·   Fisetin has neuroprotective effects in mice with memory dysfunction caused by oxidative stress and brain inflammation.
·   Fisetin has antioxidant and anti-inflammatory qualities that improve brain cell connections and cognitive abilities.

Several studies have indicated that oxidative stress, when cells have elevated levels of harmful molecules called reactive oxygen species (ROS), is responsible for different neurodegenerative conditions in various age-associated disorders. The elevated oxidative stress triggers cellular damage, disrupting the functions of the brain to cause neurodegeneration. So, the neurodegeneration caused by elevated oxidative stress could be a therapeutic target to tackle age-related diseases like neurodegenerative disorders.

According to a study published in Frontiers in Pharmacology by Ahmad and colleagues, a plant-derived molecule called fisetin has antioxidant and neuroprotective effects in mice with oxidative stress, neuroinflammation, and memory dysfunction. By preventing the buildup of ROS accumulation through regulating the cell’s antioxidant mechanisms and, ultimately, inflammatory signaling molecules, fisetin improves brain cell connections and cognitive abilities. “Hence, our results together with the previous reports suggest that fisetin may be beneficial in age-related neurological disorders,” proposed Ahmad and colleagues.

Fighting Brain Aging With Phytonutrients

Recently, the use of plant-derived nutrients (phytonutrients) and medicinal herbs have gained a special interest to treat neurological disorders like Alzheimer’s disease. Among the phytonutrients is fisetin — a natural flavonoid found in different fruits, such as legumes, mangoes, kiwis, strawberries, grapes, cucumbers, nuts, beans, and onions. Fisetin has shown strong anticarcinogenic, anti-inflammatory, and antioxidant effects as well as neuroprotection against different neurodegenerative diseases. There is evidence suggesting that fisetin may exert multi-targeted neuroprotective effects, but how it exerts its beneficial effects remains unclear.

Fisetin Pushes Back on Cognitive Dysfunction

Ahmad and colleagues evaluated the effect of fisetin (20 mg/kg/day for 30 days) on the presence of proteins that represent neuronal connections, called synaptic proteins, in mice treated with D-galactose, an activator of oxidative stress, neuroinflammation, and cognitive dysfunction. At the level of molecules, fisetin abrogates the D-galactose-induced oxidative stress and neuroinflammation by regulating the inflammatory mediators and markers related to the vital process of autophagy, or how cells recycle materials.

At the level of networks in the brain, Ahmad and colleagues found that mice treated with D-galactose had major drops in the levels of proteins at the synapse, a brain cell structure necessary for cell connectivity and communication. Fisetin was able to recover the levels of synaptic proteins in mice exposed to D-galactose to that of unexposed mice. Importantly, these effects on synaptic proteins were present in the brain regions important for cognition (cortex) and learning and memory (hippocampus). “Collectively, our findings suggested that fisetin reversed the D-gal-induced synaptic dysfunction in d-galactose-treated mice brains,” concluded Ahmad and colleagues.

(Ahmad at al. 2021| Front Pharmacol.) Effects of fisetin against synaptic dysfunction. Ahmad and colleagues observed a significant downregulation in the expression of synaptic proteins SNAP-25 and PSD-95 in the brain regions important for cognition (cortex) and learning and memory (hippocampus and dentate gyrus). D-galactose-treated mice were compared to the control group, and the fisetin-treated group showed a synaptic protein upregulation. Hippo, hippocampus; DG, dentate gyrus.

To assess the effects of fisetin at the behavioral level, Ahmad and colleagues used various mazes to assess cognitive dysfunction. For the evaluation of the spatial working memory, they used the Y-maze test, which is based on the animals’ natural curiosity for exploration. The animals typically tend to explore a new arm of the maze rather than returning to one that was previously visited. In the Y-maze, D-gal-injected mice exhibited less spontaneous alternations compared to the saline-treated control mice. These findings indicate that oxidative stress from D-galactose inhibits cognition as shown by reduced maze exploration.

Fisetin treatment enhanced the spontaneous alternation behavior, though, showing that fisetin restores the spatial working memory of the D-gal-injected mice. Moreover, the arm entries were also considered, to analyze the effects of fisetin on the motor performance of mice, which suggested that the number of arm entries was markedly upregulated with the administration of fisetin, indicative of improved motor function.

(Ahmad at al. 2021| Front Pharmacol.) Fisetin improved spatial memory. Ahmad and colleagues examined how fisetin affected the cognition of D-gal-treated mice by looking at their performance in a test called the Y Maze. These mice recovered cognitive function, as shown by their improvement in spontaneous alternation behavior (A) and the number of arm entries in the Y-maze test (B). Con: Control, D-gal: d-galactose, Fis: Fisetin.

For the analysis of the memory formation, Ahmad and colleagues performed the Morris Water Maze test. Here, the mice were trained to find a submerged hidden platform in a pool of murky water lined by visual cues. After the training session, they analyzed the time required to arrive at the hidden platform position. The D-galactose-injected mice took more time (increased latency time) to reach the hidden platform compared to the control mice.

Interestingly, fisetin reversed the D-galactose effects and enhanced the memory function, as indicated by the mice taking less time to arrive at the hidden platform, decreased the number of platform crossings, and increased the time spent in the target quadrant compared to the D-galactose-treated mice. Ahmad and colleagues also checked the swimming speed, to show the effects of fisetin on motor performance. According to their findings, fisetin significantly improved the swimming speed of the mice in the Morris Water Maze test compared to the D-galactose injected mice.

(Ahmad at al. 2021| Front Pharmacol.) Fisetin improved cognitive functions in the D-gal-injected mice. Ahmad and colleagues looked at the ability of the mice to perform in the Morris Water Maze by looking at the latency to reach the hidden platform during the training days (C). On the fifth day of training, they evaluated the latency to reach the platform (D). Administering fisetin improved the mice’s ability to find the hidden platform as shown by a decreased latency Con: Control, D-gal: D-galactose, Fis: Fisetin.

“Here, we have conducted detailed synaptic and behavioral studies, which strongly supports the notion that fisetin may regulate the age-related synaptic and memory impairment in mice,” concluded Ahmad and colleagues. “Hence, our results together with the previous reports suggest that fisetin may be beneficial in age-related neurological disorders.”