Alzheimer’s disease (AD) is a neurodegenerative disorder associated with cognitive decline. Despite worldwide efforts to find a cure, no proper treatment has been developed yet, and the only effective countermeasure is to prevent the disease progression by early diagnosis. The reason why new drug candidates fail to show therapeutic effects in clinical studies may be due to misunderstanding the cause of AD. Regarding the cause of AD, the most widely known is the amyloid cascade hypothesis, in which the deposition of amyloid beta and hyperphosphorylated tau is the cause. However, many new hypotheses were suggested. Among them, based on preclinical and clinical evidence supporting a connection between AD and diabetes, insulin resistance has been pointed out as an important factor in the development of AD. Therefore, by reviewing the pathophysiological background of brain metabolic insufficiency and insulin insufficiency leading to AD pathology, we will discuss how can insulin resistance cause AD.

Postmenopausal syndrome refers to symptoms caused by the gradual decrease in female hormones after mid-40 years. As a target organ of estrogen, decrease in estrogen causes various changes in brain function such as a decrease in choline acetyltransferase and brain-derived neurotrophic factor; thus, postmenopausal women experience cognitive decline and more depressive symptoms than age-matched men. Radix Polygalae has been used for memory boosting and as a mood stabilizer and its components have shown neuroprotective, antidepressant, and stress relief properties. In a mouse model of estrogen depletion induced by 4-vinylcyclohexene diepoxide, Radix Polygalae was orally administered for 3 weeks. In these animals, cognitive and depression-related behaviors and molecular changes related to these behaviors were measured in the prefrontal cortex and hippocampus. Radix Polygalae improved working memory and contextual memory and despair-related behaviors in 4-vinylcyclohexene diepoxide-treated mice without increasing serum estradiol levels in this model. In relation to these behaviors, choline acetyltransferase and brain-derived neurotrophic factor in the prefrontal cortex and hippocampus and bcl-2-associated athanogene expression increased in the hippocampus. These results implicate the possible benefit of Radix Polygalae in use as a supplement of estrogen to prevent conditions such as postmenopausal depression and cognitive decline.

Depression is a disease with increasing prevalence worldwide, and it is necessary to develop a therapeutic agent with better efficacy than existing antidepressant drugs. Antidepressants that act on the glutamatergic nervous system, such as ketamine, have a rapid-onset antidepressant effect and are effective against treatment-resistant depression. However, because of the addictive potential of ketamine, alternative substances without psychological side effects are recommended. In particular, many natural compounds have been tested for their antidepressant effects. The antidepressant effects of Nelumbinis semen (NS) have been tested in many studies, along with the various actions of NS on the glutamatergic system. Thus, it was expected that NS might have a rapid-onset antidepressant effect. To test the antidepressant potential, despair and anhedonic behaviors were measured after administering NS to mice exposed to social hierarchy stress (SHS), and biochemical changes in the prefrontal cortex and hippocampus were analyzed. NS reduced despair-like responses in the forced swim test and tail suspension test. Mice exposed to SHS showed depression-like responses such as increased despair, reduced hedonia, and an anxiety-like response in the novelty suppressed feeding test. NS, but not fluoxetine, improved those depression-like behaviors after acute treatment, and NBQX, an AMPA receptor blocker, inhibited the antidepressant-like effects of NS. The antidepressant-like effect of NS was related to enhanced phosphorylation of mTOR in the prefrontal cortex and dephosphorylation of GluR1 S845 in the hippocampus. Since NS has shown antidepressant-like potential in a preclinical model, it may be considered as a candidate for the development of antidepressants in the future.

Ji Hye Yoon, Seung-Yun Cha, Sungho Maeng, Yongjin Shin, Myeongae Park, and Jinkyung Kim. Journal of the Korean Society of Food Science and Nutrition 2024;53:1239-44. https://doi.org/10.3746/jkfn.2024.53.12.1239