Date palm fruits, rich in polyphenolic antioxidants, including PCA, demonstrate neuroprotective properties in model systems, suggesting potential to reduce AD risk, delay onset or slow progression (48). PCA could be responsible for the beneficial health effects of polyphenol-rich foods, as they can easily cross the BBB (49). Bioavailable PCA extracted from edible chicory has been shown to undergo partial glucosylation and sulfation in human adults (50). Among the four primary active components of Alpiniae oxyphyllae fructus (nootkatone, tectochrysin, chrysin and PCA), PCA exhibits high BBB permeability via passive diffusion, whereas lactoferrin demonstrates relatively poor permeability (51).

PCA exhibits diverse pharmacological activities, including antioxidant, anti-inflammatory, neuroprotective, antibacterial, antiviral, anticancer, anti-osteoporotic, analgesic and anti-aging effects, metabolic syndrome prevention, and protection of liver, kidney and reproductive functions (52,53). PCA also modulates neuroprotective factor expression, suppresses apoptosis, activates the autophagy-lysosomal pathway, reduces oxidative stress and inflammation, enhances synaptic plasticity, inhibits amyloid-β (Aβ) accumulation, decreases amyloid precursor protein (APP) processing, strengthens the cholinergic system and mitigates neuronal excitotoxicity (54). Consequently, PCA, present in various fruits, vegetables and grains, shows promise as a dietary supplement for alleviating cognitive deficits associated with NDs.

In protein-misfolding disorders such as AD and PD, neuroinflammatory pathway activation triggers concomitant oxidative and nitrosative stress (66). Inhibition of neuroinflammatory nitric oxide signaling can mitigate functional neurodegeneration and reduce cellular stress associated with aberrant nitrogen metabolism and protein glycosylation (67). The neuroimmune axis exhibits complex interdependencies, serving as the primary pathogenic driver in multiple sclerosis with similarly amplified involvement in other NDs, including AD, ALS and PD (68). Chronic innate immune cell activation, a hallmark of age-related NDs, exacerbates neurodegeneration by promoting Aβ plaque formation and τ hyperphosphorylation, as exemplified in AD (69). A range of neurological conditions, including NDs and COVID-19 neurological sequelae, share persistent neuroinflammation, with mounting evidence implicating inflammasome activation in driving their pathogenesis (70). Aggregated proteins linked to NDs, such as Aβ, τ, α-syn and TAR DNA-binding protein 43, function as damage-associated molecular patterns (DAMPs), activating innate immune responses via multiple pattern recognition receptors, including Toll-like receptors, NOD-like receptors, cytosolic DNA sensors and other DAMP receptors (71). As resident immune cells of the CNS, microglia play a protective role by phagocytosing pathological protein aggregates, yet excessive phagocytosis can impair their function, induce neuroinflammation and ultimately promote neurodegeneration in various NDs (72).

PCA exerted anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated BV2 microglia by inhibiting the Toll-like receptor 4-mediated NF-κB and MAPK signaling pathways (73). PCA also inhibited the immune response in LPS-activated BV2 microglia via the SIRT1/NF-κB pathway and suppressed PC12 cell apoptosis induced by microglial activation (74). In addition, PCA promoted the M1/M2 phenotypic shift via m-TOR pathway inhibition, thereby ameliorating inflammation in mouse models of brain haemorrhage (75). 3,4-Dihydroxyphenylacetic acid, PCA and dihydrocaffeic acid, and their conjugated forms, significantly attenuated neuroinflammation by scavenging ROS, thereby protecting neuronal cells. Notably, phenolic acid conjugates demonstrated superior efficacy in mitigating oxidative stress and inflammatory damage to neuronal SH-SY5Y cells stimulated by bacterial lipopolysaccharide and tert-butyl hydroperoxide compared with their free forms (76).

Neural regeneration refers to the restoration of neurological function through complex biological processes, including neuronal regrowth, proliferation or differentiation of NSCs, and participation of dual roles of glial cells (such as microglia and astrocytes) (77). Post-injury, damaged neurons release neurotrophic factors (including BDNF and NGF) and cytokines that promote axonal regeneration and synaptic reconnection (78). Neural regeneration also relies on signal transmission between cells and microenvironmental regulation, such as the influence of BDNF and NGF, which enhance neuronal survival and promote neuronal growth and differentiation (79). Concurrently, NSCs contribute to repair via their self-renewal capacity and multilineage differentiation potential, essential for maintaining CNS homeostasis (80). MSCs also play an important role in reconstructing neural networks and restoring their functions with burgeoning preclinical evidence (81–83).

PCA promotes neural regeneration, with its mechanism potentially involving the insulin-like growth factor 1 receptor/PI3K/Akt signaling pathway (84). PCA increased the survival of primary cultured cortical neurons in newborn rats and promoted neurite growth in these neurons (85), and this neurotrophic protective effect exerted by PCA was correlated to its regulation of phosphorylated AKT expression (86). In addition, PCA promoted RSC96 Schwann cell migration, regeneration and peripheral nerve repair by regulating MAPK, plasminogen activator and MMP signaling pathways (87). When combined with fetal bovine serum in vitro, PCA promoted neuronal differentiation, induced neuronal maturation and enhanced neurite growth in cultured neural stem and progenitor cells (88). PCA treatment significantly reduces ROS levels, caspase 3 activity and apoptosis in NSCs (89). Therefore, PCA has also gained increasing attention in neural regeneration and neurotrophic protective effects.

Despite clinical differences, NDs share fundamental pathological mechanisms, such as abnormal protein deposition, intracellular calcium overload, mitochondrial dysfunction, REDOX homeostasis imbalance and neuroinflammation (90). NDs are characterized by a suite of interconnected hallmark features, such as pathological protein aggregation, synaptic dysfunction, disrupted proteostasis, cytoskeletal defects, metabolic imbalance, nucleic acid alterations, neuroinflammation and neuronal loss, all of which collectively drive disease onset and progression through complex interactions modulated by genetic determinants and biochemical pathways (91).

The pathological mechanisms of AD mainly include the formation of amyloid plaques, abnormal phosphorylation of τ protein, neuroinflammation and oxidative stress. As a primary metabolite in blueberry extracts, PCA mitigates neuronal damage by enhancing autophagy, supporting its potential for dietary AD intervention (13). While okadaic acid induces AD-like pathology, including τ hyperphosphorylation, neurofibrillary tangle formation and Aβ deposition, PCA counteracted this cytotoxicity in PC12 cells by regulating Akt/glycogen synthase kinase-3β (GSK-3β)/myocyte-specific enhancer factor 2D signaling and modulating autophagic activity, thereby demonstrating neuroprotective efficacy (92). In a rat model of mild memory impairment induced by long-term intragastric administration of D-galactose, PCA improved learning and spatial memory abilities in the Morris water maze test and restored dysregulated serotonergic and dopaminergic activity (93).

The abnormal aggregation of Aβ and α-syn drives the formation of amyloid plaques in AD and Lewy bodies in PD, with the latter also characterized by progressive degeneration of dopaminergic neurons in the substantia nigra. Treatment of amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice (a double-transgenic mouse model co-expressing mutant human APP/PS1, commonly used to model AD) with PCA significantly increased BDNF levels in the hippocampus and cerebral cortex, reduced Aβ deposition, decreased APP expression and inflammatory responses, and improved learning and memory abilities (94). High doses of PCA (50 mg/kg) alleviated symptoms in an AD mouse model induced by Aβ injection into the hippocampus, potentially via the cholinergic synaptic signaling pathway (95). By downregulating inflammatory mediators in the brain of Aβ_25-35-injected AD model mice, particularly inducible nitric oxide synthase and cyclooxygenase-2, PCA significantly alleviated neuroinflammation and inhibited lipid peroxidation in the brain, kidney and liver tissues (96). As the main metabolite of anthocyanins, PCA, also known as anthocyanin 3-glucoside, inhibited the aggregation of Aβ and α-syn, destabilizing their pre-formed fibrils and preventing the PC12 cell death mediated by the toxicity of the Aβ and α-syn (97).

PCA exerted neuroprotective effects in both 1-methyl-4-phenylpyridinium (MPP+)-treated PC12 cells and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, and was associated with the inhibition of α-syn oligomerization (98,99). Although PCA significantly increased dopamine turnover in the striatum and improved cognitive function in experimental memory impairment mice, it did not significantly affect memory performance in healthy rats (100). The combination of PCA with ginkgolide B significantly restored the motor ability of PD mice, alleviated neuronal damage, boosted the activity of antioxidant enzymes in brain tissue and increased the expression in the midbrain substantia nigra (101). The combination of honokiol with PCA reduced neuronal loss in 6-hydroxydopamine-treated zebrafish PD models (102). PCA demonstrated neuroprotective efficacy in ALS transgenic mice by extending survival time, suppressing spinal glial proliferation, preventing motor neuron apoptosis, alleviating pathological manifestations and preserving neuromuscular junction integrity, thereby countering key features of this severe disease (103).

Arsenic and common heavy metals (including plumbum, hydrargyrum, cadmium and manganese) exhibit neurotoxic effects, with notable sex-specific differences observed in response to exposure (104). Neurotoxic compounds, such as rotenone, 6-hydroxydopamine, MPTP, MPP+, paraquat and maneb, are commonly used in preclinical models of PD (105). In anisodamine-induced amnesia models, PCA administered orally could protect against oxidative stress-related learning and memory deficits (10). PCA enhanced the antioxidant defense system, suppressed inflammation and apoptosis, and thereby counteracted cadmium-induced neurocortical toxicity (106). PCA could also exert protective effects against cisplatin-induced neurotoxicity by inhibiting neuroinflammation and restoring the oxidative/antioxidative balance (107). As a toxic metalloid, arsenic exposure increased pro-inflammatory cytokine levels (TNF-α and IL-1β), upregulated apoptosis-related molecules (caspase-3 and Bax), and reduced acetylcholinesterase activity and BDNF levels in the mouse cerebral cortex. PCA pretreatment attenuated arsenic-induced histopathological alterations in brain tissue (108). PCA also markedly reduced hippocampal neuronal death and microglial activation in a model of intraperitoneal injection of pilocarpine-induced epilepsy in adult male rats (109).

PCA prevented rotenone-induced apoptosis of PC12 cells by alleviating mitochondrial dysfunction (110). Additionally, PCA significantly alleviated MPP(+)-induced mitochondrial dysfunction in these cells (111). Although bromate, used as a food additive, was shown to disrupt the CNS, PCA protected the cells from bromate-induced gastric mucosal ulceration (112). PCA alleviated oxidative stress, elevated neurotransmitter levels, and improved learning and memory deficits in lead-exposed rats (113). Additionally, PCA prevented cadmium-induced neurotoxicity by altering the activities of key enzymes, such as Na⁺/K⁺-ATPase, acetylcholinesterase, butylcholinesterase and endogenous antioxidant enzymes (114).

Depression and anxiety are mental disorders characterized by persistent dysregulation of emotional and behavioral responses, which is associated with reduced levels of 5-HT, DA and NE in the CNS (115). Chronic corticosterone exposure induces depressive-like behavior in mice, accompanied by oxidative stress, neuroinflammation and medial prefrontal cortex synaptic plasticity impairment, further supporting the pivotal role of oxidative stress in depression pathogenesis (116).

Acute inhibitory stress triggers depression-like behavior via oxidative neuronal damage in mice. Ethyl PCA mitigates serum corticosterone elevation and lipid peroxidation induced by acute inhibitory stress while restoring enzymatic antioxidant levels in the cerebral cortex and hippocampus (117). In scopolamine-induced long-term memory impairment of mice, following acute treatment, PCA induced an anxiogenic effect, whereas repeated administration produced anxiolytic effects and enhanced cognitive function in both acute and chronic models, but their impact on long-term memory was greater than on short-term memory (118). PCA not only reduced the immobility time, serum corticosterone, cytokines TNF-α and IL-6, and malondialdehyde (MDA) levels in mice exposed to chronic unpredictable mild stress, but also improved sucrose preference and restored BDNF levels (119). PCA exhibited antidepressant-like effects by enhancing BDNF, 5-HT, DA and NE levels in the hippocampus and cerebral cortex, while reducing oxidative and inflammatory markers, including MDA, IL-6 and TNF-α (120).

PCA alleviated post-traumatic stress disorder-like symptoms in rats induced by single prolonged stress, through modulation of central monoaminergic systems, improved freezing behavior and demonstrated antidepressant and anxiolytic properties (121). PCA also markedly reduced the biomarkers of inflammation and oxidative stress in the hypothalamus, testis and epididymis (122). Furthermore, PCA improved the hypothalamic-pituitary-gonadal axis function defect in rats exposed to furan by inhibiting oxidative inflammatory stress and apoptosis (123). Both hyperoside and PCA, two polyphenolic compounds, were shown to mediate antidepressant-like effects in mice by modulating the monoamine system and upregulating BDNF levels (124).

CIRI, a major cause of adult disability and mortality, refers to the secondary brain damage that results following the restoration of blood flow to previously ischemic brain regions (125). The pathological mechanisms of ischemic stroke involve oxidative stress, apoptosis, ferroptosis and mitochondrial dysfunction, whereas N-butylphthalide with ligustrazine confer anti-ischemic effects via the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (NRF2) pathway and isocitric rutinine provides neuroprotection in CIRI mice through Nrf2 activation to alleviate oxidative stress and mitochondrial impairment (125,126).

The protective effects of PCA against CIRI are considered to be mediated by the upregulation of NRF2 expression (127). PCA may have the potential to prevent early reperfusion injury, restore the balance between survival and death proteins, and serve as a cost-effective adjunctive treatment for stroke (128). PCA could also reduce brain edema and BBB damage caused by intracerebral hemorrhage via the Nrf2/HO-1 signaling pathway (129). In a collagenase IV-induced mouse model of intracerebral hemorrhage, PCA attenuated oxidative stress, inflammation and apoptosis through downregulation of the p38/JNK-NF-κB pathway, thereby reducing third-stage brain edema, improving neurological function and decreasing TNF-α, IL-1β and IL-6 expression at both the protein and gene levels (130). In a rat model of global CIRI, both silymarin and ethyl PCA improved cognitive and motor function, and reduced histopathological damage, cerebral edema and infarct volume, with silymarin demonstrating superior efficacy compared with piracetam and ethyl PCA (131). In a mouse model of intestinal ischemia-reperfusion injury, PCA exerted protective effects on both the local intestine and remote liver damage, which were mediated through its anti-apoptotic and antioxidant properties (132).

Neuralgia, one of the most debilitating neurological disorders, poses a major therapeutic challenge due to the complex interplay of pathogenic mechanisms involving oxidative stress, neuroinflammation and mitochondrial dysfunction (133). Trigeminal neuralgia is a severe facial pain disorder primarily attributed to neurovascular compression and demyelination of afferent fibers leading to neuronal hyperexcitability, with carbamazepine and oxcarbazepine serving as first-line pharmacotherapy (134). Furthermore, a longer duration and a broader involvement of trigeminal neuralgia are associated with more severe depression, anxiety and insomnia, while these emotional disorders in turn can exacerbate the risk and manifestation of neuralgia (135).

In a chronic constriction injury-induced neuropathy rat model, PCA exhibited similar therapeutic effects as carbamazepine and mitigated the adverse effects caused by neurogenic pain drugs alone (136). PCA alleviated neuropathic pain in rats with chronic constriction injury by inhibiting the JNK/CXCL1/CXCR2 signaling pathway, which contributes to improved oxidative stress (137). A pharmaceutical co-crystal composed of pentoxifylline and PCA effectively reduced allodynia in rats with complex regional pain syndrome following chronic ischemia, through mechanisms involving reduced peripheral tissue ischemia/hypoxia and suppression of hypoxia-induced mitochondrial dysfunction (138).

Additionally, various other neurological diseases are associated with neuroprotection and PCA. PCA prevents blood-spinal cord barrier disruption and hemorrhage by downregulating sulfonylurea receptor 1/transient receptor potential melastatin 4 and matrix metalloproteinases, thereby enhancing functional recovery following spinal cord injury (139). Administration of PCA reduced elevated levels of ROS, protein carbonyls, carboxymethyl lysine and methylglyoxal in the brains of D-galactose-treated mice, indicating its potential to delay or prevent age-related changes (140). PCA regulated blood glucose levels, alleviated cerebral mitochondrial dysfunction and prevented oxidative stress in the brains of streptozotocin-induced diabetic rats (141).

In a rat model of thiamine deficiency, PCA not only ameliorated systemic rigidity and improved motor coordination but also enhanced cognitive function, specifically memory consolidation and retrieval, while restoring normal alanine and glutamate concentrations in the medulla oblongata, which are dysregulated due to the deficiency (142). In a rat model of chronic intermittent hypoxia, which mimics the hallmark cognitive impairment of obstructive sleep apnea, PCA mitigated cognitive dysfunction by reducing cerebral IL-1β levels, upregulating BDNF and synapsin expression, attenuating oxidative stress, apoptosis and reactive gliosis, and ultimately improving learning and memory (143). Beyond neurological effects, PCA exhibited organoprotective properties, demonstrating cardioprotective and lipid-lowering activity in rats with high-fat/high-fructose-induced coronary artery disease (144).

Neuronal death is a common feature of neurological diseases, and protecting neurons and rebuilding damaged neural networks are key to treating NDs such as HD (145). In fact, neuronal injury and death across various NDs converge on shared pathological mechanisms, including oxidative stress, neuroinflammation, ion dyshomeostasis and proteotoxicity (146,147). PCA has exerted broad protective effects across multiple ND models, not by targeting a specific disease but by modulating these fundamental, shared pathological pathways. The most prominent and conserved mechanisms of PCA in NDs include inhibiting abnormal protein aggregation (such as Aβ and α-syn), attenuating neuroinflammation (for example, suppressing the NF-κB pathway), enhancing antioxidant defenses, and modulating autophagy and cell survival signaling (for example, Akt/GSK-3β). These mechanisms often work in concert, ultimately promoting neuronal survival and function (Table II). The roles and mechanisms of PCA related to neuroprotection are summarized in Fig. 2, including antioxidant activity, anti-inflammatory modulation, anti-apoptotic regulation, mitochondrial protection and homeostasis maintenance.