Synergistic Enhancement of BDNF-Mediated Neurotrophic Activities by Apigenin: Implications for Neurodegenerative Disease Therapy

Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis are the leading causes of decline in cognitive and motor functions in neurodegenerative diseases patients. Currently there are limited effective treatment available for these diseases despite decades of extensive research. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of growth factors plays an essential role in neuronal survival, growth, maintenance, and synaptic plasticity which made it a promising therapeutic candidate for neurodegenerative diseases. However, the brain delivery of the large size BDNF is a significant challenge because it does not cross the blood-brain barrier. Therefore, there is still an urgent need for new and innovative approaches to enhance BDNF’s neuroprotective and neurotrophic functions. To this account, a research study published in CNS Neuroscience & Therapeutics and led by Professor Karl Wah-Keung Tsim from the Hong Kong University of Science and Technology and conducted by Alex Xiong Gao, Tracy Chen-Xi Xia, Lish Sheng-Ying Lin, and Tina Ting-Xia Dong, the researchers investigated the neurotrophic potential of apigenin, in synergy with BDNF and they studied in detail the mechanisms underlying the neuroprotective and neurotrophic effects of apigenin and BDNF combination on neuronal cells.  Apigenin is a known bioactive flavonoid commonly found in a variety of plants, including fruits, vegetables, and herbs like chamomile and has attracted significant interest in the medical research community because of its potential therapeutic applications in various diseases.

In their studies, the team used molecular docking and computational modeling to predict the binding efficiency and orientation of apigenin to BDNF to reveal the favorable binding energy. Moreover, they performed ultrafiltration assay, to confirm the physical binding of apigenin to BDNF and demonstrated an increased retention of apigenin in the presence of BDNF. Furthermore, they conducted surface plasmon resonance and obtained vital data about the binding affinity between apigenin and BDNF and the direct interaction with a calculated dissociation constant. Afterward, the researchers used cultured SH-SY5Y cells and rat cortical neurons to evaluate the pharmacological effects of apigenin and BDNF on neurogenesis and cell viability. They applied apigenin and BDNF, either each alone or in combination to cultured neurons, and observed their effects on cell viability and neurite outgrowth. According to the authors apigenin and BDNF synergistically maintained cell survival and promoted neurite outgrowth. To simulate the pathological aspects of Alzheimer’s disease in vitro, the researchers incubated amyloid-beta (Aβ)25-35 to the neuronal cultures and evaluated the protective effects of apigenin and BDNF. They used propidium iodide statin to quantify Aβ-induced cell death, and showed reduced cytotoxicity with the combined administration of apigenin and BDNF. Moreover, the team employed mitochondrial membrane potential analysis to evaluate the mitochondrial health and showed that the apigenin-BDNF synergy mitigated Aβ-induced mitochondrial dysfunction. Additionally, the study investigated the mechanistic aspects of the activation of the tyrosine kinase receptor B (TrkB) signaling pathway, which is an important pathway for BDNF’s neurotrophic effects. They measured using western blotting the levels of phosphorylated Trk B receptor, along with downstream signaling molecules (ERK1/2, Akt, PLCγ1, and CREB), showing enhanced activation in the presence of both apigenin and BDNF. They also used the Trk inhibitor, K252a to confirm that the neurotrophic and protective effects were mediated through Trk B signaling. This insight advances our understanding of the molecular underpinnings of neuroprotection and neurogenesis highlights the therapeutic potential of targeting TrkB signaling in neurodegenerative diseases.

In conclusion, the work of Professor Karl Wah-Keung Tsim and colleagues is compelling evidence for the neurotrophic and neuroprotective benefits of apigenin, when used in combination with BDNF. Their elegant experiments successfully showed that Apigenin directly binds to BDNF and enhances its neurotrophic functions, promotes cell survival, neurite outgrowth, and protects against amyloid-beta-induced toxicity. The synergy between apigenin and BDNF was shown to be mechanistically mediated through the activation of the Trk B signaling pathway. Overall, these results advance our understanding of the molecular basis of neurodegeneration and the potential for natural compounds in therapeutic intervention.