Natural Products and Their Neuroprotective Effects in Degenerative Brain Diseases: A Comprehensive Review

Abstract

As the global population ages, the incidence of neurodegenerative diseases such as Alzheimer's and Parkinson's is rapidly rising. These diseases present a significant public health challenge, as they severely impair cognitive and motor functions, ultimately leading to a substantial reduction in quality of life and placing a heavy burden on healthcare systems worldwide. Although several therapeutic agents have been developed to manage the symptoms of these diseases, their effectiveness is often limited, and there remains an urgent need for preventive strategies. Growing evidence indicates that bioactive compounds from natural products possess neuroprotective properties through antioxidant and anti-inflammatory effects, modulating key pathways such as phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and brain-derived neurotrophic factor-tropomyosin receptor kinase B-cAMP response element-binding protein (BDNF-TrkB-CREB), which are crucial for neuronal survival. These compounds may also reduce amyloid-beta and tau pathology, as well as enhance cholinergic neurotransmission by inhibiting acetylcholinesterase activity. By targeting oxidative stress, neuroinflammation, and neurodegeneration, natural products offer a promising approach for both prevention and treatment. These findings suggest that natural products may be promising for preventing and treating neurodegenerative diseases. This review aims to explore the pathogenesis of neurodegenerative diseases, the limitations of current therapies, and the potential role of natural products as therapeutic agents.

Keywords: Alzheimer’s disease; degenerative brain disorders; medical plants; natural products; neuroprotection.

Figure 1

Degenerative brain diseases that occur mainly in each major brain region and their representative symptoms.

Figure 2

Oxidative stress and its role in the pathogenesis of degenerative brain diseases. Degenerative brain diseases are largely driven by oxidative stress caused by excessive ROS production, often triggered by factors like mitochondrial dysfunction, protein accumulation (Aβ, tau, α-synuclein), and genetic risk factors like APOE ε4. ROS impair neuronal survival, differentiation, and synaptic plasticity by disrupting key signaling pathways such as BDNF/TrkB and PI3K/AKT, leading to neuronal damage and cell death. They also activate microglia and inflammatory responses, creating a cycle of oxidative stress and inflammation. Additionally, ROS impair mitochondrial function and BBB integrity, further exacerbating neuronal damage and disease progression. sAPPα: soluble amyloid precursor protein alpha, sAPPβ: soluble amyloid precursor protein beta, N: N-terminus, CTFα: C-terminal fragment alpha, C: C-terminus, CTFβ: C-terminal fragment beta, AICD: amyloid precursor protein intracellular domain, Aβ: amyloid beta, ROS: reactive oxygen species, NF-κB: nuclear factor kappa B, IL-1β: Interleukin-1 beta, IL-6: Interleukin-6, TNF-α: Tumor necrosis factor alpha, BDNF: brain-derived neurotrophic factor, TrkB: tropomyosin receptor kinase B, AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, NMDAR: N-methyl-D-aspartate Receptor, PI3K: phosphoinositide 3-Kinase, AKT: protein kinase B, RAS: Rat Sarcoma virus, MAPK: mitogen-activated protein kinase, CaMII: calcium/calmodulin-dependent protein kinase II, PKC: protein kinase C.

Figure 3

A natural product with well-established neuroprotective potential can exert its effects through multiple mechanisms. These mechanisms include AChE inhibition to enhance cholinergic transmission, a reduction in Aβ peptide and tau protein levels, and activation of the PI3K-AKT-GSK-3β pathway to improve synaptic function. Additionally, antioxidant and anti-inflammatory properties contribute to neuronal protection, while activation of the BDNF-TrkB-CREB pathway promotes synaptic plasticity. Furthermore, natural products may ameliorate synaptic dysfunction caused by oxidative stress and ROS generation. BACE1: beta-site amyloid precursor protein cleaving enzyme 1, APP: amyloid precursor protein, sAPPβ: soluble amyloid precursor protein beta, APOE ε4: apolipoprotein E epsilon 4 allele, Ach: acetylcholine, AchE: acetylcholinesterase, P85: phosphoinositide 3-kinase regulatory subunit p85, P110: phosphoinositide 3-kinase catalytic subunit p110, PI3K: hosphoinositide 3-kinase, AKT: protein kinase B, GSK3-β: glycogen synthase kinase 3 beta, ROS: reactive oxygen species, BDNF: brain-derived neurotrophic factor, TrkB: tropomyosin receptor kinase B, ERK1/2: extracellular signal-regulated kinase 1/2, CREB: cAMP response element-binding protein.