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The Effects of Ginkgo Biloba Behavior Using Rodent Models

By May 17, 2019November 13th, 2019No Comments

Ginkgo biloba extract (GBE) has been used as a supplement for neurocognitive diseases like Parkinson’s and Alzheimer’s, with promising and evident neuroprotective effects. Most of the research focuses on molecular mechanisms, but we see several studies that measure behavior. Most findings show that GBE’s power as a neuroprotector comes from its antioxidant capacities. Most rats tested for behavioral symptoms of diseases such as Parkinson’s, Alzheimer’s, even depression and anxiety, show improvement when treated with ginkgo biloba extract. It can attenuate the decline in memory, cognition, and learning that such conditions trigger due to brain cell damage or loss.

What is Ginkgo Biloba?

Ginkgo biloba is a plant with origins in China dating all the way back to 270 million years (found in very old fossils). It’s a very ancient tree and currently the only type within its phylum or category. Traditional Chinese tea involved the boiling of the Gingko biloba leaves to drink regularly in order to treat lung and heart conditions. Its components, mostly flavonoids and two specific terpenes named ginkgolides and bilobalide have positive effects on several body organs.

Most research and findings indicate that it has neuroprotective properties but can also aid cardiovascular diseases.[1] These can be measured and observed in the context of Alzheimer’s and other conditions through the studying of rat behavior. Mazes that test learning, memory, and such conducts have been used to study how ginkgo biloba extract affects these. EGb 761, has been used as a dietary supplement for Alzheimer’s dementia. It’s potential to treat and prevent Alzheimer’s disease and other neurodegenerative conditions like dementia lie in the capacity to both upregulate and downregulate several mechanisms in the nervous system. Through this mechanism, it can protect the brain in neurodegenerative scenarios, which is what researchers found in several behavioral measurements done in rats.

Effects on Age

Ginkgo biloba’s strong potential to fight oxidative stress can be studied and framed in the context of aging. Because most of the processes of aging come from oxidative stress in different cells of our systems, ginkgo biloba extract, which is referred to as Egb 761, is suggested as a solution. The protective mechanism it offers possibly works at a mitochondrial level. In this setting, elderly rats’ cardiomyocite mitochondria were tested in hypoxic conditions. Ultrastructural morphometry was used to observe the mitochondria and how they changed. Hypoxic conditions were induced by the controlled application of a O2N2O mixture that could be lowered and manipulated through time.  The group that was treated with Egb 761 were dosed with 100 mg per kg by oral means 3 months before the experiment. Compared to the control group that did not receive ginkgo biloba extract, the Egb 761  showed less membrane damage, leading to the conclusion that Egb 761 has a protective effect.[2]

Sastre et. al measured the oxidative stress associated with age by looking at oxo 8 dG as an oxidative DNA biomarker. Researchers looked at 27 months old rat’s brain and liver cells and found less DNA damage in the group that took ginkgo biloba extract.[3]

Anti-oxidative Effects of Ginkgo Biloba

Dubbed ‘free radical scavenger’, ginkgo biloba can reduce oxidative stress in several scenarios. This experiment focused on the cochlear or auditory system of rodents and researchers found that the group treated with gingko biloba extract showed less apoptosis of neural stem cells in the organ of Corti. The GBE group was supplemented with a media of 0.2 mM H2O2 (hydrogen peroxide induced the oxidative stress) and 50 mg/L of GBE, while the control group received the media without GBE. The extract seems to reverse intrinsic factors in the apoptotic pathway, meaning it can play a therapeutic role in hearing loss.[4]

Effects on Alzheimer’s Disease

Various studies show that ginkgo biloba extract has neuroprotective effects. Because Alzheimer’s disease is caused by neurodegeneration due to a combination of inflammation, oxidative stress, and neuronal apoptosis, most research focuses on preventing or treating these. The loss of cognition and memory that Alzheimer’s disease triggers can be minimized with gingko biloba since it is has multiple mechanisms of providing neuroprotection.[5]

1. Amyloidogenesis and AB Aggregation Protection

One of the main mechanisms through which Alzheimer’s disease takes over the brain is AB plaque accumulation. In 2000, Bastianetto et. al took a look at Ginkgo biloba extract’s neuroprotective effects and it proved effective on hippocampal neurons. AB toxicity was induced to simulate Alzheimer’s AB plaque accumulation. Toxicity was induced in cultured cells through exposure to solubilized peptides AB 25-35, AB 1-40 and AB 1-42. The control group was exposed to only the AB peptides and the treated group was exposed to both AB peptides and EGb 761. The group treated with the highest concentration of ginkgo biloba extract (100 µg/mL) inhibited cell apoptosis and showed a protective effect.[6]

It also protects against amyloidogenesis, the process of amyloid production. EGb761 seems to regulate the amyloid precursor protein (APP) pathway. The group treated with EGb761 had an increase in the release of alphaAPP, the enzyme responsible for the regulation of the non-amyloidogenic processing of APP.[7]

In a particular study, Tg-2576 mice, which represent a model for Alzheimer’s disease, were treated with ginkgo biloba extract. Transgenic mice ‘Tg2576’ have overexpression of human AB precursor protein in order to simulate cognition decline, oxidative brain damage, and AB plaque deposition. Mice were tested in a Morris water maze and the untreated group displayed impaired spatial learning. The treated group showed enhanced memory and spatial learning. Although this behavior was observed, it was unclear how ginkgo biloba affected the B-amyloid plaque deposition. [8]

2. Mitochondria Function Protection

Another underlying mechanism that Alzheimer’s disease is related to is mitochondrial dysfunction. Experiments with ginkgo biloba extract have shown positive neuroprotective effects against mitochondrial dysfunction. Senescence-accelerated strain mice were treated with EGb761 and mitochondrial function in platelets was tested. SAMP8 mouse is the senescence-accelerated mouse-prone 8 strain which displays accelerated aging. Mitochondrial membrane potential, as well as ATP content, was measured. It was found that Ginkgo biloba extract protected against mitochondrial dysfunction.[9]

In a different setup and aim, the effect of EGb761 was investigated in ovariectomized rats. Postmenopausal physiological changes include several degenerative processes which can be treated with ginkgo biloba. Mitochondrial dysfunction induced by estrogen withdrawal was measured by looking at COX activity and mitochondrial ATP content. This was done under the assumption that with age, the brain is more vulnerable to mitochondrial dysfunction. The group treated with EGb761 displayed a buffered decrease of COX activity, mitochondrial ATP and glutathione content in both hippocampi and platelets. Researchers suggest ginkgo biloba extract can help enhance the mitochondria functional reserve in the central nervous system.[10]

3. Antioxidant Properties Also Provide Protection

Bridi et. al looked into ginkgo biloba extract’s antioxidant capacity in relation with neuroprotective effects. GBE is often referred to as a free radical scavenger, meaning it can effectively attenuate the damage free radicals cause to cells. This particular experiment measured lipid peroxidation in the striatum, hippocampus and substantia nigra of rats. In comparison to the untreated group, the group that had the EGb 761 treatment showed a decrease in lipid peroxidation, a specific type of free radical activity. Researchers concluded that EGb 761’s antioxidant capacity is effective in this type of oxidation.[11]

4. Anti Apoptotic Effect as Protection

A main cause of neurodegenerative diseases like Alzheimer’s is cell apoptosis. Ginkgo biloba extract has anti-apoptotic effects in several intracellular signaling pathways that lead to apoptosis. In this experiment, Defeudis et. al took a look at the effect that the component of ginkgo biloba extracts bilobalide had on brain edemas. Brain edemas can lead to brain cell apoptosis. In this setup, edemas were induced by triethlytin. Bilobalide was administered systemically and cerebral edemas were reduced. One mechanism attributes it to the inhibition of apoptotic cell damage. [12]

Effects on Cognition and Memory

Ginkgo biloba extract can benefit cognitive brain functions in rats with dementia. Wang et. al evaluated Sprague Dawley rats on a Y-maze to test learning and memory. Sprague Dawley ‘dementia’ model rats are treated with a D-galactose intraperitoneal injection, to induce dementia. Immunohistochemistry staining, cresyl violet staining, and TUNEL assays are used in these models to assess morphological changes. Dementia was induced by a D-galactose injection. The pyramidal cell layer in the hippocampus was measured too. The group that was treated with GBE performed better and showed less apoptotic cells in comparison to the untreated control group. GBE treatment was able to attenuate the effects of memory impairment in dementia induced rat models.[13]

Chen et. al used the Morris water maze test to test the neuroprotective effects of GBE on learning and memory. This experiment focused on rats who had brain damage caused by +Gz exposure. BALB/c mice or albino mice were used in this experiment. By using the force of inertia, blood flow is accelerated and cerebral ischemia occurs. Both rats in the control group that were untreated and the ginkgo biloba groups (three different doses) that were treated with GBE were exposed in an animal centrifuge chamber. They were then tested in the Morris Water Maze Test were swimming traces were filmed. The three groups with the different EGB doses displayed a decrease in escape latency as well as an increase in crossing the platform areas and in the target quadrant. EGB improved learning and cognitive behavior impairment in rats whose brain damage was induced by +Gz exposure. [14]

Effects on Depression and Anxiety

As a powerful antioxidant, ginkgo biloba extract can play a role in diminishing depression-like behavior. In a forced swim test, rats that were treated with EGb761 displayed a reduced immobility time, a measure of depressive-like behavior. In such a test, the survival instinct reflects in more mobility or attempts to swim. On the other hand, less mobility reflects depression. In the case of ginkgo biloba extract treated rats, the immobility associated with depressive-like behavior was actually reduced. This means that EGb761 has antidepressant-like effects on rodents.[15]

In another setup, mice were tested in the elevated plus-maze and motor activity was assessed to test the anxiolytic-like effects of ginkgo biloba extract treatment. In the four arms of this maze, the activity of rats into each open arm is recorded and observed. Increased open arm activity reflects antianxiety behavior. The group treated with GBE showed inhibited motor activity, suggesting ginkgo biloba extract has anxiolytic like effects. [16]

Locomotor Effects and Parkinson’s Disease

Ginkgo biloba extract can aid and improve locomotion deficits in rodents with Parkinson’s disease. Kuang et. al looked at the locomotor activity of A53T transgenic mice. These rats have overexpression of human alpha-synuclein which is associated with Parkinson’s Disease mutation. They were placed in a forced swim test, pole test, and wire-hang test. The three groups of mice treated with GBE (high, intermediate and low doses) displayed an improvement in locomotor activity compared to the control group that went untreated.[17]

Conclusion

Plenty of studies in rats show how Ginkgo biloba extract can alleviate the symptoms of neurocognitive diseases. Furthermore, clinical studies with humans also show positive results. It has shown a reduction in symptoms in schizophrenic patients, [18] improvement in self-reported quality of life and mental health, and also improved cognitive and memory processes. [19] The extract of such an ancient plant has a strong potential to treat several neurocognitive diseases and the research in rodents is vast.

Resources

  1. Christen, Yves & Maixent, Jean Michel. (2002). What is Ginkgo biloba extract EGb 761? An overview – From molecular biology to clinical medicine. Cellular and molecular biology (Noisy-le-Grand, France). 48. 601-11.
  2. Welt, K., Fitz, F., and Schaffranietz, L.: Ginkgo biloba extract (EGb 761) protects ultrastructure of hypoxic myocardium in elderly rats, in Proceedings of the International Symposium on Natural Antioxidants. Molecular Mechanisms and Health Effects, edited by Packer, L., Traber, M.G., and Xin, W., Champaign (IL), AOCS Press, 1995, pp. 424-433.
  3. Sastre, J., Millan, A., de laAsuncion, J.G., Pallardo, F.V., Droy-Lefaix, M.T., and Vinat, J.: Prevention of age-associated mitochondrial DNA damage by Ginkgo biloba extract EGb 761, in Proceedings of the VIII Biennial Meeting International Society for Free Radical Research, Barcelona, J.R. Prous.
  4. Wang, C., & Wang, B. (2016). Ginkgo Biloba Extract Attenuates Oxidative Stress and Apoptosis in Mouse Cochlear Neural Stem Cells. Phytotherapy Research, 30(5), 774-780.
  5. Shi, C., Liu, J., Wu, F., & Yew, D. T. (2010). Ginkgo biloba extract in Alzheimer’s disease: from action mechanisms to medical practice. International journal of molecular sciences, 11(1), 107–123.
  6. Bastianetto, S., Ramassamy, C., Doré, S., Christen, Y., Poirier, J., & Quirion, R. (2000). The ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by β-amyloid. European Journal Of Neuroscience, 12(6), 1882-1890.
  7. Colciaghi, F., Borroni, B., Zimmermann, M., Bellone, C., Longhi, A., & Padovani, A. et al. (2004). Amyloid precursor protein metabolism is regulated toward alpha-secretase pathway by Ginkgo biloba extracts. Neurobiology Of Disease, 16(2), 454-460.
  8. Stackman, R., Eckenstein, F., Frei, B., Kulhanek, D., Nowlin, J., & Quinn, J. (2003). Prevention of age-related spatial memory deficits in a transgenic mouse model of Alzheimer’s disease by chronic Ginkgo biloba treatment. Experimental Neurology, 184(1), 510-520.
  9. Shi, C., Xiao, S., Liu, J., Guo, K., Wu, F., Yew, D., & Xu, J. (2010). Ginkgo bilobaextract EGb761 protects against aging-associated mitochondrial dysfunction in platelets and hippocampi of SAMP8 mice. Platelets, 21(5), 373-379.
  10. Shi, C., Fang, L., Yew, D., Yao, Z., & Xu, J. (2009). Ginkgo biloba extract EGb761 protects against mitochondrial dysfunction in platelets and hippocampi in ovariectomized rats. Platelets, 21(1), 53-59.
  11. Bridi, R., Crossetti, F., Steffen, V., & Henriques, A. (2001). The antioxidant activity of standardized extract of Ginkgo biloba (EGb 761) in rats. Phytotherapy Research, 15(5), 449-451.
  12. Defeudis, F. (2002). Bilobalide and neuroprotection. Pharmacological Research, 46(6), 565-568.
  13. Wang, N., Chen, X., Geng, D., Huang, H., & Zhou, H. (2012). Ginkgo biloba leaf extract improves the cognitive abilities of rats with D-galactose induced dementia. Journal of biomedical research, 27(1), 29–36.
  14. Chen, L. E., Wu, F., Zhao, A., Ge, H., & Zhan, H. (2016). Protection Efficacy of the Extract of Ginkgo biloba against the Learning and Memory Damage of Rats under Repeated High Sustained +Gz Exposure. Evidence-based complementary and alternative medicine : eCAM, 2016, 6320586.
  15. Rojas, P., Serrano-García, N., Medina-Campos, O., Pedraza-Chaverri, J., Ögren, S., & Rojas, C. (2011). Antidepressant-like effect of a Ginkgo biloba extract (EGb761) in the mouse forced swimming test: Role of oxidative stress. Neurochemistry International, 59(5), 628-636.
  16. Kuribara, H., Weintraub, S., Yoshihama, T., & Maruyama, Y. (2003). An Anxiolytic-Like Effect of Ginkgo biloba extract and Its Constituent, Ginkgolide-A, in Mice. Journal Of Natural Products, 66(10), 1333-1337.
  17. Kuang, S., Yang, L., Rao, Z., Zhong, Z., Li, J., & Zhong, H. et al. (2017). Effects of Ginkgo Biloba Extract on A53T α-Synuclein Transgenic Mouse Models of Parkinson’s Disease. Canadian Journal Of Neurological Sciences / Journal Canadien Des Sciences Neurologiques, 45(02), 182-187.
  18. Brondino, N., De Silvestri, A., Re, S., Lanati, N., Thiemann, P., & Verna, A. et al. (2013). A Systematic Review and Meta-Analysis of Ginkgo biloba in Neuropsychiatric Disorders: From Ancient Tradition to Modern-Day Medicine. Evidence-Based Complementary And Alternative Medicine, 2013, 1-11.
  19. Mix JA, Crews WD Jr., (2002). A double-blind, placebo-controlled, randomized trial of Ginkgo biloba extract EGb 761 in a sample of cognitively intact older adults: neuropsychological findings. Hum Psychopharmacol, 17: 267-277
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