Neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive degradation of neuronal structure and function in the central nervous system [1]. Among them, AD is the most common NDD with cognitive impairment as the main clinical performance, and its main pathological features are deposition of amyloid-β (Aβ) protein and neurofibrillary tangles composed of hyperphosphorylated tau protein. PD presents with movement disorders such as bradykinesia, tremor, and unsteady gait, commonly attributed to the loss of nigrostriatal dopaminergic neurons and aggregates of α-synuclein. HD is a devastating inherited NDD caused by the mutant huntingtin (mHTT) gene that induces non-functional or toxic misfolded proteins, characterized by choreiform movements, psychiatric abnormalities, and cognitive deficits. ALS is known for rapid progression of severe muscle weakness and atrophy owing to the degeneration of motor neurons in brain and spinal cord, usually leading to death due to respiratory failure within two to five years of onset.

Although the clinical symptoms and pathological manifestations of NDDs are well recognized, they are still incurable. The incidence of NDDs not only rises rapidly with the aging of the world’s population, but also presents a younger trend in recent years. Existing drugs can only relieve some symptoms but fail to block disease progression, so there is an urgent need to explore effective therapeutic strategies to combat NDDs. Given that the pathogenesis of NDDs is complex and still not fully elucidated, there is a prevailing view that the most widely studied pathological manifestations such as characteristic protein aggregation are only the consequences rather than the causes of disease development. Some conventional pathogenic mechanisms, such as oxidative stress, neuroinflammation, and mitochondrial dysfunction, have been recognized to be closely related to the progression of NDDs. Specifically, oxidative stress caused by excessive production and weak clearance of reactive oxygen species (ROS) and reactive nitrogen species can lead to the oxidation of intracellular biomolecules for neuronal apoptosis. Aberrant activated glial cells can secrete large amounts of pro-inflammatory cytokines, inducing chronic neuroinflammation to damage neuronal structure and function. Abnormal mitochondrial division, fusion, and degradation can alter energy production and signal transduction in neurons or glial cells, resulting in neuronal death and synaptic loss. In contrast, several emerging pathogenic mechanisms have recently been discovered to be involved earlier and more deeply in the occurrence and development of NDDs, including ferroptosis, energy metabolism disorders, autophagy-lysosomal dysfunction, endoplasmic reticulum (ER) stress, and gut microbiota dysbiosis [2,3,4,5,6].

2. Intracerebral Administration Strategies for Natural Molecules

3. Clinical Trails of Natural Molecules for NDD Treatment