The Therapeutic Role Of Ketogenic Diet in Neurological Disorders Part 4
May 24, 2024
Inflammation and high concentrations of substance P cause arterial dilation and headache, which is the most characteristic symptom of a migraine attack [189]. Hypoglycaemia is shown to prolong the occurrence of cortical spreading depression [190].
Inflammation is the body's self-protection mechanism after injury or infection, but the excessive inflammatory response can also hurt health, especially brain function, which may lead to problems such as memory decline or amnesia.
However, some research shows that taking steps to reduce inflammation can also benefit memory and brain function. For example, changing your eating habits and consuming more foods rich in antioxidants, magnesium, zinc, and other minerals can reduce the level of inflammation while promoting brain health.
In addition, moderate aerobic exercise can also reduce the impact of inflammation on the brain. Long-term time in nature, especially in the wild, can relieve anxiety and stress, which can also help reduce the negative effects of inflammation.
So while inflammation has potential effects on human health, we can slow these effects through an active lifestyle and diet, while improving brain function and health and maintaining good memory. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the many active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health in a variety of ways.
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Nutritional ketosis, by providing an alternative energy source, spares glucose and mitigates hypoglycemia, which may result in a reduction of cortical spreading depression [191].
Additionally, many in vitro and animal studies have shown that redirection of the path of metabolism of selected amino acids towards increased synthesis of GABA-an inhibitory neurotransmitter [52], which balances excitatory and inhibitory neurotransmission, the anti-inflammatory effects [5,8,40,142], as well as the enhancing antioxidant systems [12,13], exhibited by ketone bodies may contribute to the efficacy of a low-carbohydrate diet in migraine. For each patient, the "migraine threshold" is different.
This balance between stimulation and inhibition of areas of CNS depends on several factors at the molecular level, such as ion channel function, magnesium levels, and excitatory amino acids. Theoretical considerations and research, however, allow us to believe that KD may be effective in both the prevention and treatment of migraine [192].
4.3.2. Clinical Data
To date, a clinical trial by di Lorenzo et al. [193] (Table 2) has shown that a Very Low Carbohydrate Ketogenic Diet (VLCKD) is effective in reducing migraine attacks. The number of migraine attacks decreased by -3.02 when using VLCKD compared with a very low-calorie non-ketogenic diet. However, exogenous administration of ketone bodies did not improve the patient's condition [194].
4.4. Alzheimer's Disease
4.4.1. Etiopathogenesis and Potential Role of Ketogenic Diet
Generally speaking, the term dementia describes a decrease in cognitive abilities to a degree that makes it impossible to perform daily activities. The most common form of dementia, especially in the elderly, is Alzheimer's disease (responsible for nearly two-thirds of dementia cases in people over the age of 65) [195]. The risk of this disease increases with the age of the patient [196].
Experts predict that the number of cases of Alzheimer's disease will gradually increase in the coming years [197]. Determining the beginning of the changes leading to the development of this disease is extremely complicated.
This disorder leads to complete impairment of cognitive functions. It noticeably affects memory processes, understanding of uncomplicated issues, language proficiency, and the ability to focus attention [195]. Symptoms in most cases begin with mild short-term memory loss, including recent memories [197]. In understanding the essence of this disease, it is important to determine the risk factors.
Increasing age, serious head injuries, vascular disorders in the brain area, nicotinism, or depression likely affect the rate of development of the disease [195]. Furthermore, genetic factors seem to play an important role in disease progression. The primary pathological process underlying Alzheimer's disease is the deposition of abnormal neuronal plaques and neurofibrillary tangles [198].
Plaques are defined as microchanges in neurons that involve a core of Aβ surrounded by groups of enlarged axons. Beta-amyloid, under physiological conditions, derives from the amyloid precursor protein (APP). APP is split mainly by alpha and beta-secretase. As a result of this process, small fragments of harmless Aβ arise. In the case of pathological changes, APP is split by gamma and beta-secretase.
As a result of this process, Aβ (42 peptides) is formed. Its accumulation and subsequent aggregation lead to the above-mentioned pathological changes. Beta-amyloid is deposited mainly in the vessels and the gray matter of the brain.
In the described process, the genetic factors perform an important role, the gene responsible for the mentioned process of APP breakdown is located on chromosome 21, which is an important link in the family etiology of Alzheimer's disease [195].
The amyloid beta conglomerate is also deployed in the blood vessels of the brain leading to more or less extensive angiopathies that are responsible for extensive micro bleeding all around the brain's areas. Currently, it is believed that the deposition of amyloid plaques begins 20 years before the development of clinical manifestations [199].
The second important mechanism in the etiology of Alzheimer's disease is an aggregation of neurofibrillary tangles composed of tau protein. Due to excessive aggregation of Aβ, hyperphosphorylation of this structure occurs, which leads to its aggregation into larger, pathological conglomerates. It has been proven that these structures in the initial stages of the disease are present in the hippocampus.
As the disease progresses, its presence can be found in neurons of the entire cerebral cortex [195]. The above-mentioned processes contribute to a significant reduction in the number of neurons in the cerebral cortex and specific subcortical regions. Animal studies have shown that KD reduces the volume of Aβ and tau protein aggregates, and reduces their toxicity [20,26,78].
However, this effect is limited to preventing the formation of new plaque. Thus, it can be speculated that KD may represent an interesting adjuvant therapy, resulting in slower disease progression and associated loss of cognitive function.
Furthermore, inflammatory processes initiated by the clusters of Aβ and tau protein can affect the expansion of the disease into new areas of the brain. Pro-inflammatory cytokines also play an important role in the destruction of brain tissue structures [138–141]. Oxidative stress and environmental factors may contribute to the development of the disease via disruption of the hypothalamic-pituitary-adrenal (HPA) axis and insufficient removal of neurotoxic 4-hydroxynonenal [200].
Furthermore, the ApoEε4 allele responsible for late-onset Alzheimer's disease induces accelerated cellular aging, as well as neuroinflammation and oxidative stress [201]. Studies performed on cell lines and animals provide evidence that the above-mentioned pathological phenomena may be alleviated by the application of KD, via limiting inflammation and oxidative stress [6–10,40,83].
4.4.2. Medical Foods
There is no possibility of treating AD these days. The current approach to this disease is based on delaying the serious symptoms as long as possible [202]. Alleviation of that disease can be achieved both ways: pharmacological and non-pharmacological methods.
The latter focuses on cognitive training, physical activity, and prescribed diets. One such diet is the Mediterranean Diet. Extra-virgin olive oil (EVOO) contained in this diet seems to be crucial. According to Klimova and others [202], oleuropein, the secoiridoid contained in EVOO, may induce a neuroprotective effect, which indicates its potential use in the prevention of neurodegenerative diseases, in particular AD [202,203].
EVOO activity has been studied using animal mice models. Based on the results, it was determined that the active ingredients of EVOO improve the cognitive functions of mice's brains by improving hippocampus synaptic activity and reducing the accumulation of Aβ aggregate. EVOO may also alleviate the cytotoxic and neuroinflammatory consequences of the accumulation of Aβ aggregates [202,203].
Long-term supply of EVOO, excluding the impact on the metabolism of Aβ aggregates, significantly affects the reduction of phosphorylation of tau protein [203]. A diet rich in EVOO has been described as one that has no adverse effects such as cell death or neurodegeneration [202].
Another component of the Mediterranean diet is walnuts (Juglans regia L.) which, through the high content of antioxidants such as n-3 α-linolenic acid, juglone, or tocopherol (vitamin E), are an important factor for the anti-neuroinflammatory effect of the diet. Enriching the diet of laboratory mice with walnuts resulted in improved memory and learning ability [204].
4.4.3. Clinical Data
Many studies also indicate that insulin resistance may be a contributing factor in the development of neurodegenerative diseases [69]. The concomitant hyperglycemia leads to changes in the brain, causing memory impairment.
Weinstein et al. [205] have noted a reduction in gray matter volume in young people with hyperglycemia, while Kerti et al. [206] have observed a reduction in hippocampal volume. Several studies have documented the association of impaired insulin signaling with protein Aβ [70,71] and thus Alzheimer's disease [72–74]. Studies performed on Alzheimer's patients indicate that KD normalizes carbohydrate metabolism in the brain, reduces insulin levels, and increases insulin sensitivity [75–77].
The patients showed higher scores in tests of cognitive function, which indicates potential efficacy in neurodegenerative diseases [75,76]. The clinical studies conducted so far (Table 3) suggest that the ketogenic diet improves the cognitive performance of Alzheimer's patients.
The significance of risk factors is still under the observation of researchers, but proper prevention and leading a healthy lifestyle are undoubtedly an important aspect in therapy and reducing the risk level of neurodegeneration. This is extremely crucial because the current pharmacotherapy strategy is based on alleviating the symptoms of the disease, but it does not contribute to the fight against its cause.
4.5. Parkinson's Disease
4.5.1. Etiopathogenesis and Potential Role of Ketogenic Diet
Parkinson's disease is one of the most important neurodegenerative disorders next to Alzheimer's disease. It occurs mainly in well-developed societies. Risk factors for PD include environmental toxins, drugs, genomic defects, and cerebral vascular damage [211,212].
The risk of developing PD increases with the age of the patient. The risk of developing PD in people between the ages of 85 to 89 is 3.5%. In comparison, people under 60 years of age have a probability of development of PD at the level of 1% [212,213].
Diagnosis of PD takes place after the first psychomotor symptoms appear, which include muscle rigidity, resting tremors, and motor retardation [214]. Bradykinesia is considered the primary diagnostic factor for the disease [215].
In addition to the typical motor symptoms, PD is accompanied by constipation, salivation, dysgraphia, and extremely important cognitive and behavioral disorders, depression, sensory disturbances, sleep disorders, dementia, and hallucinations [216]. The initial period of the disease is characterized by a postural defect and difficulties in walking.
Freezing of gait, defined as a brief, episodic lack or restriction of foot progression despite the desire to walk is quite often noticed [217,218]. The main factor responsible for the development of the symptoms of the disease is the degeneration of neurons in the black matter, involved in the dopamine transmission of the nucleus basalis and the striatum [219].
Damage to these neurons leads to impaired dopamine transport which leads to dysfunction of neuronal circuits involving areas of the basal ganglia and motor cortex, which ultimately manifests as movement disorders [220]. Symptoms of PD only appear when the dopamine present in the basal nuclei and black matter drops to 20% of its maximum value [221].
In addition, one of the neuropathologies found in PD that may contribute to the death of dopaminergic neurons are Lewy bodies and Lewy neurites, composed of misfolded α-synuclein [222]. Currently, the primary drug for the treatment of PD is levodopa (L-DOPA), which has an effect on PD symptoms but no neuroprotective effect.
It also appears that L-DOPA may favor the increased aggregation of α-synuclein, via the metabolite 5-S-cysteineldopamine, which induces oxidative stress in vivo, thereby promoting dopamine depletion [223]. Studies show that KD significantly improves the bioavailability of L-DOPA, which is associated with a reduction in dietary protein supply.
The combination of symptom control pharmacological treatment and KD may be effective in inhibiting further disease progression [78,121,224]. Kashiwaya et al. [225] conducted a study to elucidate the neuroprotective effects of β-HB. Heroin analog, 1-methyl-4-phenylpyridinium, MPP(+), was used to induce black matter dopaminergic cell death by inhibiting the multi-enzyme mitochondrial NADH dehydrogenase complex, causing a Parkinson's disease-like syndrome in cultures of midbrain neurons.
One study confirmed previous findings that β-HB has neuroprotective effects on dopaminergic neurons [225–227]. This is related to increased mitochondrial respiration and increased ATP production.
KBs also increase the efficiency of the mitochondrial respiratory chain by reducing oxygen free radicals [35]. One of the more recent potential therapies for PD is targeting KATP channels, the opening of which has been shown to have neuroprotective effects and to reduce neuronal excitability. However, it is presumed that activation of KATP channels located on GABAergic neurons may be one of the causes of PD development through inhibition of GABAB receptors, which in turn stimulates glutamatergic terminals to secrete α-synuclein [228].
The effects of agonists or antagonists tested in animal models are inconclusive, suggesting that their impact on these channels is difficult to predict due to the high prevalence of KATP channels in the brain [228,229]. Nevertheless, in contrast to individual substances affecting KATP channels, the ketogenic diet acts simultaneously on multiple pathological processes, providing potentially better therapeutic efficacy.
y better therapeutic efficacy.
4.5.2. Clinical Data
In recent years, PD has been increasingly associated with alterations in the gut microbiota [113,121,230,231]. Alfonsetti et al. [113] reviewed microbiome composition and the effects of diet, probiotic, prebiotic, and synbiotic administration on pathological processes occurring in the course of PD.
Studies indicate that the microbiota of PD patients differs significantly from that of healthy individuals and is characterized by low numbers of Prevotellaceae and increased numbers of Enterobacteriaceae [232].
Alterations in the quality of the microbiota result in impaired intestinal permeability (i.e., "leaky gut"), which, through the LPS produced by bacteria, induces inflammatory processes and oxidative stress, thus promoting α-synuclein aggregation [233]. The ketogenic diet is known to reverse this ratio and thus increases Prevotella and decreases Enterobacteriaceae [131].
Changes in dietary habits (incorporating more omega-3 polyunsaturated fatty acids, probiotics, prebiotics, and synbiotics into the diet) have been shown to have a beneficial effect on the course of the disease, through gut-sealing, anti-inflammatory, oxidative stress-relieving, and BDNF upregulation effects [113]. A randomized controlled trial conducted in 2018 by Phillips et al. [234] for 8 weeks on 47 patients showed that both high-fat and low-fat diets had positive effects on motor and non-motor symptoms.
However, the ketogenic diet exhibited greater improvements in non-motor aspects of the ability to perform daily activities, i.e., urinary disturbances, pain, fatigue, or cognitive impairment compared to the low-fat diet.
5. Adverse Effects of the Ketogenic Diet
Clinical studies show that maintaining a ketogenic diet can be challenging for patients. Poor tolerance and lack of motivation may therefore provide causes for discontinuation of the diet [158]. Ketogenic diet modifications such as MAD were better tolerated among children with epilepsy [170], while alleviation of anxiety and cognitive activation was observed in the group using mostly MCTD (20/28 children) [159], suggesting that modifications of the ketogenic diet may be associated with greater compliance.
Since the groups using the ketogenic diet are mainly children suffering from epilepsy, its balance is a key element in determining a child's proper growth. The diet should be well balanced to counteract the deficiencies brought about by abandoning a whole group of products rich in carbohydrates and other nutrients such as thiamin, folate, vitamin A, vitamin E, vitamin B6, calcium, magnesium, iron, or vitamin K [235].
Patients may suffer from a deficiency of dietary fibers, which are essential for the proper functioning of the intestines, due to the exclusion of a certain group of products. A fiber deficiency leads to disorders in the proper absorption of nutrients, disruptions in the production of hormones responsible for satiety, and a decrease in immunity [236]. The most difficult period for patients is the introduction to KD.
During this time, the most common side effects of dieting are hypoglycemia, dehydration, and gastrointestinal disorders [237,238]. In the study conducted by Lin et al. [237], 57 out of 126 children experienced vomiting. Hypoglycaemia below 40 mg/dL occurred in 44 patients. In addition, constipation, irritability, or negative mood changes were also observed. Six patients developed excessive ketosis with urinary ketone levels of 160 mg/dL, which manifested in facial flushing.
Various adverse gastrointestinal effects can occur during the use of KD. One of the main ones is constipation, which may result from an insufficient supply of fiber in the diet. Constipation can be managed by increasing the amount of fiber in the diet, performing enemas, or administering polyethylene glycol [238]. One of the more common controversies surrounding the use of a high-fat diet is its effect on the lipid profile. Increased intake of fat-rich foods is the main cause of increased serum lipid fractions.
In a study carried out by Cai et al. [239], it was shown that children suffered from hyperlipidemia while taking KD, but at the same time, this side effect was less frequent than the aforementioned gastrointestinal disorders. The mean cholesterol levels of the patients studied were slightly higher than before starting the diet. There was a rapid response to the adverse changes regarding the increase in serum lipid fractions. Researchers Guzel et al. [166] proposed reducing dietary fat intake by 20–25% to improve lipid profile.
The procedure was to eliminate products containing unsaturated fats and egg yolk sources, in addition, atorvastatin 10 mg daily was administered to inhibit endogenous cholesterol biosynthesis.
A study by Freeman et al. [18] also suggests a negative effect of the ketogenic diet on the kidneys and the urinary system. In a group of 150 children, 3 of them had urate stones and 3 of them had calcium oxalate or phosphate stones. It is therefore recommended that potassium citrate be used as a preventative measure throughout the diet [18,240].
6. Conclusions
Changes in eating habits can have a beneficial effect on the condition of our body, but also on the development and course of many diseases. This review provides evidence that the ketogenic diet may provide therapeutic benefits in patients with neurological problems associated with increased oxidative stress and neuro-inflammation or disruption in brain energy metabolism.
The review of the scientific literature shows that KD could affect not only the progression of neurological disorders but also the course and outcome of their treatment. The effectiveness of KD has been proven in epilepsy and other neurological diseases, such as depression, migraine, or neurodegenerative diseases e.g., AD and PD. KD should be also considered as an adjuvant therapeutic option in other neurological diseases.
Author Contributions: Conceptualization, I.P.-C.; methodology, I.P.-C.; writing-original draft preparation, D.P., K.K., and P.R.; review and editing, I.P.-C. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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