The Effect of Natural Compounds on Cognitive Impairment Through BDNF / TrkB / CREB Pathway: A Review

ABSTRACT Considering the global prevalence of Alzheimer's disease (AD) and the restrictions of current treatment procedures, natural compounds (such as curcumin, hesperidin, and rutin) have been evaluated as multifaceted therapeutic agents. This review demonstrated that these compounds employ neuroprotective effects primarily through upregulating the brain‐derived neurotrophic factor/tropomyosin receptor kinase B/cAMP response element binding protein (BDNF/TrkB/CREB) pathway. After inducing this pathway, they subsequently decrease apoptosis through the regulation of B‐cell lymphoma protein 2‐associated X/B‐cell lymphoma 2 protein (Bax/Bcl2) ratio and the inhibition of apoptosis signal‐regulating kinase 1 (ASK1) (e.g., icariin). They also modulate oxidative stress via increasing superoxide dismutase, catalase, and glutathione peroxidase (e.g., hesperidin), and suppress neuroinflammation through the inhibition of nuclear factor kappa‐light‐chain‐enhancer of activated B cells (Nf‐κB) and proinflammatory cytokines (e.g., curcumin). These compounds enhance the level of postsynaptic density protein (PSD‐95), a key enhancer of neuronal plasticity, improve synaptic signaling (e.g., oleanolic acid), and reduce cognitive disorders by reducing the formation of amyloid beta (Aβ) plaques (e.g., rutin). The phosphatidylinositol 3‐kinase/protein kinase B (PI3K/Akt) signaling pathway is modulated (e.g., icariin), and cholinergic neurons are restored (e.g., maslinic acid). Despite the beneficial potential of natural compounds, the extrapolation of their findings to clinical application requires more precise preclinical studies and validated biomarkers.