Aluminum-caused brain degeneration may be defeated …

Hesperidin Combats
Aluminum Brain Disorders

… Including Alzheimer’s disease

By Will Block

From a lab at Annamalai University in India, researchers reported last year that hesperidin—a bioflavonoid found in citrus fruits such as limes, lemons, oranges, and grapefruit—reversed memory loss caused by aluminum intoxication (AI) through lessening acetylcholine esterase activity and the expression of amyloid β biosynthesis related markers.1 The former breaks down the important memory molecule acetylcholine, and the later hinders brain functionality. AI has been reported to cause oxidative stress associated with apoptotic neuronal loss in the brain. In this study, hesperidin was effective in an animal model of Alzheimer’s disease (AD), alleviating pathological changes induced by aluminum.

Continuing their work in a new report,2 the same Indian researchers investigated the protective effect of hesperidin against aluminum chloride (AlCl3)-induced cognitive impairment, oxidative stress, and apoptosis. Experimental rats were divided into four groups, and were given one of the following:

1. AlCl3

2. AlCl3 and hesperidin

3. Hesperidin alone

4. Placebo

Preventing Cognitive Damage

Compared to AlCl3 alone, administration of hesperidin (100 mg/kg, the human equivalent of 1,215 mg for a 165 lb person) for 60 days along with AlCl3 prevented the cognitive deficits, biochemical anomalies, and apoptosis induced by AlCl3 treatment (also 100 mg/kg).

Metal ion homeostasis in the brain is required for normal cognitive performance. Deregulation of these ions is one of the key factors in the progression of neurodegeneration. In 2014, researchers reported that various metals such as aluminum, copper, zinc, and iron might be involved in neurotoxicity.3 A few of these metals, including copper, zinc, and lithium, however, indisputably have important usages in the brain, when the dose is correct.

Aluminum has only recently been confirmed to be a major risk factor AD, amyotrophic lateral sclerosis, and Parkinson’s disease—even at low doses.4 AD is a progressive neurodegenerative disorder of the aging process, characterized by short-term memory loss in its early stage, and manifested by confusion, aggression, mood swings, long-term memory loss, and social isolation in advanced stages. The hallmarks of AD include the deposition of amyloid β fibrils in senile plaques and the presence of abnormal tau protein filaments in the form of neurofibrillary tangles.

How Aluminum Enters the Brain

Aluminum enters into the brain via diet, antacids, cosmetics, toothpastes, inhaled fumes/particles, cooking utensils, and even through drinking water. It can be deposited in the hippocampus, cortex, and cerebellum, the parts of the brain that are responsible for memory and cognition.

In these regions, aluminum induces AD-associated pathologies such as oligomerization and accumulation of amyloid β aggregation of hyperphosphorylated tau, lipid peroxidation, impaired exchange of calcium ions, and apoptosis.

The currently available agents for AD include galantamine, drug AChEIs, memantine, carvedilol, rofecoxib, and memoquin. Unfortunately, except for galantamine (especially when taken with choline and other nutrients), these only offer symptomatic relief without preventing the progression of the disease, and several have considerable side effects.

Figure 1 Albert “The Lemon” Einstein

Hesperidin Readily Crosses the Blood-Brain Barrier

Phytochemicals may be good candidates for therapeutic implications of AD due to their ubiquitous nature and fewer side effects, along with long lasting benefits. Citrus fruits are generally consumed worldwide, and are important sources of health-promoting constituents.

Hesperidin, a phytoflavanone that exists abundantly in citrus fruits, crosses the blood–brain barrier easily due to its lipophilic nature, and affords neuroprotection against AD, Parkinson’s disease, Huntington’s disease, immobilization stress, cerebral ischemia/reperfusion, and stroke by virtue of its antioxidant, anti-inflammatory, and anti-apoptotic actions. Albert Einstein was said to love lemons, a high-hesperidin citrus fruit (see Fig. 1).

Oxido-Nitrosative Stress and Hippocampal Inflammation

As already mentioned, the earlier Indian study found that hesperidin protects the brain against aluminum intoxication by reducing AChE activity and amyloid β biosynthesis-related markers.1 Other scientists5 have investigated the effect of hesperidin against AlCl3-induced AD rats and suggested that the neuroprotection might be attributed to the hindrance of oxido-nitrosative stress (caused by reactive nitrogen species) and inflammation in the hippocampus.

Metal ion homeostasis in the brain is
required for normal cognitive
performance. Deregulation of these
ions is one of the key factors in the
progression of neurodegeneration.

However, what was new with the second Indian study (2016) was the investigation of the protective effect of hesperidin against learning and memory deficits, oxidative stress and apoptosis in the hippocampus, cortex and cerebellum of AlCl3-induced AD rats.

Among the findings of the second Indian study, hesperidin improved AlCl3-induced contextual and exteroceptive (sensitivity to stimuli originating from outside the body) memory impairments. In the radial arm maze test, the animals injected with AlCl3 exhibited more errors both in the reference and working memory task and required more time to end the maze as compared to the control group.

Also, co-treatment of hesperidin and AlCl3-treated rats significantly reversed the learning and memory deficits as compared to AlCl3 alone treated animals.

In the elevated plus maze test, the animals treated with AlCl3 exhibited significant increases in retention transfer latency (they were slower) as compared to the control group. Treatment with hesperidin significantly reduced retention transfer latency as compared to the AlCl3 alone-treated group.

Performance in passive avoidance task showed a decrease in step-through latency in aluminum exposure group as compared to control group, whereas co-administration of hesperidin significantly reversed the aluminum-induced memory and learning deficits as compared to aluminum-treated rats. Hesperidin lessened aluminum-induced oxidative stress.

Hesperidin Improved AlCl3-Induced Oxidation

Co-treatment of hesperidin and AlCl3 significantly decreased the levels of reduced lipid peroxidation (TBARS) and increased measures of antioxidants [GSH (glutathione), SOD (superoxide dismutase), catalase, and GPx (Glutathione peroxidase)] in the hippocampus, cortex, and cerebellum of experimental rats.

The increased TBARS levels in AlCl3-
treated rats may be due to the
inhibition of SOD, catalase, and GPx
activities and other antioxidant levels.

Hesperidin Prevents AlCl3-Induced Apoptosis

The researchers also performed western blots (a widely used analytical technique used to detect specific proteins in a sample of tissue) to investigate changes in pro- and anti-apoptotic markers in control and experimental groups.

Rats treated with a chronic AlCl3 regimen manifested significant inductions in the expressions of Bax and depletion in Bcl-2 (members of the family of proteins that regulate cell death [apoptosis]) in the hippocampus, cortex and cerebellum. Meanwhile, co-treatment with hesperidin significantly reduced the expression of pro- and anti-apoptotic markers.

The Pathogenesis of AD in Animal Models

Copious learning and memory assessment tests have been used to study the pathogenesis of AD in rat models. In the radial arm maze test, aluminum exhibited a significant increase in the time required to end the task, which indicates the decline in reference and working memory. The elevated plus maze test evaluates learning and memory in rodents. The recent Indian research results indicated that rats treated with AlCl3 showed impaired performance in passive avoidance task as evidenced by decreased step-through latencies and enhanced retention transfer latency in elevated plus maze test.

Acetylcholine is very well related with learning and memory processes. Aluminum causes disturbances in cholinergic neurotransmission, which may be associated with altered memory and learning processes.

The previous Indian study indicated that the co-administration of hesperidin to AlCl3 animals reversed memory loss caused by aluminum intoxication by reducing AChE activity and amyloidogenic pathway. The brain is more susceptible to free radical damages when glutathione is low and there is a high proportion of polyunsaturated fatty acids in its membranes, along with high iron content and its ability to consume about 20% of total body oxygen.

Reactive Oxygen Species Cause Lipid Peroxidation

Excessive formation of reactive oxygen species (ROS) subsequently attacks a great many cell components including membrane lipids and causes lipid peroxidation. Although aluminum is relatively a low redox mineral, it can induce iron and non-iron-mediated lipid peroxidation processes. Lipid peroxidation is a consequence of ROS production and is an indirect measure of a metal induced oxidation.

Aluminum Exposure Leads to Brain Damage

AlCl3 treatment significantly increased brain TBARS levels, a sensitive marker of lipid peroxidation processes. Aluminum exposure leads to an increased lipid peroxidation and oxidative damage in specific areas of brain including cerebral cortex, hippocampus, cerebellum, medulla oblongata, hypothalamus, and brain stem.

SOD is considered the first line of defense against oxidative stress, as it converts toxic superoxide anion to less toxic H2O2 and O2. H2O2 is then converted to H2O by catalase and GPx at the expenditure of GSH. Therefore, the increased TBARS levels in AlCl3-treated rats may be due to the inhibition of SOD, catalase, and GPx activities and other antioxidant levels. SOD and catalase are protective enzymes and both function in very close association for the detoxification of highly reactive free radicals. Glutathione in its reduced form is the most abundant intracellular antioxidant, which directly scavenges free radicals or serves as a substrate for the glutathione peroxidase enzyme.

Hesperidin easily enters into the cell
because of its lipophilic nature,
strengthening the antioxidant
potential of hesperidin.

In the second Indian study, treatment of hesperidin to AlCl3 rats decreased the levels of TBARS and increased the levels of GSH and activities of enzymatic antioxidants. This corroborated earlier studies, where flavonoids with antioxidant properties had been used for the treatment of different types of neurodegenerative diseases including AD.

Hesperidin easily enters into the cell because of its lipophilic nature, strengthening the antioxidant potential of hesperidin. Recently, other scientists demonstrated the protective effects of hesperidin against Aβ-induced cognitive dysfunction, oxidative damage and mitochondrial dysfunction in transgenic mice. AI causes neuronal degeneration in the hippocampus and loss of cholinergic terminals in the cortical regions by down-regulating the anti-apoptotic mediators and up-regulating the pro-apoptotic factors.

Hesperidin lessened apoptosis against experimental autoimmune encephalomyelitis, AD, global cerebral ischemia/reperfusion and H2O2-induced cytotoxicity. Interestingly, neohesperidin, another flavanone glycoside of citrus fruits, inhibited the middle cerebral artery occlusion-induced upregulation of Bax, cytochrome c, and cleaved caspase-9 and -3, as well as the downregulation of Bcl-2 by its antioxidant properties.

Hesperidin Appreciation Continues

From Durk Pearson & Sandy Shaw (see “Improved Galantamine Formulation at No Extra Cost” in the April, 2014 issue): “‘Everybody knows’ that citrus fruits are healthful, right? Sure, but we bet you didn’t know about some of these new findings about how hesperidin—a flavonoid found plentifully in citrus fruits—can help protect your brain from the ravages of aging, and based on newer discoveries about it, may help reduce the risk of Alzheimer’s disease. So, without further adieu, here’s an update on hesperidin, one of the oldies but goodies that has far surpassed earlier expectations. Here’s why we’ve added it to our galantamine formulation without adding a single penny to the price. (The formulation is a premium-priced dietary supplement because of the natural cholinesterase inhibitor, galantamine, contained in it, which is currently a very costly ingredient. One reason for this is that FDA forces us to jump through hoops at Customs to make it as difficult as possible to import the ingredient. There is no health or safety reason for this—the FDA is just another government bully that wants to support prescription drug companies that will sell it to you at a much higher price as an FDA-approved drug.”


  1. Justin Thenmozhi A, Raja TR, Janakiraman U, Manivasagam T. Neuroprotective effect of hesperidin on aluminium chloride induced Alzheimer’s disease in Wistar rats. Neurochem Res. 2015 Apr;40(4):767-76.
  2. Justin Thenmozhi A, William Raja TR, Manivasagam T, Janakiraman U, Mohamed Essa M. Hesperidin ameliorates cognitive dysfunction, oxidative stress and apoptosis against aluminum chloride induced rat model of Alzheimer’s disease. Nutr Neurosci. 2016 Feb 15. [Epub ahead of print] PubMed PMID: 26878879.
  3. Geng G, Luo HM. [The research progress of metals correlated to Alzheimer’s disease]. Yao Xue Xue Bao. 2014 Oct;49(10):1372-6. Review. Chinese. PubMed PMID: 25577865..
  4. Sharma DR, Wani WY, Sunkaria A, Kandimalla RJ, Sharma RK, Verma D, Bal A, Gill KD. Quercetin attenuates neuronal death against aluminum-induced neurodegeneration in the rat hippocampus. Neuroscience. 2016 Mar 2;324:163-176.
  5. Jangra A, Kasbe P, Pandey SN, Dwivedi S, Gurjar SS, Kwatra M, et al. Hesperidin and silibinin ameliorate aluminum-induced neurotoxicity: modulation of antioxidants and inflammatory cytokines level in mice hippocampus. Biol Trace Elem Res. 2015;168:462–71.

Will Block is the publisher and editorial director of Life Enhancement magazine.

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