Prospects of antidiabetic drugs in the treatment of neurodegenerative disease

Neurodegenerative diseases (NDs) stand for a group of disorders characterized by the progressive loss of neurons in the brain and peripheral organs, resulting in motor and cognitive dysfunction. The global prevalence of NDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, is on the rise globally, primarily due to an aging population, positioning NDs as an increasing significant public health concern. Despite intensive research, few effective therapies that prevent or delay ND progression have been developed. Mounting evidence indicates that one of the well-defined risk factors for NDs is type 2 diabetes mellitus, and insulin resistance has also been proven to be related to cognitive decline. Certain antidiabetic drugs, such as glucagon-like peptide-1 receptor agonists, peroxisome proliferator-activated receptor gamma agonists, and metformin, have shown promise in offering neuroprotective benefits and alleviating ND symptoms beyond their glucose-lowering effects. Although the exact mechanisms remain elusive, these drugs offer a promising novel strategy for managing cognitive disorders. In this review, we first highlight the benefits and specific neuroprotective effects of multiple antidiabetic drugs and discuss the main mechanisms of action of antidiabetic drugs in treating NDs. These mechanisms include reducing protein aggregation and improving apoptosis, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Finally, we summarize clinical trials evaluating these drugs for treating NDs.