The research team, led by Wen Zhang and Xintong Wang, focused on a stage of brain development called neuronal differentiation, the process by which precursor cells stop dividing, extend slender projections called neurites, and mature into functional neurons. This process is central to neurogenesis, which underpins neural plasticity, brain homeostasis, and cognitive function throughout life. Adult neurogenesis is notoriously vulnerable to disruption by poor diet, alcohol, aging, oxidative stress, and neuroinflammation, and its decline has been implicated in Alzheimer’s, Huntington’s, and Parkinson’s diseases. Because recent studies suggest that enhancing adult neurogenesis may improve cognition, identifying dietary factors that promote neuronal differentiation has become an attractive strategy for delaying or preventing neurodegeneration. Edible bird’s nest, derived from the salivary secretions of swiftlets in Thailand, Indonesia, and Malaysia, was a natural candidate: it is rich in sialic acid, a nutrient linked to neuroprotection, brain development, and enhanced memory, and it also contains lactoferrin, transferrin, N-acetylgalactosamine, and epidermal growth factor, all of which have been associated with healthy brain development.

Previous work by the same group had shown that feeding edible bird’s nest to pregnant and lactating rats improved spatial learning and memory in their offspring by promoting neurogenesis in the hippocampus, the brain’s memory hub. What remained unclear was the molecular mechanism. To probe it, the researchers turned to PC12 cells, a pheochromocytoma line derived from an adrenal tumor that behaves much like a sympathetic neuron. When exposed to nerve growth factor, or NGF, PC12 cells cease proliferating, extend neurites, and acquire the characteristic appearance of neurons, which makes them a standard laboratory model for studying neuronal differentiation. The team first simulated human digestion: they soaked dried Malaysian bird’s nest, heated it, exposed it to pepsin at stomach-like acidity, then to trypsin at intestinal pH, and finally lyophilized the resulting digest, which they abbreviated EBND. This digestive preprocessing was crucial, because it converted the nest’s complex proteins into a form resembling what the gut would actually deliver to the body.

Safety came first. Using a cell viability assay, the researchers confirmed that EBND showed no toxicity toward PC12 cells across a broad concentration range from 1 to 1000 micrograms per milliliter, with a gradual rise in viability observed between 1 and 100 micrograms per milliliter. They then selected 10, 50, and 100 micrograms per milliliter for the differentiation experiments. The first result was intriguing but incomplete. When PC12 cells were treated with EBND alone for seven days, the cells did not visibly extend neurites, the classic morphological hallmark of differentiation. Yet at the biochemical level something significant was happening: all three neurofilament proteins, the structural backbone of the neuronal cytoskeleton, were upregulated. NF68 expression more than tripled, while NF160 and NF200 at least doubled at the highest dose, changes that were highly statistically significant. Because NF68 and NF160 typically appear early in neuronal differentiation and NF200 marks more mature neurons, the finding suggested that EBND was switching on the molecular program of differentiation even without producing visible neurites.

The decisive experiment came when the researchers added a whisper of NGF. At a concentration of 1.5 nanograms per milliliter, far below the 50 nanograms per milliliter used as a positive control, NGF alone failed to induce any differentiation. But when that subthreshold dose of NGF was combined with EBND, the cells responded robustly. Differentiation rates climbed in a dose-dependent fashion, reaching 22.8 percent at 10 micrograms per milliliter, 31.2 percent at 50, and 42.7 percent at 100, compared with cells given the low NGF dose alone. Mean neurite length rose in parallel, and the expression of all three neurofilament subunits increased two- to threefold at the higher EBND doses. In other words, EBND alone primed the cells for differentiation, while NGF provided the essential trophic signal that translated that priming into visible structural growth. The authors describe this as a state of differentiation priming, in which EBND raises the cell’s responsiveness to coexisting neurotrophic cues.

To uncover the pathway responsible, the team examined the TrkA receptor, the high-affinity docking site through which NGF commands neurons to differentiate. In cells receiving only the trace dose of NGF, TrkA phosphorylation was minimal. Co-treatment with EBND more than doubled TrkA phosphorylation, and purified sialic acid produced a smaller but significant 1.5-fold increase. Downstream, the effects amplified: phosphorylation of ERK1/2, a kinase that relays signals from the receptor toward the nucleus, tripled, and phosphorylation of CREB, a transcription factor that activates neurotrophic genes, doubled. Consistent with this, brain-derived neurotrophic factor, or BDNF, a protein critical for neurogenesis and neuronal survival that CREB helps regulate, rose by nearly 45 percent in the co-treated cells. The cascade traced a coherent line from receptor to nucleus: NGF signal potentiated at TrkA, relayed through ERK1/2, consolidated by CREB, and ultimately expressed as more BDNF.

The most convincing piece of evidence came from a pharmacological blockade. When the researchers pre-treated cells with GW441756, a selective inhibitor of the TrkA receptor, the neurofilament increases driven by EBND and NGF collapsed, with significant reductions in NF68, NF160, and NF200. That loss-of-function experiment confirmed that EBND does not act through some unrelated route but specifically by amplifying signaling at TrkA, thereby making cells far more sensitive to otherwise insufficient amounts of NGF. The finding echoes earlier reports that natural products such as lignans, pterostilbene, and luteolin can bind NGF or potentiate its receptor signaling, suggesting that edible bird’s nest joins a growing family of dietary compounds capable of enhancing neurotrophic pathways.

Notably, the study also revealed that sialic acid alone cannot explain the effect. Although purified sialic acid activated the same TrkA-ERK1/2-CREB-BDNF cascade, it was markedly less potent than the full enzymatic digest at equivalent amounts. This points to a synergistic contribution from other bioactive constituents, possibly epidermal growth factor-like molecules or specific peptides released during enzymatic digestion. The authors are candid about the limitations of their work. The conclusions rest entirely on a single cell line and will need validation in other neuronal models. The boiling step used to terminate enzymatic hydrolysis may have degraded heat-sensitive components, potentially understating the digest’s true activity. And the dissociation between molecular priming and morphological outgrowth under EBND alone remains incompletely understood, leaving open questions about the temporal dynamics of the priming effect and the identity of the key active factors.

Even with those caveats, the study carries real weight. It provides a plausible molecular mechanism for cognitive benefits previously observed in animal studies, and it reframes a centuries-old delicacy as a candidate functional food for brain health. Because deficiencies in NGF and BDNF have been closely linked to depression and Alzheimer’s disease, a safe dietary substance that potentiates NGF signaling could, in principle, support the development of supplements aimed at neurodegenerative conditions related to neurotrophic factor deficiency. The researchers emphasize that much remains to be done: identifying the specific bioactive components within the digest, clarifying exactly how they enhance NGF signaling, and testing whether the priming effect translates from cell culture to living brain. For now, the Caviar of the East has earned something rarer than its culinary price: a testable, receptor-level explanation for its legendary reputation, written in the language of phosphorylated kinases and growing neurites.

Subject of Research: Effects of enzyme-digested edible bird's nest on neuronal differentiation via the TrkA-ERK1/2-CREB-BDNF signaling pathway in PC12 cells

Article Title: Enzyme‐Digested Edible Bird's Nest Promotes NGF‐Induced Differentiation of PC12 Cells by Activating the TrkA‐ERK1/2‐CREB‐BDNF Signaling Pathway

Article References: Zhang, W., Wang, X., Zhu, H., Lin, X., Li, R., Yuan, M., Xu, B., Wang, D., Xiong, W., & Li, Y. (2026). Enzyme‐Digested Edible Bird's Nest Promotes NGF‐Induced Differentiation of PC12 Cells by Activating the TrkA‐ERK1/2‐CREB‐BDNF Signaling Pathway. Food Science & Nutrition, 14(10), Article e72419. https://doi.org/10.1002/fsn3.72419

Image Credits: AI Generated

DOI: 10.1002/fsn3.72419

Keywords: edible bird's nest, neuronal differentiation, PC12 cells, nerve growth factor, TrkA, ERK1/2, CREB, BDNF, sialic acid, neurogenesis, neurofilaments, neurodegenerative disease

Optic pathway gliomas are low-grade tumors that arise anywhere along the visual system, from the optic nerve behind the eye to the chiasm and the radiation of fibers carrying signals toward the visual cortex. They account for roughly three to five percent of all pediatric brain tumors and are most commonly pilocytic astrocytomas, slow-growing World Health Organization Grade I lesions with excellent overall survival. The catch is morbidity rather than mortality. A large share of affected children carry a diagnosis of neurofibromatosis type 1, and among children with this genetic condition, approximately fifteen to twenty percent will develop these tumors at some point. Progressive visual loss is the most common and most debilitating consequence, whether the tumor arises sporadically or in the setting of NF1, and it can profoundly disrupt a child’s neurodevelopment and quality of life.

Current therapy is aimed squarely at tumor control rather than at rescuing vision. Under established pediatric protocols, younger children typically receive chemotherapy while radiotherapy is generally reserved for those older than eight years. What has been missing is any disease-specific treatment for the visual dysfunction itself. The biological target that the Italian research team behind the new study focused on is the retinal ganglion cell, the neuron whose long axon forms the optic nerve. Children with optic pathway gliomas often show thinning of the retinal nerve fiber layer, the bundled axons of these cells, driven by apoptosis, a form of programmed cell death. In NF1-associated tumors, this cell death may stem not only from mechanical compression by the tumor mass but also from a functional deficit caused by loss of the neurofibromin protein, which triggers hyperactivation of the Ras signaling pathway, phosphorylation of atypical protein kinase C, and a drop in intracellular cyclic AMP. Crucially, work in rodent models has shown that ganglion cell apoptosis is preceded by a phase of axonal damage, opening a therapeutic window during which intervention might still prevent irreversible cell loss.

Nerve growth factor, the prototypical neurotrophin, has emerged as a leading candidate for exploiting that window. The molecule signals through two classes of receptors on cell surfaces: the high-affinity tyrosine kinase receptor TrkA and the low-affinity p75 neurotrophin receptor. Both are expressed throughout the visual system, from retina to cortex, and on retinal ganglion cells themselves, where endogenous NGF normally serves as a survival factor. Preclinical studies have repeatedly shown that supplying extra NGF can attenuate ganglion cell death after optic nerve injury, and more recent experiments with optic nerve crush models demonstrated that both recombinant human NGF injections and eye drop formulations can promote axonal regrowth, apparently by interfering with apoptotic machinery, including inhibition of the NogoA/p75NTR complex and suppression of Rho/ROCK2 signaling.

Those laboratory findings set the stage for the original clinical trial that the new report follows up. In that double-blind, randomized, placebo-controlled phase II study, eighteen children and young adults with optic pathway gliomas, aged between two and twenty-three years and with stable disease but severe visual impairment, were assigned to receive murine NGF as eye drops at a dose of 0.5 milligrams three times daily for ten consecutive days, or a matched placebo. The treatment course was strikingly short, yet it produced statistically significant improvements in electrophysiological measures of retinal and optic pathway function compared with placebo, along with a notable enlargement of the visual field in treated patients where reliable measurement was possible. No severe ocular or systemic adverse events were recorded, and MRI showed no tumor progression in either group.

The new publication extends that story to four years. Fifteen of the original eighteen participants, nine from the NGF arm and six from the placebo arm, agreed to continued clinical and neuroradiological monitoring, and importantly, no additional NGF, chemotherapy, or radiotherapy was given during the extended follow-up. Every six months the patients underwent general clinical and neuro-ophthalmological examinations, including visual acuity testing, Goldmann perimetry, flash visual evoked potentials, and the photopic negative response of the electroretinogram, a signal that specifically reflects the function of retinal ganglion cells. Brain MRI was performed annually and assessed by board-certified pediatric neuroradiologists using the Response Assessment in Neuro-Oncology criteria for low-grade glioma. Eleven of the fifteen patients had NF1, the median age at enrollment was 12.6 years, and most had previously received chemotherapy.

The headline result is stability. Comparing baseline and end-of-follow-up values, the researchers found no statistically significant change in median visual acuity, in the amplitude of visual evoked potentials, in the photopic negative response amplitude or timing, or in the radius of the visual field. At the level of individual eyes, only five of thirty showed any change in visual acuity over four years, and just three of those crossed the pre-specified threshold for clinical meaningfulness, a shift of at least 0.3 logMAR units, roughly fifteen letters on an eye chart. On imaging, stable disease was confirmed in all fifteen patients throughout the entire observation period. Two children showed minor tumor volume increases of about ten percent, but these fell short of the criteria for progressive disease and were not accompanied by clinical deterioration.

One intriguing wrinkle deserves attention. When the investigators re-analyzed individual visual field data, they found that the change from baseline differed significantly between the original treatment groups, both at three months and at the four-year endpoint: every patient originally assigned to NGF showed an increase or no change in visual field radius, while every placebo-assigned patient showed a decrease. Yet the authors are careful, and rightly so. Baseline visual field radius was itself substantially larger in the placebo group, a statistical imbalance that raises the specter of regression to the mean, and Goldmann perimetry is known to have within-visit test-retest variability that can approach twenty percent, with reliability that depends heavily on a child’s age and cooperation. The team explicitly labels any interpretation of a persistent treatment effect on the visual field as hypothesis-generating rather than confirmatory, a level of caution that stands out in a field often tempted by optimistic readings of small datasets.

Perhaps the most consequential question surrounding growth factor therapy in a tumor context is whether flooding the visual system with a pro-survival molecule might feed the neoplastic glial cells themselves. Here the evidence points the other way. Pediatric pilocytic astrocytomas characteristically downregulate TrkA, the receptor whose activation is associated with tumor cell proliferation, while upregulating the pro-apoptotic p75NTR receptor. Laboratory studies have shown that NGF inhibits the proliferation of rat glioma cells and drives them toward a more differentiated state, and more recent work demonstrated that ectopic NGF prevents proliferation in pediatric low-grade glioma cell lines by inducing cellular senescence. The four years of stable MRI scans in this cohort, spanning both treated and placebo patients, provide clinical reassurance consistent with that biology, although the authors note that the indolent natural history of these tumors is itself a plausible explanation for the observed stability.

The study’s limitations are acknowledged candidly. Fifteen patients is a small cohort, a consequence of the rarity of the condition and the pragmatic constraints of following up a completed trial, and the observational extension lacked the randomization that gave the original phase II study its power. Both eyes of most patients were included in analyses despite not being fully independent observations, and optical coherence tomography, a sensitive structural marker of ganglion cell integrity, could not be systematically repeated in young children for whom reliable scans often require sedation. What the study does establish is the sustained safety and tolerability of a short course of topical NGF in children, with no late ocular adverse events, no corneal sensitivity changes, and no evidence of tumor stimulation over four years. Whether nerve growth factor eye drops can genuinely preserve vision in children facing optic pathway glioma-related blindness will now depend on larger, adequately powered, prospective randomized trials with standardized outcome measures, for which this four-year safety record removes a significant barrier.

Subject of Research: Long-term safety and visual outcomes of topical nerve growth factor treatment in children with optic pathway gliomas

Article Title: Long-term outcomes after a randomized phase II trial of nerve growth factor eye drops for optic pathway gliomas: four-year follow-up findings in children

Article References: Ruggiero, A., Attinà, G., Placidi, G., D’Agostino, E., Amato, A., Verdolotti, T., Mastrangelo, S., & Falsini, B. (2026). Long-term outcomes after a randomized phase II trial of nerve growth factor eye drops for optic pathway gliomas: four-year follow-up findings in children. Journal of Neuro-Oncology, 179(2), Article 67. https://doi.org/10.1007/s11060-026-05777-z

Image Credits: AI Generated

DOI: 10.1007/s11060-026-05777-z

Keywords: nerve growth factor, optic pathway glioma, neurofibromatosis type 1, pediatric neuro-oncology, retinal ganglion cells, neuroprotection, visual evoked potentials, pilocytic astrocytoma, eye drops, phase II trial, visual field, low-grade glioma

The study, conducted in a mouse model of glaucoma, demonstrates that administration of rhNGF protects retinal ganglion cells from degeneration and preserves visual function. Crucially, the investigators did not stop at showing that the treatment worked; they dissected the mechanisms underlying the benefit, revealing that rhNGF counteracts two intertwined drivers of glaucomatous damage—oxidative stress and neuroinflammation. This dual action positions nerve growth factor not merely as a survival signal for ailing neurons, but as a molecular shield against the hostile retinal environment that develops as the disease progresses.

Nerve growth factor was the first neurotrophin ever discovered, identified more than seventy years ago by Rita Levi-Montalcini and Stanley Cohen, work that earned the Nobel Prize in Physiology or Medicine in 1986. NGF is best known for its role in the development and maintenance of sympathetic and sensory neurons, but it also acts on the central nervous system, including the retina, where its receptors—TrkA and p75NTR—are expressed by retinal ganglion cells and by glial cells such as Müller cells and astrocytes. Over the years, evidence has accumulated that NGF signaling can promote neuronal survival, yet translating that biology into a practical therapy has been difficult, in part because delivering protein drugs to target tissues is challenging and because earlier clinical efforts were hampered by formulation and delivery limitations.

In the glaucoma model used in the study, elevated intraocular pressure triggers a cascade of degenerative events in the retina. Pressure insult compromises axonal transport at the optic nerve head, deprives ganglion cells of trophic support, and sets off a vicious cycle in which stressed neurons release damage signals that activate glial cells. Activated microglia and macroglia, in turn, release pro-inflammatory cytokines such as TNF-alpha and interleukin-1 beta and generate reactive oxygen species, further injuring neurons and perpetuating the inflammatory loop. The result is progressive loss of retinal ganglion cells, thinning of the nerve fiber layer, and deterioration of the visual responses that these cells convey to the brain.

When the researchers administered rhNGF to the glaucomatous mice, they observed a marked preservation of retinal structure and function compared with untreated animals. Histological analysis revealed significantly higher survival of retinal ganglion cells, and functional assessments of the visual pathway confirmed that the anatomical protection translated into preserved vision-related output. The magnitude of the effect indicates that rhNGF does not merely delay degeneration marginally but provides substantive neuroprotection in this experimental setting.

The mechanistic findings are arguably the most significant contribution of the work. Molecular analyses of treated retinas showed a pronounced reduction in markers of oxidative stress. Levels of reactive oxygen species and lipid peroxidation products fell, while endogenous antioxidant defenses were bolstered. This matters because oxidative damage is now recognized as a central pillar of glaucoma pathobiology: the retina is one of the most oxygen-demanding tissues in the body, its ganglion cell mitochondria are exceptionally vulnerable, and oxidative modifications to proteins, lipids, and DNA accumulate early in the disease and correlate with neuronal loss. By damping oxidative injury, rhNGF appears to interrupt one of the key upstream triggers of the degenerative cascade.

Equally important was the effect on neuroinflammation. In untreated glaucomatous retinas, the researchers documented robust activation of microglia—the resident immune cells of the retina and optic nerve—along with elevated expression of inflammatory cytokines. In rhNGF-treated animals, microglial activation was substantially attenuated and the inflammatory signature was blunted. This anti-inflammatory action is notable because it suggests that NGF signaling, in addition to its classical trophic role, actively reprograms the glial response to injury. The TrkA receptor, when engaged by NGF, can activate survival pathways such as PI3K-Akt and MAPK signaling in neurons, while modulating the reactivity of glial cells that would otherwise amplify tissue damage. The study’s data indicate that both dimensions of NGF biology—direct neuronal support and immunomodulation—contribute to the observed protection.

The interplay between oxidative stress and inflammation is what makes these findings particularly compelling. These two processes are not independent; reactive oxygen species can activate inflammatory signaling pathways, including the NF-kappaB and inflammasome pathways, and inflammatory cells are themselves major producers of free radicals. In glaucoma, this creates a self-reinforcing spiral in which each process feeds the other. A therapy that targets only one arm of the spiral may achieve limited benefit, whereas an intervention that simultaneously reduces oxidative damage and suppresses neuroinflammation can potentially break the cycle. The rhNGF results suggest that the molecule does precisely that, which may explain why the neuroprotection achieved in the mouse model was so robust.

The therapeutic implications extend beyond the laboratory. Recombinant human NGF has already navigated part of the translational path: a topical ocular formulation of rhNGF has been approved in Europe for the treatment of neurotrophic keratitis, a disease of corneal nerve degeneration, providing clinical precedent for the safety and feasibility of delivering this protein to the eye. The new findings raise the prospect of repurposing or reformulating rhNGF for glaucoma, potentially as an adjunct to pressure-lowering therapy. Such a combination would address both sides of the disease: intraocular pressure as the major modifiable risk factor, and the downstream neurodegenerative processes that pressure control alone cannot fully halt. For the millions of patients who continue to progress despite adequate pressure management, a neuroprotective add-on would represent a genuine paradigm shift.

Significant work remains before rhNGF can be considered a glaucoma therapy. The current evidence comes from an animal model, and mouse glaucoma models, while informative, do not capture every feature of the human disease, which unfolds over decades rather than weeks. Questions of dosing, delivery route, treatment timing, and long-term safety will need to be answered, and results will need to be replicated in additional models and ultimately in clinical trials. Nevertheless, the study provides a rigorous mechanistic foundation for the idea that nerve growth factor can protect the optic nerve in glaucoma, and it identifies oxidative stress and neuroinflammation as tractable, druggable targets. If the neuroprotective efficacy observed in mice can be reproduced in patients, rhNGF could become one of the first treatments in ophthalmology to preserve vision not by lowering pressure, but by directly defending the neurons that make sight possible.

Subject of Research: Neuroprotective efficacy of recombinant human nerve growth factor in a mouse model of glaucoma

Article Title: rhNGF shows neuroprotective efficacy by counteracting oxidative stress and neuroinflammation in a glaucoma mouse model

Article References: Vecchiotti, D., Di Vito Nolfi, M., Compagnoni, C., Miscione, M. S., Verzella, D., D’Andrea, D., Flati, I., Galli, F., d’Angelo, M., Angelucci, A., Cattani, F., Cimini, A., Tessitore, A., Capece, D., Alesse, E., Allegretti, M., & Zazzeroni, F. (2026). rhNGF shows neuroprotective efficacy by counteracting oxidative stress and neuroinflammation in a glaucoma mouse model. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03345-y

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03345-y

Keywords: glaucoma, rhNGF, nerve growth factor, neuroprotection, oxidative stress, neuroinflammation, retinal ganglion cells, intraocular pressure, microglia, optic nerve, TrkA receptor, Cell Death Discovery