Aβ-induced apoptosis (55,56). Mitogen-activated protein kinases (MAPKs) are serine-threonine kinases that mediate intracellular signaling related to various cellular activities, including cell proliferation, differentiation and transformation (57). When OS is triggered, ROS activates downstream apoptosis pathways through the MAPK pathway, such as NF-κB and p53, triggering cell death (58-60). Safranal may reduce the ROS levels in cells, thereby reducing Aβ-induced apoptosis through the PI3K/AKT and MAPK/extracellular regulated protein kinase (ERK)1/2 pathways (61). Following treatment of AD rats with safranal, the hippocampal levels of MDA, ROS and protein carbonyl were observed to be reduced, while the activity of SOD and myeloperoxidase was increased in the hippocampal tissue (62).

Abnormal Tau phosphorylation is also one of the leading causes of AD. In the brain of patients with AD, abnormally phosphorylated tau protein has been observed, which, unlike normal tau protein, does not bind to microtubule proteins; instead, its presence also prevents the latter from promoting the assembly of tubulin into microtubules, leading to neurofibrillary tangles (63). Therefore, decreasing Tau hyperphosphorylation is an effective way to treat AD. Trans-CR 4 and trans-crocetin were selected to treat two AD neuronal cell culture models and the results demonstrated that these two compounds did not affect the viability of neuron-like cells. Both trans-CR 4 and trans-crocetin exerted a crucial effect to inhibit amyloidogenic pathways and were influential in suppressing the active forms of ERK1/2 kinases and glycogen synthase kinase-3β, as well as markedly reducing Tau phosphorylation (64). Furthermore, CR was able to significantly decrease MDA, Aβ and phosphorylated Tau levels by modulating the MAPK signaling pathway (65). AD is also characterized by abnormal Tau aggregation, whereas CR is able to inhibit Tau aggregation and suppress the formation of Tau protein filaments (66). Fig. 2 illustrates the relationship between saffron components, Aβ aggregation and Tau abnormal phosphorylation in AD.

In addition to AD, saffron also improves PD symptoms through its antioxidant effects. CR has a protective effect in terms of reducing mitochondrial permeability transition pore-induced dopaminergic neuron damage and PD complications, in addition to ameliorating 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD complications and reducing substantia nigra cell death (67). It was reported that the antioxidant capacity of saffron contributes to PD treatment. After validating the neuroprotective efficacy of methanolic saffron extract and its active constituent, CR, in a drosophila model of Parkinson's disease, studies have proposed that saffron may be used as a complementary therapeutic agent for PD-mediated NDs (68,69). While common NDs, such as AD and PD, have been found to cause oxidative damage in neuronal tissues, saffron and its active compounds may reduce oxidative stress by inhibiting Aβ aggregation, tau protein phosphorylation or ROS production, proving that saffron has considerable therapeutic potential for NDs. Table I presents the relevant research progress regarding the use of saffron to treat NDs through its antioxidant effects.

OS has an essential role in the pathological changes of NDs, whereas neuroinflammation is also crucial for ND pathogenesis (70). Neuroinflammation is a defense mechanism that protects the central nervous system (CNS) from tissue damage or viral attack (71). However, a continuous inflammatory process in the CNS may inflict severe damage to the nervous system and eventually lead to CNS damage (72). Inflammation-derived ND is a specific CNS damage disease. The primary hallmark of inflammation in the brain is the activation of glial cells, particularly microglia, and ROS is involved in microglial activation (73). Microglia cells influence the NF-κB signaling pathway. Tumor necrosis factor-α (TNFα) and interleukin (IL)-1β are common cytokines secreted by activated glial cells (74).

Studies have demonstrated the therapeutic potential of saffron and its active constituents for neuroinflammation-mediated NDs. Saffron extracts were able to upregulate the synaptic proteins in the brains of 5XFAD mice, transgenic mice transfected with five Familial Alzheimer's disease mutations, and reduce Aβ pathology-related neuroinflammation (48). In AD mice, safranal not only reduced the expression of NF-κB and its downstream TNFα, IL-6, apoptosis markers and glial fibrillary acidic protein, but also elevated the mitochondrial membrane potential (∆ψm) (62). Safranal exerts anti-inflammatory effects by inhibiting the classic NF-κB inflammatory pathway, thereby improving AD (75). Safranal also reduces the hyperactivity of acetylcholinesterase (AChE) and inhibits cholinesterase overexpression. Furthermore, crocetin may suppress NF-κB activation and P53 expression in the hippocampus, significantly decreasing the pro-inflammatory cytokine secretion and increasing anti-inflammatory cytokine levels in plasma, while inhibiting apoptosis and decreasing Aβ in various brain areas (76).

Acute NDs, such as CI, are also affected by neuroinflammation, a crucial pathological process in the later stage of CI (77). It has been indicated that inflammation mediates CI-reperfusion injury. Ischemic stroke may cause depression, which is a severe disease inflicted by CI, and post-stroke depression (PSD) is a severe complication of stroke (78). It has been demonstrated that persistent CI leads to PSD (79). Thus, PSD is closely associated with inflammation. CR was able to inhibit the inflammatory response by inhibiting the activation of the Toll-like receptor 4/myeloid differentiation factor 88/NF-κB signaling pathway in the hippocampal tissue, thereby preventing the occurrence of PSD (80). Table II displays the relevant research progress regarding the use of saffron for treating NDs through its anti-inflammatory effects. Fig. 3 presents the anti-inflammatory mechanisms of saffron components in ND treatment.

Mitochondria are organelles with a double membrane structure found in the cytoplasm of eukaryotes containing extranuclear genetic material. Their internal membranes are the aggregation sites of respiratory chain complexes. Mitochondria, the main site of the body's energy metabolism, regulated the oxidative phosphorylation process and synthesize ATP, which may also be produced via glycolysis in microglial cells and astrocytes (81). Mitochondria generate energy and control the storage and release of Ca²⁺ to maintain the dynamic balance of the intracellular Ca²⁺ concentration. Furthermore, Ca²⁺ may participate in multiple cell activities, such as cell-matrix metabolism, cell apoptosis and initiation of signal transduction pathways (82). Mitochondrial dysfunction may prevent the aforementioned functions and is a major risk factor for neurodegeneration (83).

PD was the first ND associated with mitochondrial dysfunction. In the compact part of the substantia nigra, the nigrostriatal dopaminergic system and platelets of patients with PD, a 30% reduction in the activity of the mitochondrial respiratory chain complex I and a decrease in rate-limiting enzymes of the tricarboxylic acid cycle-ketoglutarate dehydrogenase complex were observed (84). In the rotenone-induced PD model in Drosophila, the level of mitochondrial enzyme activity in the Drosophila head was significantly reduced. Following treatment with saffron extract and CR, mitochondrial enzymes, succinate dehydrogenase and cytochrome c reductase returned to normal levels, indicating that saffron and its active constituents may improve mitochondrial dysfunction (68). Experiments using specific targeted small interfering RNA to knock down the expression of the C/EBP homologous protein (CHOP) revealed that CR-induced protection and inhibition of ER stress is mediated by inverting the 1-methyl-4-phenylpyridinium (ion)-induced decrease of Wnt protein through the CHOP pathway, thereby reducing cell damage and apoptosis, inhibiting mitochondrial dysfunction and maintaining ATP synthesis and ∆ψm (85).

Transient CI is responsible for sudden, temporary and reversible neurological dysfunction. It has been demonstrated that mitochondrial dysfunction may occur after CI reperfusion (86). After pre-treatment of BI rats with CR, it was observed that CR increased the mitochondrial membrane fluidity, membrane phospholipid content, ∆ψm, mitochondrial respiratory function, respiratory enzyme activity and ATP content. CR also reduced MPTP opening and the free Ca²⁺ concentration and protected the hippocampal mitochondrial structure and function in rats with ischemic BI by significantly ameliorating the hippocampal mitochondrial pathology (87). In addition, CR can improve the energy metabolism of cells after oxygen-glucose deprivation, restore ∆ψm, reduce the intracellular Ca²⁺ concentration, upregulate optic atrophy 1 (Opa1) expression, downregulate dynamin-related protein 1 (Drp1) expression and restore the normal mitochondrial fusion and fission (88). Given the effects of the active constituents of saffron on improving mitochondrial dysfunction in cells, saffron extract was used to treat rats with focal brain ischemia/reperfusion injury. The results suggested that saffron extract significantly inhibited rat neuronal necrosis and astrocyte proliferation, upregulated the expression of Opa1, downregulated the expression of Drp1 and restored normal mitochondrial fusion and fission (89). Table III presents the relevant research progress of studies using saffron in treating NDs by improving mitochondrial dysfunction. Fig. 4 illustrates the mechanisms of saffron components in improving mitochondrial dysfunction for ND treatment.

Depression is one of the psychological symptoms of NDs. Studies have demonstrated that patients with NDs, including AD and PD, exhibit depressive symptoms. Furthermore, elevated levels of pro-inflammatory factors, such as IL-1β, IL-6 and TNFα, are frequently found in the cerebrospinal fluid of patients with depression, indicating the relationship between depression and the occurrence of neuroinflammation (110-115). The antidepressant mechanism of saffron has only been studied in the last decades. CR had a significant antidepressant effect in a chronic corticosterone-induced depression model in rats, as evidenced by a substantial reduction in IL-1β and SOD levels in the hippocampus, suggesting that the inhibition of inflammation and OS is associated with the antidepressant effect (116). Patients with depression usually have higher plasma corticosterone than normal individuals, it has been demonstrated that saffron water extract and CR were able to reduce the plasma levels of corticosterone in a rat model of depression (117,118). Increasing the transcriptional level of BDNF in the hippocampus may also have an antidepressant effect (119,120), demonstrating that saffron may alleviate the depressive symptoms of NDs. Therefore, saffron may not only relieve the main symptoms of NDs, such as nervous disorders and limb and cognitive dysfunction, but also have an antidepressant effect treating its potential complications, which is an advantage that other drugs do not possess.

Epilepsy is a chronic disease characterized by sudden abnormal discharges of nerve cells in the brain, leading to temporary brain dysfunction. NDs are characterized by cell death and destruction of brain structures, which may increase the risk of epileptic seizures (121). The appearance and increase in the levels of inflammatory cytokines, such as TNF, IL-1 and IL-6, is closely linked to the onset of epilepsy (122). CR and crocetin, the active constituents of saffron, inhibit the increase in the inflammatory cytokines to varying degrees (75). This finding suggests that the anti-epileptic action of saffron may be mediated by its anti-inflammatory properties.

As the second messenger in neurons (123), Ca²⁺ regulates nerve synapses and has a vital role in cell growth, apoptosis, neuronal development and the regulation of various metabolic channels (124). An abnormal Ca²⁺ concentration may lead to cell damage and even apoptosis. The entry of Ca²⁺ from the external cell environment, a central characteristic associated with cell death, leads to Ca²⁺ imbalance and has an essential role in Ca²⁺ overload in NDs, such as PD and AD (125). For instance, the significant reduction of Ca²⁺ in the platelets of patients with early AD (detected as Aβ oligomer and associated with hypomnesia) increases the secretion of parathyroid hormone. This essential hormone maintains Ca²⁺ homeostasis and promotes calcium influx, leading to increased Ca²⁺ in brain cells, which causes dementia by damaging mitochondrial function and reducing cellular energy metabolism (126). Studies have reported that saffron and its active constituents may maintain Ca²⁺ homeostasis in neurons, but the specific mechanism of action remains to be elucidated (10,127). Therefore, the mechanism by which saffron regulates Ca²⁺ homeostasis requires further investigation.