Neuroprotection is a strategy that actively protects
the brain, spinal cord and peripheral nervous system from acute and
progressive neurodegenerative diseases (NDs) by preventing or
limiting damage to neurons and other components (1). NDs are a group of disorders
characterized by the progressive loss of neurons in the brain and
spinal cord. Their manifestations fall into two main categories:
One affects movement (for example, cerebellar ataxia) and the other
affects memory (for example, dementias) (2). NDs include Alzheimer's disease (AD),
amyotrophic lateral sclerosis (ALS), Huntington's disease (HD),
multiple sclerosis, Parkinson's disease (PD) and spinal muscular
atrophy (3,4). The nervous system is characterized by
high oxygen consumption, a high content of unsaturated fatty acids
and vulnerability to lipid peroxidation (5). Oxidative stress, resulting from an
imbalance between reactive oxygen species (ROS) and antioxidant
defenses, damages cellular structures and contributes to the
pathogenesis of NDs such as AD and PD (6). Oxidative stress also disrupts the
blood-brain barrier (BBB), permitting entry of neurotoxic plasma
components, blood cells and pathogens into the brain, leading to
amplified ROS production, mitochondrial dysfunction and
inflammation, ultimately driving neuronal apoptosis and the
progression of NDs (7).
Neuroprotection employs targeted biological and pharmacological
interventions to preserve neuronal function and network integrity
by mitigating neuronal damage, preventing cell death and
maintaining central nervous system (CNS) functionality (8).
Protocatechuic acid (PCA) is a natural phenolic
acid, widely found in plants and chemically defined as
3,4dihydroxybenzoic acid (9). PCA
occurs mainly in vegetables (10–12),
fruits (13), green tea (14) and walnuts (15), and is an active compound found in
several traditional Chinese medicines (such as Alpiniae
oxyphyllae Fructus) (16). PCA
shows a good neuroprotective effect by inhibiting oxidative stress,
regulating inflammatory response and promoting neuronal survival.
For instance, PCA reduces cyclophosphamide-induced neuronal
degeneration by regulating the NOD-, LRR- and pyrin
domain-containing protein 3 inflammasome, and sirtuin (SIRT)1,
thereby reducing the production of pro-inflammatory cytokines
(17). In addition, PCA enhances
the antioxidant capacity of nerve cells, promotes cell survival and
significantly improves scopolamine-induced learning and memory
impairment (10). PCA, melatonin
and hydroxytyrosol confer neuroprotection by inhibiting abnormal
α-synuclein (α-syn) assembly, reducing its toxicity, and
upregulating SIRT-2, Heme oxygenase-1 (HO-1) and 70-kDa heat shock
protein expression (18). The
present study provides a systematic summary of the role of PCA in
neuroprotection to offer novel mechanistic insights and a
theoretical foundation for developing novel therapeutic
strategies.
Neuroprotection after neural injury, which is
pivotal in neuroscience, involves mechanisms such as
anti-inflammation, antioxidation and anti-apoptosis, and is linked
to disorders such as neurodegenerative diseases, anxiety,
depression, ischemic/hemorrhagic stroke and drug-induced
neurotoxicity (19). Due to the
depletion of endogenous neurotrophic factors in neural injury,
neuronal repair requires sustained exogenous neurotrophic factor
supplementation to meet neuronal metabolic demands (20). Neuroprotective agents [such as
saffron, coenzyme Q10 and nerve growth factor (NGF)] may offer new
therapeutic benefits through anti-apoptotic mechanisms (21). In fact, NGF has been used
clinically to treat optic nerve-related diseases, but its short
half-life and poor bioavailability limit its efficacy (22).
The neurotransmitter system regulates the functions
of target organs by transmitting nerve impulses based on the types
of neurotransmitters it releases (including cholinergic,
glutamatergic, γ-aminobutyric acidergic, dopaminergic, serotonergic
and aminergic systems) (23). The
imbalance of neurotransmitters is closely associated with the
occurrence of various neurological disorders, especially in NDs,
where the abnormal metabolism of neurotransmitters and oxidative
stress are considered as important pathological mechanisms
(24). For instance, the gradual
reduction of dopaminergic neurons in the substantia nigra compacta
of the brain and the decrease in dopamine (DA) content are
important pathological features of PD (25). The addition of partial agonists of
DA and 5-hydroxytryptamine (5-HT) on top of norepinephrine
(NE)/5-HT reuptake inhibitors is often used to enhance the
antidepressant effect (26).
Moreover, the levels of acetylcholine and glutamate excitotoxicity
are related to AD (27).
Neural stem cells (NSCs)/precursor cells have
long-term potential for neural function recovery (28). Mesenchymal stem cell (MSC)
secretions exhibit neuroprotective effects in traumatic brain
injury (29). Through their
interaction with neuropeptides, MSC-derived extracellular vesicles
promote brain-derived neurotrophic factor (BDNF) expression and
neural repair, making them a promising therapeutic agent for
alleviating brain stroke damage (30). Recently, a growing amount of
research has highlighted the non-motor functions of the cerebellum,
such as cognitive, behavioural and emotional processing, which are
increasingly associated with mechanisms such as neurodegeneration,
neuroinflammation, oxidative stress and metabolic dysregulation via
multiple pathways (31–33).
Overall, neuroprotective strategies target
neuroinflammation, oxidative stress and impaired neural repair to
promote functional recovery through pathways involving abnormal
protein aggregation, toxin-induced injury via redox modulation,
neurotrophic/TrkB/PI3K/Akt signaling, microglial activation and
mitochondrial dysfunction (Fig. 1)
(34). Neuroprotective agents
function through multifaceted mechanisms, including antioxidant
activity, anti-inflammatory effects via microglial suppression and
NF-κB inhibition, enhanced energy metabolism, mitochondrial
stabilization, apoptosis suppression through PI3K/Akt signaling,
clearance of pathological protein aggregates, and promotion of
neuronal repair and stem cell differentiation (35). In addition, various neuroprotective
or neurological disorders-related agents were summarized in
Table I (35–47).
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.
Oxidative stress, characterized by a systemic
oxidant/antioxidant imbalance, leads to excessive ROS production
that damages critical biomolecules (such as lipids, proteins and
DNA), resulting in neuronal dysfunction and ultimately cell death
in brain tissue (55,56). Due to its high metabolic oxygen
consumption characteristic, the brain is extremely sensitive to
oxidative stress, which is a key pathogenic factor for NDs
(57). Consequently, antioxidant
strategies, including phytochemical-rich dietary supplements,
combined with moderate exercise, may mitigate oxidative
stress-induced neurodegeneration (1).
As a natural antioxidant, PCA demonstrates broad
potential for neuroprotection and antioxidant therapy. Pretreatment
with Lycium barbarum polyphenols, such as PCA, attenuated
hydrogen peroxide (H2O2)-induced toxicity in
PC12 cells, a rat adrenal pheochromocytoma-derived neuroendocrine
cell line, by reducing ROS production, restoring mitochondrial
membrane potential and inhibiting apoptosis (58). In a global ischemia model in rats,
PCA significantly reduced cell death, oxidative stress, microglial
and astrocyte activation, and BBB disruption in degenerative
neurons, and increased glutathione concentration in hippocampal
neurons (59). PCA and chrysin
exerted synergistic neuroprotection in 6-hydroxydopamine-treated
PC12 cells by enhancing viability, reducing lactate dehydrogenase
release and modulating cellular redox status through upregulation
of key antioxidant enzymes (60).
Pre-treatment with PCA significantly reduced apoptosis,
inflammation and oxidative stress in the neonatal mouse hippocampus
following sevoflurane exposure (61).
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
Aβ25-35-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.
To establish the efficacy and safe dosage of PCA,
conducting rigorous human clinical trials, including
pharmacokinetic, dose-finding and efficacy studies as a single
compound, is essential. In a mouse study, PCA appeared to be
rapidly absorbed, achieving a peak plasma concentration of 73.6 µM
at 5 min, with an initial elimination half-life of ~3 min and a
terminal half-life of 16 min, and remaining detectable for up to 8
h (148). A pH-responsive,
rapidly adjustable hydrogel based on PCA enabled sustained and
controlled drug release, demonstrating excellent clinical potential
for NDs (149). However, clinical
observations indicate a higher incidence of stroke onset during the
human active phase (daytime), whereas most rodent models are
conducted during the animals' inactive phase, introducing a
chronobiological discrepancy that may limit translational
predictability (150). Currently,
there are limited direct clinical studies on PCA; it is more
frequently investigated as a metabolite, and since it derives from
various natural sources often containing other compounds, detected
doses across studies may vary substantially (151). As a phenolic acid metabolite from
anthocyanin degradation, PCA is a key urinary bioactive compound
whose increased excretion is associated with reduced serum oxidant
status, indirectly supporting its role in boosting antioxidant
defences (152).
While PCA exhibited neuroprotective properties in
animal models by mitigating oxidative stress and neuronal
apoptosis, a 9-week clinical trial using PCA-rich juices (such as
cranberry or red grape) in elderly men (age ≥67 years, n=30) with
memory deficits showed no notable improvement in choice memory
scores, but led to a reduction in biomarkers of inflammation and
tissue damage (153). This
finding is significant, indicating successful engagement of the
intended therapeutic targets, namely, the suppression of chronic
inflammatory and oxidative stress pathways. The negative primary
cognitive outcome may be attributed to the short intervention
duration, insufficient dosage, limited sample size or heterogeneity
within the study population. Therefore, the reduction in
inflammatory markers should be regarded as a positive
pharmacodynamic signal, suggesting potential for cognitive benefit
with optimized or longer-term intervention strategies.
PCA, a natural compound with multiple biological
activities, exhibits considerable neuroprotective potential in
diverse neurological disorders, including AD, PD and cerebral
ischemia, primarily through mechanisms such as antioxidation,
anti-inflammation and the promotion of neuronal survival. Although
preclinical studies have underscored its broad efficacy, clinical
translation remains limited by a scarcity of large-scale human
trials and inconsistent outcomes attributable to its multi-target
nature, which complicates mechanistic clarity and reproducibility.
Future clinical studies to elucidate the disease-specific
mechanisms of PCA, optimize its dosing and delivery strategies, and
evaluate long-term safety and efficacy for neurological disorders
are anticipated.
Not applicable.
This study was supported by the Natural Science Foundation of
Jiangxi Province (grant no. 20242BAB25585) and the 2022 Ganzhou
Municipal Science and Technology Project (grant no.
2022-YB1414).
Not applicable.
XYX, YCL, SSS, LPW and LFW contributed to the
manuscript conception and design. The first draft of the manuscript
was written by XYX and LFW. XYX, YCL and LFW contributed to
reference investigations and figure visualization. YCL, SSS and LPW
commented and critically revised previous versions of the
manuscript. All authors have read and approved the final version of
the manuscript. Data authentication is not applicable.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
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