Ellagic acid is a natural phenol antioxidant found in numerous fruits and vegetables. Several studies showed that ellagic acid has potent neuroprotective properties.

 

    Cognitive defects such as thinking, memory, and behavior or mental health disorders are the most frequent effects of severe and moderate traumatic brain injury. A rat study was performed to examine the ellagic acid preventive effects on cognitive impairments, long-term potentiation (long-term potentiation is widely considered one of the major cellular mechanisms that underlie learning and memory) deficits in the hippocampus, and brain inflammation induced by diffuse traumatic brain injury. Ellagic acid was given orally at 100 mg/kg dose for 7 consecutive days before induction of trauma. Pre-treatment of ellagic acid significantly prevented traumatic brain injury-induced memory and hippocampal long-term potentiation impairments (p<0.001). Traumatic brain injury-induced elevation in brain content of IL-1β, IL-6, and blood-brain barrier permeability was decreased significantly (p<0.001) due to ellagic acid pre-treatment. The study showed that ellagic acid can prevent cognitive and long-term potentiation deficits and also prevent brain inflammation following traumatic brain injury (1).

 

    Sporadic Alzheimer's disease, age-associated dementia, is described as neuronal loss and marked cognitive impairment. Therapeutic effects of ellagic acid were tested in streptozotocin-induced Sporadic Alzheimer's disease rats. Treatment with ellagic acid (50 mg/kg) for 30 days revealed a reduction in streptozotocin-prompted Sporadic Alzheimer's disease and associated biochemical abnormalities in experimental rats which included diminished oxidative stress profile, pro-inflammatory markers, and amyloid-β plaque level. The ellagic acid-treated group had an elevated level of synaptophysin indicating improved synaptic connectivity, and intact neural architecture suggesting its neuroprotection effect. The behavioral investigation by maze tests revealed that Sporadic Alzheimer's disease rats had reduced locomotor behavior, irregular spontaneous alternation, declination in memory score, and increased memory errors. Ellagic acid treatment normalized these Sporadic Alzheimer's disease-associated abnormal behavioral representations in rats. The study findings suggest neuroprotective effects of ellagic acid and improvement in cognitive behavior in Sporadic Alzheimer's disease rats (2).

 

    Sleep disorder is a prevalent issue in current society and is connected with the deterioration of neurobehaviors such as mood, cognition, and memory. Ellagic acid ameliorated behavioral abnormalities in sleep-deprived mice, associated with increased dendritic spine density, and reduced shrinkage and loss of hippocampal neurons. Ellagic acid reduced the inflammatory response and oxidative stress injury caused by sleep deprivation. In addition, ellagic acid significantly reduced the mortality and reactive oxygen species levels (ROS is an indicator for oxidative stress) in glutamate-induced hippocampal neuron injury. The study findings suggested that ellagic acid may be a promising nutraceutical ingredient to prevent cognitive impairment and anxiety caused by sleep loss (3).

 

    Ellagic acid treatment reversed the dendritic spine loss caused by sleep deprivation. Sleep is a restorative process that facilitates learning and memory consolidation. Sleep deprivation is understood to impair both emotional and contextual memories by modifying the neuronal network at physiological, molecular, and synaptic levels. In this study, ellagic acid significantly improved spatial memory impairment in mice after 72 hours of sleep deprivation. Furthermore, ellagic acid reduced the shrinkage and loss of hippocampal neurons in sleep-deprived mice. The dendritic spine density was dramatically increased after ellagic acid administration. The authors suggested that the reduction in the inflammatory response and oxidative stress injury may be related to ellagic acid's protection of mice from memory impairment and anxiety caused by sleep deprivation (3).

 

    Neurological damages can also occur in diabetes when glucose management is poor. The effects of ellagic acid on the brain and sciatic nerve tissues were investigated in diabetic rats. The rats were randomly divided into four groups (n=8 each group): Normal controls (not diabetic), only ellagic acid-treated (ellagic acid controls, not diabetic), Diabetic controls (streptozotocin, diabetic), ellagic acid-treated diabetic (streptozotocin + ellagic acid). After a 4 week experiment, biomarkers for oxidative stress in the brain and sciatic nerve tissues of the rats were measured. There was significant depletion in the antioxidant levels in the brain and sciatic nerve tissues of the diabetic group compared to the control groups (p<0.05). The values of antioxidants reversed back to normal levels in ellagic acid-treated diabetic rats compared to untreated diabetic rats (p<0.05). The levels of oxidative stress markers in the brain and sciatic nerve tissues were higher in untreated diabetic rats compared to the control group  (p<0.05). These oxidative stress markers' levels were found to be significantly reduced in the ellagic acid-treated diabetic group compared to the untreated diabetic group in these tissues (p<0.05). The results of the study suggested that ellagic acid exhibits neuroprotective effects against oxidative damage in diabetic rats (4).

 

    A human study investigated if ellagic acid has beneficial effects on cognitive function in middle-aged men. A total of 150 middle-aged male participants, including 76 normal-weight and 74 overweight men, aged between 45 to 55 years, were recruited for this study. Both normal-weight and overweight participants were given either 50 mg ellagic acid or placebo cellulose daily for 12 weeks. Blood lipids, peripheral brain-derived neurotrophic factor [brain-derived neurotrophic factor is a protein that promotes the survival of nerve cells (neurons) by playing a role in the growth, maturation (differentiation), and maintenance of these cells], and saliva cortisol were assessed on the last day of the study to investigate the effects induced by ellagic acid (5).

 

    The results revealed that ellagic acid treatment improved the levels of blood lipid metabolism with a 4.7% decline in total cholesterol, a 7.3% decline in triglycerides, a 26.5% increase in high-density lipoprotein, and a 6.5% decline in low-density lipoprotein. Additionally, ellagic acid increased plasma brain-derived neurotrophic factor by 21.2% in the overweight group and showed no effects on normal-weight participants. Moreover, the increased saliva cortisol level in overweight individuals was inhibited by 22.7% in a 12-week ellagic acid treatment. Compared with placebo, overweight individuals who consumed ellagic acid showed enhanced cognitive function as measured by the Wechsler Adult Intelligence Scale-Revised and the Montreal Cognitive Assessment. This report showed that ellagic acid prevents cognitive deficits through normalization of lipid metabolism, increase in plasma brain-derived neurotrophic factor level, and reduction of saliva cortisol concentration. These results indicate that ellagic acid has the potential to restore cognitive performance related to mild age-related declines (5).

 

    These studies showed that ellagic acid has neuroprotective effects. Ellagic acid, as a powerful antioxidant, has many other health benefits such as anti-bacterial, anti-inflammatory, immune-regulatory, and inhibition of tumorigenesis (1). Ellagic acid-rich foods include pomegranates, grapes, raspberries, blackberries, strawberries, and walnuts. For those of you who may want to know specifics, here are some of the ellagic acid contents of various foods: in fruits (mg/100g fresh weight), Blackberries 150, Pomegranate 270, Raspberries 270, Strawberries 77.6; in nuts (mg/g), Walnuts 59; in beverages (mg/L): Pomegranate juice 811 (source: Wikipedia).

 

References:

1. Farbood, Y., Sarkaki, A., Dianat, M., Khodadadi, A., Haddad, M. K., & Mashhadizadeh, S. (2015). Ellagic acid prevents cognitive and hippocampal long-term potentiation deficits and brain inflammation in rat with traumatic brain injury. Life Sciences, 124, 120–127. 

2. Jha, A. B., Panchal, S. S., & Shah, A. (2018). Ellagic acid: Insights into its neuroprotective and cognitive enhancement effects in sporadic Alzheimer’s disease. Pharmacology Biochemistry and Behavior.

3. Wang, W. J., Yang, L. D., Liu, T. L., Wang, J. W., Wen, A. D., Ding, Y.(2020). Ellagic acid protects mice against sleep deprivation-induced memory impairment and anxiety by inhibiting TLR4 and activating Nrf2. Aging, 12(11):10457-10472.

4. Uzar, E., Alp, H., Cevik, M. U., Fırat, U., Evliyaoglu, O., Tufek, A., & Altun, Y. (2011). Ellagic acid attenuates oxidative stress on brain and sciatic nerve and improves histopathology of brain in streptozotocin-induced diabetic rats. Neurological Sciences, 33(3), 567–574.

5. Liu, Y., Yu, S., Wang, F., Yu, H., Li, X., Dong, W., … Liu, Q. (2018). Chronic administration of ellagic acid improved the cognition in middle-aged overweight men. Applied Physiology, Nutrition, and Metabolism, 43(3), 266–273.