Figure 1 near here

The dual role and distribution

Betaine helps maintain the intracellular osmotic pressure, as it binds little to nothing with protein surfaces and enables cellular control of water surface tension. Thus, it stabilizes protein structure and function, while protecting cells, proteins, and enzymes from osmotic stress. This role is relevant, especially in the kidney, where betaine can be present in extraordinary concentrations (>100mM) [1 ]. Other than kidney, betaine is also found in human liver and brain. However, the role of osmolyte and methyl donor has been studied in liver and kidney, and much less in the nervous system. Moreover, recently it was shown that BHMT, one of the enzymes involved in the detoxification of homocysteine, is present not only in liver and kidneys, but it is also expressed in the intestine and in white adipose tissue suggesting a role of betaine also in these tissues [4 ,9 ,10 ].
Betaine is a potential therapeutic against alcohol-induced and metabolic associated diseases, and heavy metal toxicity in liver [4 ,11 ]. Betaine supplementation was also shown to have a role in muscle strength and power [12 ]. It helps to improve body composition in both males and females, but improvement of muscular performance only in males has been reported [13 ]. Betaine also helps against heat tolerance and increases resilience against thermal stressors[14 ]. At the same time, the increasing number of studies showing beneficial effects of betaine in cognition, early-stage neuronal development, and in reducing neurodegeneration and memory impairment, suggesting an important role of betaine in human (neuro)physiology[7 ].

Betaine: a therapeutic nutrient

Traditional eastern medicines have effectively used herbs and food ingredients as therapeutics for several different diseases. The primary advantage of such substances over modern medicine would be the absence of any severe side effects. One approach by modern pharmacologists has been to integrate these herbs and nutrients with currently effective drug administration and develop new therapies. Betaine is one such stable, natural, and non-toxic substance that has shown beneficial effects in several diseases.
Homocystinuria, a sulphur metabolism pathway disorder characterized by increased accumulation of homocysteine in cells and plasma, can cause osteoporosis, arteriosclerosis, dislocated eye lenses, intellectual disability, and neurodegenerative pathologies such as Alzheimer’s, Parkinson’s, and dementia[15 ]. As a treatment, betaine therapy (6-9 g/day of oral administration) is used to decrease Hcy levels by converting it to methionine, and thus increasing the flux through re-methylation pathway. Since 2020, betaine is an FDA approved drug marketed as Cystadane®. This treatment has not been reported to cause any severe side effects except mild body odour and a rare possibility of cerebral edema due to hypermethioninemia[15 ,16 ]. Apart from homocystinuria, betaine supplementation also shows beneficial effects on diseases such as alcohol-induced liver diseases, hepatic steatosis, heart disease, dehydration, heat tolerance etc[1 ,2 ,4 ,12 ,14 ,17 ]. The positive role of betaine is not limited to the diseases involved with liver and kidney; increasing number of papers and studies demonstrate the beneficial role of betaine in the brain as well. However, the positive effects in the CNS are very little understood and reviewed. In this work, we present an overview of papers highlighting the potential therapeutic role of betaine in neuronal disease and disorders and when known the cellular or molecular mechanism involved.

The presence of betaine in the brain

The betaine/GABA transporter 1 (BGT-1), a member of the solute carrier family 6, can transport γ-aminobutyric acid (the primary inhibitory neurotransmitter in the CNS)[18 ] and also betaine across the blood-brain barrier[7 ]. Compared to liver and kidneys, the reported amount of betaine in the brain is relatively low[8 ,19 ].
Since the relationship between blood plasma concentration and tissue accumulation of betaine is not very related, there are some anomalies in the reported betaine blood plasma concentration (1-3mM)[8 ,20-22 ]. Knight et al. have shown time, dose, and osmolarity-dependent betaine accumulation in the hippocampal tissues of mice[7 ]. They showed that the active betaine accumulation also affects the accumulation of other osmolytes in nervous tissues. Under isosmotic conditions, betaine significantly reduces the accumulation of creatine, taurine, myo-inositol, but not glutamate. On contrary, under hyperosmotic conditions, betaine increases the accumulation of glycine and glutamate. Also, to be noted that the betaine intracellular accumulation reaches at peak (8h post first exposure) around 12mM, which is four times higher than the given extracellular concentration (3mM). This work suggests that apart from being an osmolyte and serving as a methyl donor, betaine could also influence GABA production/recycling and GABAergic pathways, which resonates with the findings of Kunisawa et al that showed mediation of GABAergic pathways by betaine[23 ].

Effects of betaine against neurological diseases and disorders

To have healthy physiological functioning and stable control of neuronal circuits, the excitatory/inhibitory (E/I) balance of the brain must be maintained. Since E/I ratio is essential to maintain and regulate signalling transmission, the inhibitory system represents a key point to re-stabilize the neural network function when a predominance of excitation over inhibition rises, as in brain disorders[24 ]. GABA is the primary inhibitory neurotransmitter in the adult CNS and the imbalance in its levels can be related to many neurodevelopmental and neurodegenerative diseases such as autism spectrum disorder (ADS), Schizophrenia, epilepsy, depression but also Parkinson’s and Alzheimer’s disease etc[25 ].