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Neurodegenerative diseases (NDs) are a growing medical and social problem due to the expected increase in the number of patients and the lack of effective treatments. Alzheimer’s disease and Parkinson’s disease are the most common NDs, affecting millions of people worldwide. The hallmark of NDs is the progressive loss of neurons and their functions in the brain or peripheral nervous system, leading to neuropsychiatric symptoms and permanent disability. Their complex pathology, which involves several interacting mechanisms, is the main challenge in finding a cure. Current treatments for NDs can alleviate some symptoms and slow their progression but cannot reverse the course of the disease. Recent studies have focused on neurotrophic factors (NTFs) as promising new therapies for NDs. NTFs and their receptors are essential for the development, survival, and growth of neuronal cells and play a role in the cellular defense system. Research suggests that bioactive compounds from plants and medicinal mushrooms have the potential to prevent and treat age-related neurological disorders by influencing the expression of NTFs. These natural sources provide a multi-targeted approach to improving NDs, offering both preventive and therapeutic benefits.
Neurodegenerative diseases (ND) affect millions worldwide and pose a global health challenge. They are characterized by progressive motor and nonmotor symptoms. The pathological protein aggregates underlying these diseases are observed years before the onset of symptoms [1]. Abnormal protein accumulation, along with other cellular abnormalities such as mitochondrial dysfunction and oxidative stress, leads to neurodegeneration, neurotransmitter imbalance, symptom manifestation, and disability [2]. Since neurons are terminally differentiated, their loss leads to the disruption of essential neuronal circuits. There is currently no known cure for ND; available medications can slow the progression but cannot reverse the course of the disease. This poses a serious burden on an aging society.
Results from preclinical and clinical trials suggest that phytochemicals have the potential to alleviate the symptoms of ND. Medicinal plants have been used since ancient times for the treatment of various diseases and can exert significant pharmacological effects. Phytochemicals, as therapeutic products, are well-tolerated, readily available, and inexpensive. In the context of ND, plant compounds can prevent neuronal cell death. Phytochemicals also promote the production of NTF, secretory proteins that ensure neuronal survival and growth, synaptic function, and neuroplasticity. Furthermore, plants exert multiple complementary actions, such as antioxidant, antiinflammatory, and mitochondrial-supportive effects, which collectively enhance their therapeutic potential in ND.
The exact mechanism of ND is not known. They are a result of genetic predisposition, compromised cellular defense pathways, and environmental factors. Pathological accumulation and aggregation of proteins are biomarkers for the diagnosis and classification of ND. Abnormal tau protein complexes underlie Alzheimer’s disease (AD), alpha-synuclein underlies Parkinson’s disease (PD), and Huntington’s disease is caused by a mutated huntingtin protein. Dysfunction of the ubiquitin-proteasome system, which is crucial for eliminating damaged or misfolded proteins, leads to the gradual formation of protein aggregates and a cascade of events that result in neurodegeneration [3]. Defective autophagy, mitochondrial and metabolic disorders, and chronic inflammation further contribute to the progression of the diseases. The decrease in neurons is accompanied by a decrease in the associated neurotransmitter, which leads to the manifestation of nonmotor symptoms.
AD is the most common ND and the most common cause of dementia. It is characterized by progressive memory loss, impaired reasoning, and disorientation, which disrupt the daily activities of patients. Pathoanatomically, AD is characterized by extracellular beta-amyloid plaques and neurofibrillary intraneuronal lesions containing the tau protein [4]. Abnormal protein aggregation leads to the progressive loss of cholinergic neurons and a significant reduction in acetylcholine synthesis. Neurodegeneration in AD is considered to be polypathogenic, resulting from the interaction of multiple mechanisms and risk factors [5].
PD, the second most common ND, affects approximately 2–3% of people over the age of 65. It manifests with motor symptoms, including bradykinesia, rigidity, tremor, and postural instability. The disease is often accompanied by nonmotor disorders such as depression, delayed information processing, and mild memory impairment. The pathogenesis is associated with progressive degeneration of dopaminergic neurons in the substantia nigra, caused by α-synuclein aggregation, mitochondrial and lysosomal dysfunction, impaired synaptic transport, and neuroinflammation [6].
2.1 Clinical therapies for NDs
The epidemiology of ND remains unclear. These disorders stem from complex interactions between genetic susceptibility, biochemical changes (such as oxidative stress and mitochondrial dysfunction), inflammation, and environmental factors (Figure 1). These mechanisms create a self-sustaining cycle that leads to neuronal dysfunction and cell death. As current therapies cannot reverse neurodegeneration, treatment aims to slow progression and relieve motor and nonmotor symptoms.
Figure 1.
Main molecular mechanisms and causes of neurodegeneration. Created with Canva.
A hallmark of AD pathology is cholinergic dysfunction. Current treatments for cognitive symptoms primarily target this deficit [7]. Acetylcholine (ACh) is a key neurotransmitter for learning and memory. Acetylcholinesterase (AChE) inhibitors used to treat AD (donepezil, galantamine, rivastigmine) act by inhibiting the enzyme in the synaptic cleft. This slows the breakdown of ACh and increases its synaptic availability. Glutamate, the main excitatory neurotransmitter, mediates synaptic transmission, neuronal differentiation, learning, and memory. In AD, impaired glutamate clearance causes synaptic buildup, overstimulation of N-methyl-D-aspartate receptors (NMDARs), increased Ca2⁺ influx, and neuronal degeneration known as excitotoxicity. Memantine, an NMDAR antagonist, protects neurons by limiting abnormal calcium influx. Aducanumab, a monoclonal antibody against soluble Aβ fibrils and oligomers, is the first FDA-approved therapy for reducing Aβ plaques.
Pharmacological strategies for treating PD [8] target dopaminergic dysfunction through various mechanisms, including increasing dopamine levels, directly stimulating dopamine receptors, inhibiting dopamine metabolism, modulating glutamatergic activity, and restoring neurotransmitter balance. Levodopa, the mainstay of therapy, crosses the blood–brain barrier and is converted to dopamine by aromatic L-amino acid decarboxylase. To reduce peripheral conversion and improve central availability, it is combined with decarboxylase inhibitors such as carbidopa or benserazide. Monoamine oxidase-B inhibitors slow the oxidative deamination of dopamine, prolonging its half-life in the striatum, while catechol-O-methyltransferase inhibitors, such as entacapone and tolcapone, reduce the O-methylation of levodopa and maintain its higher plasma concentrations. In addition, amantadine, an NMDAR antagonist, attenuates glutamatergic excitotoxicity. The use of anticholinergic agents plays a role in restoring the balance of neurotransmitters.
Behavioral and psychiatric symptoms, such as anxiety and depression, may also require pharmacological treatment.
2.2 Advanced therapies in preclinical and clinical trials
Advances in understanding the causative agents and molecular targets of neurological diseases have led to the development of improved therapies in clinical trials. The development of innovative strategies, such as gene therapies and stem cell therapies, holds promise for reversing these diseases [9]. Gene therapy delivers functional genes or silences deleterious genes, potentially providing lasting or permanent benefits. This can be achieved through carriers such as viral vectors, nanoparticles, or liposomes, or by modifying cells in vitro and reintroducing them into the patient [10]. In cases where specific gene targeting is impractical, gene therapy focuses on enhancing cell survival and mitigating toxicity resulting from protein aggregation or oxidative stress.
Vaccines traditionally used against infectious pathogens are also being investigated as therapies for neurological diseases. They aim to stimulate the immune system to counteract pathological protein deposits, including β-amyloid, α-synuclein, and tau [11]. Cell therapies also hold promise for reversing the course of diseases by replacing lost neurons and promoting neuronal regeneration. Stem cells, including neural, mesenchymal, induced pluripotent, and embryonic stem cells, can differentiate into multiple cell types, restore brain circuitry, and improve cognitive and motor functions [12].
These therapies face some challenges. Stem cell therapy may initiate immune responses. Autologous cells lower the risk of rejection but may not always be of high quality. Allogeneic cells are more robust but can trigger immune reactions. These treatments also need substantial funding, advanced equipment, and trained staff. As a result, finding more affordable options is essential.
The brain is a dynamic organ. It constantly reorganizes itself through neuroplasticity in response to both internal and external stimuli. Neural plasticity is the basis for learning and memory. It involves several mechanisms and structural adaptations, including the generation of new neurons and glial cells, the formation of new synaptic connections, and the modification or elimination of existing ones [13]. Neurotrophic factors (NTFs) play a central role in neuroplasticity. They regulate and maintain neurogenesis and other forms of plasticity changes [14]. The brain-derived neurotrophic factor (BDNF)-TrkB pathway is the main molecular mechanism for neuroplasticity. During development, NTFs mediate neurogenesis, maintain and protect neurons, and promote synaptic function. Their binding to intrinsic receptors initiates several signaling pathways crucial for neuronal survival. The transport of NTFs occur bidirectionally: retrogradely along the axon to the soma and anterogradely from the cell body to the synapse. This movement is mediated by microtubule motor proteins. Dysregulated trophic function is sometimes observed in ND due to the malfunctioning of these proteins.
Because of their role in survival and regeneration, NTFs have been researched in ND, such as AD and PD. Their therapeutic potential lies in two complementary actions: prolonging the survival of compromised neurons and restoring or maintaining their functional state.
3.1 Neurotrophic families
NTFs are typically classified into three major groups based on structural and signaling similarities: neurotrophins (NT), the Glial cell line-derived neurotrophic factor (GDNF) family, and neuropoietic cytokines. Recently, two additional factors, Mesencephalic astrocyte-derived neurotrophic factor (MANF) and Cerebral dopamine neurotrophic factor (CDNF), have been identified as endoplasmic reticulum–resident proteins that act through mechanisms distinct from classical NTFs.
3.1.1 Neurotrophins family
NT are secretory proteins, including nerve growth factor (NGF), BDNF, neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). Family members share about 50% sequence homology and similar molecular weights. Functional differences stem from loop regions with low sequence similarity. NT signaling begins when NTs bind to tropomyosin receptor kinases (TrkA, TrkB, TrkC) or the low-affinity p75 neurotrophin receptor (p75NTR). NGF binds primarily to TrkA, BDNF and NT4 to TrkB, and NT3 to TrkC. The NF/Trk complex activates MAPK, PI3K/Akt, or PLCγ signaling pathways. MAPK and PI3K/Akt signaling play a crucial role in neuronal survival, in part due to the expression of antiapoptotic proteins. The PLCγ pathway leads to the release of calcium from the endoplasmic reticulum, and elevated calcium levels are important for BDNF signaling and synaptic plasticity, as well as for BDNF-induced dopamine release. The binding of NT to the p75 neurotrophin receptor activates pro-survival signaling cascades or programmed cell death. The toxic β-amyloid peptide can also bind to p75NTR, potentially contributing to apoptosis of cholinergic neurons in AD. p75NTR is often coexpressed with Trk receptors, and in the absence of Trk, p75NTR induces apoptosis.
NGF, the first discovered NTF, has been shown to regulate the growth and survival of peripheral sensory, sympathetic, and central cholinergic neurons. In primate and human experiments, NGF provides trophic support, preventing degeneration of cholinergic neurons and delaying cognitive decline [15]. Additionally, it promotes neuronal recovery after ischemic or chemical injury. Beyond these functions, other therapeutic applications in humans include the treatment of ulcers, glaucoma, maculopathy, and retinitis pigmentosa [16]. Mechanistically, NGF binds to the TrkA receptor, promoting neuronal survival and differentiation, as well as to p75NTR. Studies have shown that NGF prevents cortical cholinergic neuron atrophy and improves behavioral deficits, supporting its therapeutic potential in AD [17, 18].
Serum concentration of BDNF, an important biomarker of neuronal function, is typically low in patients with ND. BDNF is a key regulator of neurogenesis, synaptogenesis, neuroprotection, and cognitive function [19]. The BDNF-TrkB complex leads to the activation of cAMP-binding proteins (CREB, CBP), which then activate survival genes. Additionally, BDNF is released autocrinally as the BDNF-TrkB complex drives PLCɣ-mediated calcium release, leading to further BDNF secretion. Clinically, low levels of BDNF are associated with cognitive decline, while higher hippocampal BDNF levels contribute to the antidepressant effects of drugs [20] and exercise [21]. Furthermore, the most studied BDNF polymorph, rs6265 (Val66Met), which results from a valine-to-methionine substitution in the pro-domain, is associated with reduced hippocampal volume and mild deficits in learning and memory [22]. In AD, BDNF levels are reduced in the entorhinal cortex and hippocampus, suggesting that diminished trophic support contributes to neurodegeneration. BDNF is crucial for dopaminergic neurons in the substantia nigra, and its loss leads to motor deficits and neurodegeneration.
NT-3 promotes neuronal survival, differentiation, and dendritic and axonal growth, primarily through TrkC signaling. NTF3-KO mice exhibit severe deficits in limb movement, peripheral sensory and sympathetic neuronal loss, and die shortly after birth. NT-3 also influences mood and anxiety disorders through its effects on monoamines, plasticity, neurogenesis, BDNF signaling, and the hypothalamic-pituitary-adrenal (HPA) axis [23]. NT-4/5, the least studied NT, primarily activates TrkB like BDNF but appears to mediate diverse neuronal functions [24]. NT4-deficient mice show only minor cellular deficits and develop normally into adulthood.
3.1.2 GDNF family
The GDNF ligand family includes four members (GDNF, neurturin, artemin, and persephin) and promotes the survival of dopaminergic neurons in the midbrain. GDNF family ligands signal through a receptor complex of the tyrosine kinase Ret [25] and the GFRα family of receptors. Ret function depends on association with the GFRα protein coreceptors – GFRα1, GFRα2, GFRα3, and GFRα4 – which selectively bind to GDNF, neurturin, artemin, and persephin, respectively. Ret activation triggers MAPK, PI3K/Akt, and PLCγ cascades, promoting neurite outgrowth and neuronal survival. In addition, NCAM can act as an alternative receptor, mediating Ret-independent effects such as Schwann cell migration and axonal growth in the hippocampus and cortex.
Although all members of the GDNF ligand family exhibit neurotrophic activity in vitro and in vivo, GDNF has been the primary focus of clinical trials in PD. GDNF acts on enteric, sympathetic, dopaminergic, and motor neurons, reducing degeneration [26]. Transplanted stem cells engineered to secrete GDNF promote neuroprotection and repair at sites of dopaminergic loss [27].
3.1.3 Neuropoietic cytokines
The final major class of NTF includes the neuropoietic cytokines. Cytokines were originally identified as immune mediators but are now known to influence a variety of physiological functions and are upregulated in response to neuronal injury [28]. They bind to the gp130 receptor complex and activate the JAK/STAT and MAPK pathways. JAK/STAT signaling is important for neuronal responses to cellular stress and injury.
3.1.4 CDNF and MANF
CDNF and MANF differ from other NTFs in sequence, structure, and mechanism. They protect dopaminergic, Purkinje, and cortical neurons in vivo by acting intracellularly to regulate endoplasmic reticulum stress and the unfolded protein response. Their effects appear to be restricted to injured neurons, where CDNF and MANF promote survival, regeneration, and tissue repair [29]. Preclinical studies have shown the protective effects of MANF in PD, AD, and stroke [30]. CDNF reduces protein aggregation and inflammation and directly interacts with alpha-synuclein [31]. Its neuroprotective and restorative effects have been demonstrated in preclinical models of PD, stroke, and amyotrophic lateral sclerosis.
3.2 NTF therapy – clinical trials and limitations
Exogenous administration of NTF has been used in many preclinical and clinical trials related to ND. Local injection of BDNF into the cortex improves memory in animal models. However, rapid metabolism and peripheral side effects limit its translation into humans [32]. Other challenges to NTF therapy include poor penetration across the blood–brain barrier, short half-life, and limited therapeutic duration. In patients with PD, intraventricular delivery of GDNF has not resulted in clinical improvement due to limited diffusion. It has also resulted in improved dopamine function, but with no long-term effects.
Therefore, the current focus of therapies is intranasal delivery, viral gene therapy, and pharmacological stimulation of endogenous NTF production. An ongoing phase I trial (NCT05040217) is testing AAV2-BDNF delivery to the cortex and hippocampus in patients with early AD. The study focuses on safety, tolerability, cognitive outcomes, and changes in imaging and biomarkers [33]. In PD, a phase I trial with AAV2-GDNF (NCT01621581) showed that the approach was generally safe and well-tolerated. Increased dopaminergic activity was detected by PET imaging. However, clinical improvements in motor symptoms were modest, with mixed results depending on disease stage and treatment cohort. A phase II randomized controlled trial investigating AAV2-NGF (CERE-110) did not show significant cognitive benefits after 24 months. Despite the lack of efficacy, the treatment was safe and well-tolerated. The trial provided key insights into the neurosurgical delivery of vectors. Postmortem analyses revealed limited radial diffusion of AAV2, which prevents adequate targeting. Although translating preclinical success into clinical outcomes remains a challenge, gene therapy holds promise for altering the course of AD and PD.
Phytochemicals are secondary plant metabolites that demonstrate multiple mechanisms of neuroprotection. They can reduce oxidative stress, promote the clearance of Aβ plaques and Lewy bodies, increase neurotransmitter levels, and promote neuronal adaptation to stress [34]. Recent studies have shown that phytochemicals stimulate the endogenous production of NTFs.
Phytochemicals encompass a wide range of bioactive molecules, including polyphenols, carotenoids, glucosinolates, terpenoids, and organosulfur compounds. Clinical trials have demonstrated that flavonoid-rich foods can enhance cognitive function across various age groups and health conditions [35]. In children, blueberry smoothies have been shown to improve attention and verbal memory. In young adults, berry smoothies have been shown to help maintain cognitive function and attention. In older adults, extracts from grapes and blueberries have also been shown to improve memory. Higher intakes of flavonoids, particularly anthocyanins, flavonols, and quercetin, have been linked to improved cognitive function. Carotenoids, which are natural plant pigments, have demonstrated antioxidant, antiinflammatory, and autophagy-modulating properties [36]. Glucosinolates, a class of sulfur-containing metabolites found in Brassicaceae plants, have shown neuroprotective effects, with potential therapeutic benefits in ND, psychiatric disorders, and epilepsy [37]. Terpenoids exhibit a diverse range of biological activities, including antimicrobial, anticancer, antioxidant, and antiinflammatory properties. Clinically, paclitaxel is a terpene-based chemotherapeutic drug, while artemisinin from Artemisia annua is an antimalarial drug. Of particular interest in neurodegeneration is their anticholinesterase activity [38]. Sulfur-containing secondary metabolites have also been shown to possess neuroprotective properties. These compounds reduce oxidative stress, inhibit inflammation and apoptosis, and enhance proteasome activity, thereby counteracting protein aggregation [39].
Plants may also complement and enhance existing drug treatments for ND, offering synergistic benefits and reducing side effects. The effect of donepezil, commonly used for dementia, may be enhanced when combined with natural compounds [40]. Synergistic effects with Ginkgo biloba, resveratrol, quercetin, and other phytochemicals improve memory, reduce oxidative stress, and enhance cholinesterase inhibition. Plant-derived compounds such as caffeine, harmine, and genistein also potentiate its antioxidant and antiamyloid actions. Similarly, huperzine A from Huperzia serrata shows potent AChE inhibition and cognitive benefits when combined with memantine or phytochemicals.
4.1 Phytochemicals in clinical trials for NDs treatment
Plant compounds with antiinflammatory and antioxidant properties are being investigated for various medical purposes [41]. Resveratrol has demonstrated benefits in metabolic syndrome and immune modulation and is being investigated for its potential cognitive effects and neuroprotective properties. Epigallocatechin gallate, derived from green tea, improves anxiety and functional capacity and reduces IL-6 in patients with multiple sclerosis. Few clinical trials have investigated the cognitive effects of curcumin, with mixed results. Some studies have shown no benefit, while others have reported cognitive improvements [42].
Several natural compounds have been studied in clinical trials for the treatment of AD [43]. Docosahexaenoic acid has demonstrated neuroprotective effects in animal models; however, a large phase III trial found no benefit in slowing cognitive decline. Similar results have been observed with resveratrol and scyllo-inositol. Curcumin and its combinations (e.g., with Ginkgo) are safe but ineffective, although some antioxidant benefits have been observed. Huperzine A improves cognitive function only at higher doses and is well-tolerated. Homotaurine reduces amyloid markers and slows hippocampal atrophy in phase III trials.
Regarding clinical trials for PD [43], nicotine has shown the most consistent benefits, improving some of the motor symptoms. Caffeine provided motor and cognitive improvements, but the effect is short-lived. Cannabidiol has reduced tremor and anxiety in small trials. Docosahexaenoic acid is well-tolerated and has been shown to reduce dyskinesia. Epigallocatechin gallate has not shown disease-modifying effects. Overall, these compounds are promising, but the evidence remains mixed and limited.
4.2 Phytochemicals increasing NTF
Research findings indicate that dietary factors, especially polyphenols such as phenolic acids and related compounds, elevate BDNF levels. Supplementation with Eriobotrya japonica leaf extract, seaweed, and ellagic acid increased serum or plasma BDNF in various groups, while curcumin supplementation significantly increased BDNF in patients with major depressive disorder [44]. In a double-blind, placebo-controlled study in patients with moderate AD dementia, curcumin-galactomannoside significantly increased BDNF levels and improved cognitive and motor performance [45]. Some edible and medicinal mushrooms increase NGF activity, promote neurite growth, and protect neurons from toxic damage. Through these neurotrophic actions, they offer protection against AD and PD, with regular intake potentially delaying age-related neurodegeneration [46].
In addition to the well-known signaling pathways of NTF, preclinical studies have demonstrated that phytochemicals can influence their production and activity through various mechanisms, including epigenetic modulation, receptor agonism, mitochondrial modulation, modulation of the gut-brain axis, and the HPA axis (Figure 2).
Figure 2.
Mechanisms by which phytochemicals can influence the synthesis of neurotrophic factors. Created with Canva.
4.2.1 Cross-talk between TrkB signaling pathway and Nrf2-are antioxidant system
TrkB signaling supports neuronal survival through the PI3K/Akt, MAPK, and PLCγ pathways. Akt disrupts the nuclear factor erythroid 2-related factor 2 (Nrf2)-Keap1 complex, which allows nuclear translocation of Nrf2, activation of the ARE antioxidant system, and induction of genes related to redox balance and GSH metabolism. Nrf2 is a key transcription factor controlling antioxidant and antiinflammatory responses. MAPK and PLCγ signaling pathways regulate the transcription of BDNF and proteins required for synaptic plasticity and neurogenesis. Together, TrkB signaling and Nrf2-ARE activation act synergistically to protect neurons, reduce oxidative stress, and preserve memory and cognitive functions in ND [47]. Recent findings have shown that Nrf2 binds to the BDNF exon I promoter, increasing its transcription [48]. Nrf2 knockout mice exhibit reduced BDNF/TrkB levels and depressive-like behavior, highlighting its role in mood regulation.
Activation of Nrf2 by sulforaphane leads to antidepressant-like effects by increasing BDNF, decreasing its repressors (HDAC2, mSin3A, MeCP2), and restoring synaptic function. These effects are absent in Nrf2 knockout mice [48]. Similarly, lycopene activates Nrf2 signaling and increases BDNF expression in H₂O₂-treated SH-SY5Y cells, thereby reducing oxidative damage and neuroinflammation [49]. 3,3′-diindolylmethane, a metabolite of indole-3-carbinol from Brassicaceae vegetables, activates the TrkB/Akt and Nrf2/ARE pathways, increasing BDNF and antioxidant enzymes [50]. Treatment with carnosic acid, a phenolic diterpene from rosemary, ameliorates depressive-like behavior in ovariectomized (OVX) mice. Administration of carnosic acid increases Nrf2, BDNF, and serotonin, while reducing oxidative stress, inflammatory markers (TNF-α, IL-1β, iNOS), and histopathological damage [51].
4.2.2 Epigenetic modulation
Epigenetics studies how reversible DNA and histone modifications regulate gene expression without altering the underlying genetic code. Epigenetic regulation of gene expression includes DNA methylation and demethylation, which control gene activation or silencing; histone modifications, which alter chromatin accessibility; and noncoding RNAs, which fine-tune transcription through effects on mRNA stability and signaling [52]. These modifications could have lasting effects on brain function and plasticity. Supplementation of quercetin to OVX animals for four weeks improved markers of neuroplasticity and increased H3 acetylation at the BDNF promoter, thereby improving cognitive function [53]. Curcumin has also been shown to promote neurogenesis, synaptic remodeling, and mitochondrial biogenesis through epigenetic modifications [54]. Sulforaphane is another example of a phytochemical that increases BDNF expression by increasing H3 and H4 acetylation at the BDNF promoter [55].
4.2.3 Receptor agonists
Among 33 flavonoids that can stimulate the production of NGF, BDNF, and GDNF in astrocytes, calycosin, isorhamnetin, luteolin, and genistein strongly increased the expression and secretion of NTF in a time and dose-dependent manner. These effects were associated with phosphorylation of the estrogen receptor (ER) and were blocked by an ER inhibitor, confirming the importance of the receptor [56]. Beta-caryophyllene, found in many essential oils, is a natural agonist of the cannabinoid receptor 2 (CB2R). It shows neuroprotective potential without the psychoactivity associated with the cannabinoid receptor 1. In human microglia, beta-caryophyllene reduces Aβ-induced inflammation, and its effects are blocked by a CB2R antagonist. Beta-caryophyllene also appears to enhance BDNF through a signaling cascade triggered by the activation of CB2R [57]. 7,8-dihydroxyflavone (7,8-DHF) is a flavonoid found in the leaves of Tridax procumbens, Godmania aesculifolia, and Primula halleri. It is a low-molecular-weight TrkB agonist that crosses the blood-brain barrier and mimics the activity of BDNF. By directly activating TrkB, it promotes neuronal survival, synaptogenesis, axonal regeneration, and memory enhancement. Safe for oral administration and validated in multiple disease models, 7,8-DHF is considered a promising compound for the treatment of BDNF-related neurological disorders [58, 59].
4.2.4 Gut–brain axis
Diet and plant-derived compounds influence NTF by modulating the gut-brain axis. The gut microbiota metabolizes dietary fiber and phytochemicals into bioactive molecules, such as short-chain fatty acids (SCFAs), which can enhance BDNF expression, reduce neuroinflammation, and improve memory [60]. Probiotics (e.g., Bifidobacterium, Lactobacillus) and prebiotics help restore microbial balance, reduce inflammatory cytokines, and support hippocampal-dependent cognitive function. Specific plant compounds, such as Gastrodia polysaccharides [61] and rosemary compounds [62], improve memory and mood by altering microbiota composition and increasing BDNF. Rye kernel bread meals improve glucose tolerance, appetite regulation, and intestinal fermentation in healthy adults. Compared with white wheat bread, rye kernel bread increases Prevotella and Faecalibacterium, while reducing Bacteroides species. The results also showed that the presence of Prevotella correlated positively with plasma BDNF levels (NCT02093481) [63].
4.2.5 Mitochondrial modulation
Mitochondrial biogenesis is regulated by peroxisome proliferator-activated receptor gamma coactivator (PGC-1α). It is a key factor linking energy metabolism and synaptic development through BDNF signaling. Overexpression of PGC-1α enhances spinogenesis, while its suppression reduces dendritic spines. BDNF promotes PGC-1α-driven mitochondrial biogenesis through ERK/CREB signaling, and PGC-1α is required for BDNF-induced spine formation [64].
In a rat model of chronic unpredictable mild stress, curcumin treatment reduced depressive-like behavior, promoted neurogenesis, and inhibited apoptosis. Molecular analysis has demonstrated that curcumin enhances PGC-1α and BDNF, thereby activating the PGC-1α/FNDC5/BDNF pathway [65]. In a similar study, quercetin prevented hypobaric hypoxia-induced memory loss in rats, as well as mitochondrial and synaptic damage in the hippocampus. Enhanced PGC-1α signaling increases BDNF expression through the PGC-1α/FNDC5/BDNF pathway [66]. Withania somnifera root extract and its withanolide-withanoside fraction increase ATP levels, mitochondrial mass, and BDNF expression in rat neurons. Inhibitor studies confirm BDNF as a key mediator of mitochondrial effects. Withanolide A and withanoside IV have been identified as active compounds that promote mitochondrial biogenesis and protect neurons from corticosterone-induced death [67]. Astaxanthin alleviates oxidative stress and improves cognitive function in an Aβ-induced mouse model of brain aging. Treatment increases the expression of BDNF and PGC-1α in the hippocampus [68].
4.2.6 The HPA axis
The HPA axis is central to the stress response. Hypothalamic corticotropin-releasing hormone (CRH) stimulates the release of adrenocorticotropin, which, in turn, drives the secretion of glucocorticoids from the adrenal cortex. Glucocorticoids help the body adapt by regulating metabolism, cardiovascular function, immunity, mood, and cognitive function. Their levels are normally controlled by negative feedback, in which increasing levels of glucocorticoids suppress CRH via receptors in the hippocampus and hypothalamus, thereby terminating HPA activation. While this feedback loop is protective in the short term, chronic activation disrupts homeostasis and increases the risk of disease [69]. Patients with AD and PD show significantly elevated total plasma cortisol levels [70]. Chronic corticosterone reduces BDNF mRNA and protein levels in the hippocampus of rats [71].
Bacopa monnieri extract protects neurons by restoring HPA axis feedback, normalizing synaptic proteins and receptors, and regulating pro and mature BDNF [72]. Withania somnifera root protects against hypobaric hypoxia-induced memory loss and neurodegeneration. Exposure to hypobaric hypoxia increases corticosterone, NO, oxidative stress, and alters synaptic proteins, leading to reduced BDNF. Supplementation with Withania somnifera extract lowers corticosterone and restores BDNF levels. Its antioxidant, antiapoptotic, and cholinergic-modulating actions further support neuroprotection, neurogenesis, and memory preservation under hypoxic stress [73]. In a rat model of chronic unpredictable mild stress, resveratrol reduced plasma corticosterone, indicating normalization of HPA axis activity. Treatment also increased BDNF and modulated inflammatory markers (IL-6, CRP, TNF-α). These effects collectively alleviated depressive-like behavior [74].
As there are currently no approved treatments capable of halting or reversing the progression of NDs, and given their increasing prevalence and associated economic burden, the search for new and effective therapies remains essential. Gene therapies hold promise, but their successful translation into clinical practice still faces challenges. In contrast, more accessible options, such as plants and phytonutrients, offer therapeutic potential through multiple mechanisms. Emerging preclinical and clinical studies also indicate that they may positively influence NTF.
Key questions remain about the role of plants in modulating NTF synthesis. Dietary levels of bioactive compounds are typically far below the pharmacological concentrations needed in vitro and in vivo to achieve meaningful neuroprotective effects. To address this gap, advanced nanoformulations offer promising solutions by improving solubility, stability, bioavailability, and brain delivery. Beyond single compounds, exploring synergistic combinations of phytonutrients may yield broader neuroprotective benefits by targeting complementary pathways, such as antioxidant defense, inflammation control, mitochondrial support, and NTF modulation.
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