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 ].