Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

Abstract

Nutritional ketosis, induced via either the classical ketogenic diet or the use of emulsified medium-chain triglycerides, is an established treatment for pharmaceutical resistant epilepsy in children and more recently in adults. In addition, the use of oral ketogenic compounds, fractionated coconut oil, very low carbohydrate intake, or ketone monoester supplementation has been reported to be potentially helpful in mild cognitive impairment, Parkinson’s disease, schizophrenia, bipolar disorder, and autistic spectrum disorder. In these and other neurodegenerative and neuroprogressive disorders, there are detrimental effects of oxidative stress, mitochondrial dysfunction, and neuroinflammation on neuronal function. However, they also adversely impact on neurone–glia interactions, disrupting the role of microglia and astrocytes in central nervous system (CNS) homeostasis. Astrocytes are the main site of CNS fatty acid oxidation; the resulting ketone bodies constitute an important source of oxidative fuel for neurones in an environment of glucose restriction. Importantly, the lactate shuttle between astrocytes and neurones is dependent on glycogenolysis and glycolysis, resulting from the fact that the astrocytic filopodia responsible for lactate release are too narrow to accommodate mitochondria. The entry into the CNS of ketone bodies and fatty acids, as a result of nutritional ketosis, has effects on the astrocytic glutamate–glutamine cycle, glutamate synthase activity, and on the function of vesicular glutamate transporters, EAAT, Na+, K+-ATPase, Kir4.1, aquaporin-4, Cx34 and KATP channels, as well as on astrogliosis. These mechanisms are detailed and it is suggested that they would tend to mitigate the changes seen in many neurodegenerative and neuroprogressive disorders. Hence, it is hypothesized that nutritional ketosis may have therapeutic applications in such disorders.

Mitochondrial Metabolism in Astrocytes Regulates Brain Bioenergetics, Neurotransmission and Redox Balance

“…The increase in ketone bodies arises primarily from metabolism outside the brain and to date it is unclear if the toxicity is mediated by ketone body accumulation (ketosis) or acidosis ( Fedorovich et al, 2018 ). A number of investigations have reported the beneficial effects of ketosis by regulating astrocytic metabolism, glutamate-glutamine cycle, glutamine synthetase (GS) activity, the function of vesicular glutamate transporters, excitatory amino acid transporters (EAAT), sodium-potassium adenosine triphosphatase (Na + /K + ATPase), potassium channels (Kir4.1 and KATP), aquaporin-4, connexins, as well as on astrogliosis ( Valdebenito et al, 2016 ; Morris et al, 2020 ). It has also been clearly shown that production of ketone bodies is used as a signaling mechanism to regulate food intake ( Le Foll and Levin, 2016 ).…”

Increased Beta-Hydroxybutyrate Level Is Not Sufficient for the Neuroprotective Effect of Long-Term Ketogenic Diet in an Animal Model of Early Parkinson’s Disease. Exploration of Brain and Liver Energy Metabolism Markers

“…Astrocytes have been shown to act protective towards neurons, among many functions by ketone body production [ 51 , 52 , 53 ]. Astrocytes also benefit from ketone body substitution from the periphery more than neurons due to the greater b-HB uptake [ 11 , 54 ]. Astrocyte dysfunction affects neuron viability [ 35 , 36 ].…”

“…Astrocyte dysfunction affects neuron viability [ 35 , 36 ]. Ketone bodies provided by the diet or applied directly might have relieved the burden put on astrocytes by the toxin, and in this way may also cause neuroprotection in MPTP/MPP+ models [ 54 ].…”

Vascular endotelial dysfunction is a pathogenetic factor in the development of neurodegenerative diseases and cognitive impairment

“…В связи с этим следует упомянуть, что в настоящее время повышенное внимание привлекают особенности образа жизни, в частности, показатели качества диеты, компоненты питания и его калорийность. Так, установлена связь между ожирением материнского организма и развитием нейродегенеративных заболеваний у ребенка [25], установлено позитивное влияние кетогенной диеты и интервального голодания как профи-лактических и даже лечебных факторов при нейродегенеративных заболеваниях [16,64,74]. Это особенно актуально для оценки состояния эндотелия и корректировки сосудистых заболеваний.…”