The Therapeutic Role Of Ketogenic Diet in Neurological Disorders Part 2

2.3. The Impact of the Ketogenic Diet on Insulin Signalling

Insulin is a hormone produced by pancreatic β cells that increases glucose uptake by the cells, thereby reducing blood glucose levels [60]. 

Hormones are important chemicals in the human body that are secreted by endocrine glands. Hormones have a wide range of effects and can control many physiological functions in the human body, including memory. The effects of hormones on memory vary from person to person, but most studies show that certain hormones can enhance memory and improve cognitive abilities.

Thyroxine is a hormone that promotes brain cell growth. Research shows that people who are deficient in thyroid hormone are prone to problems such as memory impairment and cognitive decline. If people with thyroid disease are not treated in time, their memory and thinking ability may be affected.

Testosterone is another important hormone that has significant positive effects on the brains of both men and women. Research shows that testosterone levels are strongly linked to memory. People with low testosterone levels are more likely to experience memory loss. Increasing testosterone levels can significantly improve cognitive and memory abilities.

In addition to thyroxine and testosterone, other hormones such as estrogen and corticosteroids have also been found to be related to human memory. Estrogen has a protective effect on the brain, can prevent brain aging, and can also enhance memory. Corticosteroids have an impact on memory under conditions of stress and anxiety, which can lead to memory loss.

Armed with these findings, people can take some steps to improve their memory. For example, you can maintain a healthy lifestyle, maintain adequate sleep time, exercise more, maintain a good mentality, etc. Of course, if there is an imbalance in hormone levels, it can be adjusted and treated with the advice of a doctor.

All in all, hormones have a strong impact on memory, but not all hormones have a positive effect on memory. If you want to maintain a good memory, you need to do some practical work, such as maintaining a healthy lifestyle, supplementing nutrients, etc. Through these measures, we can better protect our brains and improve memory and cognitive abilities. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thus enhancing the connectivity and function of neural networks. These effects can help improve memory, learning ability, and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases.

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The lack of tissue sensitivity to insulin, that is, insulin resistance, as well as defective secretion of this hormone is associated with type 2 diabetes mellitus ('T2D), defined now as a pandemic of the 21st century [60-63]. Nevertheless, its action is not limited to peripheral tissues. 

Insulin crosses the blood-brain barrier and binds to insulin receptors (lRs) in the brain, resulting in the activation of signaling pathways [64]. However, certain structures in the brain, like the hypothalamus, are more susceptible to its action due to the absence of the BBB, which allows insulin to pass more freely [65]. The Pl3K/Akt cascade is one of the main signaling pathways activated by insulin [64. 

It may subsequently activate other pathways such as asmTОRC1, GSKЗβ, and Foxà transcription factors, which are involved in many neuronal functions [66]. These pathways also have the potential to lead to the death of neurons, via the removal of damaged proteins, or increased phosphorylation of tau proteins, being one of the pathologies observed in Alzheimer's disease [67].

There is limited information on the impact of KD on insulin signaling in the brain research shows that insulin can regulate the secretion of neurotrophic factors and neurotransmitters and also interact with the gastrointestinal microbiome [15]. Gupta et al. [68focused on the possible antidepressant effect of insulin on the disrupted neurotransmitter system in diabetes. 

Insulin administration to mice with streptozocin-induced diabetes elicited higher mouse scores in the forced swim test, tail suspension test, and spontaneous locomotor activity compared to healthy mice. 

In addition, the diabetic mice showed higher serotonin levels and reduced monoamine oxidase (MAÃ) A and B activity in the brain. Taking into consideration that impaired insulin signaling in the brain is heavily associated with Alzheimer's disease [69-74], affecting levels of this hormone may improve a patient's condition. 

Studies in the last few years confirm that KD enhances insulin responsiveness and reduces fluctuations in glucose levels 75-77]. 

This effect is manifested by higher scores on cognitive tests, namely the Montreal Cognitive Assessment, suggesting that KD may have a significant influence on alleviating insulin resistance in the brain 75,76Case studies of subjects suffering from Alzheimer's disease (heterozygous ApoEe4 carriers reported by Stoykovich et al. [75 and Morrill et al. 76] demonstrated that treatment with KD for 10 months reduced (1) fasting glucose levels by 24-25%, (2) fasting insulin by67-85.3%%, (3) homeostatic model assessment for insulin resistance (HOMA-IR) by 75-88.8%respectively. 

Furthermore, a randomized controlled trial conducted by Fortier et al. [77showed that administration of ketogenic drinks to patients with mild cognitive deficits for months resulted in improved episode memory, language skills, and executive function.

2.4. The Impact of the Ketogenic Diet on Oxidative Stress

Products of cellular respiration, reactive oxygen species (ROS) and reactive nitrogen species (RNS), are highly reactive and when their detoxification is decreased, they may cause lipid peroxidation, cell membrane, DNA, and protein damage [78]. 

The imbalance between the production of ROS and RNS and their insufficient neutralization is defined as oxidative stress. It appears to play a pivotal role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease [79,80]. 

Many in vitro and animal studies confirm the beneficial effects of a ketogenic diet and ketone bodies, by enhancing free radical scavenging and improving the activity of antioxidant systems [11–14]. In vitro, administration of ACA and β-HB to HT22 cell lines and hippocampal neurons with glutamate-induced oxidative stress increased their viability [11]. 

In the study of Maalouf et al. [12], the administration of ACA and β-HB to neocortical neurons and isolated mitochondria derived from these cells decreased ROS production and the associated increased NADH oxidation. Reduced cell death was also observed. Sullivan et al. [13] observed that oligomycin (ATP-synthase inhibitor) induced ROS production was lower in KD-fed mice compared to mice fed a standard diet. 

At the same time, uncoupling protein 2, 4, and 5 (UCP 2, UCP4, and UCP5) levels were higher in KD-fed mice, resulting in increased maximum mitochondrial respiration rates. Hasan-Olive et al. [14] also found that mice with uracil-DNA-glycosylase1 enzyme mutation, which caused mitochondrial toxicity, exhibited higher UCP2 levels in hippocampal CA1 neurons when fed KD, probably due to upregulation of PGC1α-SIRT3-UCP2 axis, caused by β-HB. 

This study also showed increased oxygen consumption and amplified NAD+/NADH ratio in rats' hippocampal neurons and human fibroblast cell lines, with H2O2-induced oxidative stress.

2.5. The Impact of the Ketogenic Diet on Neuroinflammation

Recent studies imply that neuroinflammation can be not only a concomitant symptom of nervous system diseases such as epilepsy, multiple sclerosis, migraine, Alzheimer's disease (AD), or Parkinson's disease (PD)  but also an important factor in their development [69,81]. 

Neuroinflammation is associated with microglia activation and increased release of inflammatory factors such as tumor necrosis factor (TNF), interleukins (IL-1β, IL-6), and free radicals, which can result in progressive dysfunction or cell death in the brain [39,82]. 

Studies on animal models of Parkinson's disease demonstrated that KD can reduce inflammation in CNS by decreasing the microglial activation and reducing the expression of pro-inflammatory cytokines [6,83]. 

Besides, it was noticed that KD supports anti-inflammatory and antioxidant factors production which in addition favours limitation of inflammation in CNS [84]. Previous studies showed that β-HB (produced in increased amounts in KD) inhibited the inflammatory response by up-regulation of anti-inflammatory genes such as NF-κBIA, MAP3K8, and TLR5 and down-regulation of pro-inflammatory genes such as TNFSF6, TNF-α, and nuclear factor-kB (NF-κB) [6–10]. Yang et al. [83] showed that KD significantly reduces levels of inflammatory factors such as IL-1β, IL-6, and TNF-α in substantia nigra and reduces microglia activation in an animal model of Parkinson's disease induced by the administration of 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP). 

Rodents exhibited reduced inflammation, enhanced dopaminergic transmission in the substantia nigra, and improved motor function. After MPTP injections, KD-fed mice scored twice as high on the rota-rod motor coordination test as mice fed the standard diet. As previously mentioned, Taggart et al. [40] showed that β-HB is an endogenous ligand of the CA2 receptor and its action is similar to nicotinic acid. 

A study by Zandi-Nejad et al. [85] on lipopolysaccharide-induced inflammation (LPS) in murine bone marrow-derived macrophages showed that stimulation of the HCA2 receptor by nicotinic acid inhibits the production of pro-inflammatory cytokines through NF-kB signaling pathways. In turn, inhibition of NF-kB down-regulates two genes key to the inflammatory response, COX2 and enzymes involved in nitric oxide synthesis [86]. 

A study by Fu et al. [6] in rats with model Parkinson's disease induced by LPS administration to the substantia nigra also showed a neuroprotective effect of β-HB on dopaminergic neurons, as well as a reduction in microglia activity. In vitro studies confirmed that these actions were due to HCA2 receptor activation. Shimazu et al. [7] noted that β-HB inhibits histone deacetylases 1, 3, 4 (HDAC 1, HDAC 3, HDAC 4) in vitro. 

ACA also shows inhibitory activity against HDAC class I and IIa, but at concentrations that are not attainable by nutritional ketosis. Increased histone acetylation results in up-regulation of antioxidant systems, including the FOXO3A network and metallothionein 2. 

Increased FOXO3 expression causes an increase in Mn-SOD and catalase levels [87]. Pump administration of ketone bodies to the kidney of mice resulted in reduced lipid peroxidation and protein carbonylation in the kidney, compared to a control group fed a standard diet. 

Inhibition of HDACs also increases the activity of antioxidant systems by increasing PPAR-α activity [7,88]. A study by Huang et al. [9] showed that β-HB induces macrophage adaptation to anti-inflammatory morphology through the promotion of ramification and pro-phagocytic effects. 

This is due to the enhancement of the protein kinase B (Akt)-small RhoGTPase axis, which can occur through the inhibition of HDACs. Studies in mouse models of inflammatory diseases by Youm et al. [8] showed that β-HB inhibits the decrease in cytoplasm potassium ions and thus pyrin domain-containing 3 inflammasome (NLPR3) activity. 

The mechanism of this action is not fully elucidated, but it is suggested that it may be related to calcium signaling. This hypothesis is supported by the study of Lee et al. [89], which showed that the Ca2+-sensing receptor is involved in NLPR3 activation in mice. 

NLPR3 inflammasome is considered to be one of the units linking the immune system and inflammatory responses. It is a multiprotein complex, secreted mainly by immune cells, in response to a decrease in potassium ion levels in the cytoplasm. 

This results in the activation of caspase-1 (which converts IL-1β to its active form) and the production of the pro-inflammatory cytokines IL-1β and IL-18 in macrophages [90]. Shao et al. [91] proposed inflammasome NLPR3 inhibition as a potential therapy in AD, PD, multiple sclerosis, and depression.

2.6. The Impact of the Ketogenic Diet on Brain-Derived Neurotrophic Factor (BDNF)

As is known, brain-derived neurotrophic factor (BDNF) has beneficial effects on neuroprotection and neuroregeneration of cells. BDNF belongs to a group of proteins that support CNS function, namely neurotrophins (NTs). 

NTs are synthesized mainly in CNS, but also in T and B lymphocytes, monocytes, smooth muscle cells, and skeletal muscle cells, as well as in the endothelium of blood vessels [92]. BDNF influences the development of the nervous system. It enables processes of cell differentiation, and neuronal development, improves the growth and survival of neurons, and favorably influences the efficiency of neurogenesis, synaptogenesis, and synaptic plasticity [93]. 

Histone deacetylase inhibition contributes to the stimulation of BDNF secretory processes in cortical neurons. KBs formed with KD inhibit histone deacetylase and thus increase BDNF secretion. 

β-HB stimulates BNDF gene expression, which increases BDNF protein levels in cortical neurons. 

This is done through activation of the BDNF gene promoter IV and a mechanism involving the transcription factor NF-κB and the histone acetyltransferase p300. This is an extremely important property to limit the progression of neurodegenerative changes [94,95].

2.7. The Impact of the Ketogenic Diet on Activity of ATP-sensitive Potassium Channels

Bearing in mind the fact that the largest amount of potassium channels is located in the brain, it makes it the most susceptible to changes in their activity and the associated disturbances of central nervous system functions [96]. ATP-sensitive potassium channels (KATP) are a subtype closely related to cellular metabolism [96] and linked to electrical activity [97]. 

A decreasing ATP/ADP ratio induces the opening of these channels while increasing ATP levels result in their closing. Their activation is known to exert protective effects against oxidative stress by reducing ROS production and improving mitochondrial metabolism [98].

The substantia nigra pars reticulate (SNr) and the subthalamic nucleus (SN) are both abundant in KATP channels [99]. 

They belong to the basal ganglia, are involved in the control of movement [100], and have been considered as a seizure gate [101]. Impairment of these structures is associated with epilepsy and Parkinson's disease [102]. It has been noted that frequent spontaneous firing of GABA-ergic neurons in the SNr can induce seizures [103]. 

Inhibition of these neurons, on the other hand, hinders the onset of convulsions. Both β-HB and ACA have been shown to reduce the frequency of neuronal firing in SNr in the brains of mice [104,105]. This may be related to a reduction in the importance of glycolysis in the metabolism under ketosis and consequently a decrease in gglycolysisATP production, which in turn results in KATP activation and reduced excitability. 

Furthermore, β-HB increases the probability of KATP channels opening in the hippocampus, which may help granule cells maintain seizure-gate activity and prevent convulsions [106]. 

Juge et al. [55] demonstrated that administration of ACA reduced seizure intensity and decreased glutamate secretion, while not affecting dopamine levels in rats with seizures induced by 4-aminopyridine (potassium channel blocker). However, this effect was reversible: after ACA removal, the effect of 4-aminopyridine intensified. Kim et al. [107] attempted to determine the type of channels involved in reducing metabolic stress. 

For this purpose, the researchers investigated the effects of β-HB and ACA on KATP channels located in rat and mouse hippocampi. The results confirmed the protective effect of KBs, induced by the activation of ATP-dependent potassium channels against oxidative stress. 

The researchers noted that blocking mitochondrial KATP channels with 5-hydroxy decanoate and the absence of plasmalemma KATP channels abolished the neuroprotective effect of KBs, thereby indicating that the neuroprotective effect is obtained by affecting both types of channels.

2.8. The Impact of the Ketogenic Diet on Beta Amyloid and Tau Protein Synthesis

The processes leading to the development of AD are inextricably linked to abnormal transformations of beta-amyloid (Aβ) and tau protein as a result of which pathological conglomerates of these structures are formed. 

At the root of this process is the dysfunctional activity of mitochondria. This entails a decrease in the level of energy from glucose metabolism and an increase in the accumulation of tau protein and Aβ [26]. Given the complex nature of AD etiology and the positive effects of KD in older patients diagnosed with AD, there is a justification for the wide use of KD in neurodegenerative diseases [108]. 

According to studies, KD may contribute to reducing the level of accumulation of beta-amyloid and reversing its toxicity, by affecting the neuropathological and biochemical processes that are found in AD [20,26]. It has been proven that KD can reduce the volume of pathological beta aggregates of amyloid and tau protein in brain homogenates of laboratory animals [78]. 

In mice treated with a ketogenic diet for 40 days, there was a 25% reduction in amyloid beta deposits with no effect on the ability to recognize simple objects [20,26]. A resembling experiments conducted over 43 days showed similar effects, but scientists did not verify the effect of diet on the cognitive abilities of animals [109]. 

The reason for this, most likely, was too short duration of this treatment. Diet-derived ketone bodies might help to improve memory and cognitive function. The participation of KD in reducing the level of risk of developing the disease by improving the function of the cerebral circulation and improving metabolic actions (including lowering glucose levels and augmenting the intestinal microflora) was found [78]. 

To sum up, the role of the ketogenic diet in the treatment and prevention of Alzheimer's disease seems to be growing recently. The diet itself has an impact on many metabolic processes important in AD and other neurodegenerative diseases as well. 

Currently, it is believed that the positive effect on cognitive, metabolic, and biochemical functions depends on the length of maintaining high levels of ketone bodies in the blood [26]. It is difficult to determine the importance of KD in the treatment of neurodegenerative diseases in the future, if only because of the limitations in the use of this diet in older patients with particular comorbidities [78]. 

Despite the lack of definition of precise mechanisms determining the action of KD in neurodegenerative diseases and the lack of consistency in the results of independent laboratory tests, it seems worthwhile to continue research determining the exact mechanisms behind the improvement of a patient's condition [26]. It is equally important to determine the long-term impact of KD on the overall well-being of patients using it [78].

3. The Impact of the Ketogenic Diet on Gut Microbiota

Recently, the influence of the gut microbiota has been increasingly studied in the context of neurological diseases [110–113]. However, it is not known whether changes in the composition of the microbiota are a cause or an effect of neurological disorders. 

The gut microbiota–brain axis involves a bidirectional flow of information between the two organs. The brain affects the gut through norepinephrine release, which modulates conditions in the intestine [114]. The gut microbiota, on the other hand, influences the central nervous system through the vagus nerve and via bioactive substances, such as short-chain fatty acids (SCFAs), tryptophan derivatives, and secondary bile acids. 

The composition of the microbiota is constant throughout most of an adult's life and it is generated by, among other things, individual lifestyle, eating habits, or health conditions [115]. Certain types of bacteria that inhabit the large intestine are crucial for the proper functioning of the human body, due to the synthesis of K- and B-group vitamins, as well as the synthesis of neurotransmitters [116,117]. 

SCFAs (acetate, propionate, and butyrate) produced from indigestible carbohydrates, by the strains of Firmicutes and Bacteroidetes along with Bifidobacteria, are not only a source of energy for colonocytes but also exhibit a variety of beneficial actions for the human organism [118,119]. 

High concentrations of SCFAs in the intestinal lumen inhibit the growth of Gram-negative bacteria of the Enterobacteriaceae family [120]. These bacteria, through the production of LPS, can lead to inflammation [113,121]. 

Hence, inhibiting their growth may indirectly suppress the inflammatory process. In addition, butyrate exhibits anti-inflammatory and oxidative stress-modulating effects via inhibition of NF-κB activation, histone deacetylases, and up-regulation of peroxisome proliferator-activated receptor γ (PPAR- γ) [122]. Many studies show that the effect of probiotics, prebiotics, symbiotics, and antibiotics may affect the course of diseases such as Parkinson's disease, depression, and Alzheimer's disease, confirming the vital impact of the gut microbiota composition on the proper nervous system functioning [113,123–125]. 

Studies also suggest that a favorable microbiota profile may be possible during KD, which results in an alleviation of epilepsy symptoms [126–130]. This may be related to the beneficial effects of certain bacteria inhabiting the large intestine on inflammation, or rebalancing of neurotransmitter systems.

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