Figure 2 near here
Role in epilepsy
The GABA transporters regulate GABA synaptic concentration by the
cellular uptake and regulate GABA activity, consequently are often
predominant targets for the antiepileptic and anticonvulsant
drugs[26 ]. Since the majority
of GABA uptake in the CNS is done by GABA transporter 1 (GAT1), it has
been a pharmaceutical target to treat disorders related to GABAergic
imbalance. The FDA-approved antiepileptic drug Tiagabine is a selective
inhibitor of GAT1[27 ]. The
synergic anticonvulsant effect of tiagabine with the selective inhibitor
EF1502 on GAT1 and BGT1 both raised a functional role of BGT-1 in
regulating diffused GABA from synaptic
regions[28 ,29 ].
However, the seizure threshold experiments on BGT-1 knock-out mice
showed no alteration and ruled out a role of BGT-1 in seizure
susceptibility[30 ]. Given the
limitations of this study, it is possible that the BGT-1 still might be
playing a role in epileptic seizures and GABAergic imbalance in CNS.
Also, the great uncertainty in the localization of BGT-1 in the brain
and in cell cultures also questions the role of betaine in the
brain[19 ].
Role in stress-related
disorders
The stress-induced psychiatric disorders like depression, anxiety, and
post-traumatic stress disorder (PTSD) are associated with abnormalities
in GABAergic neurotransmission
functioning[25 ,31 ,32 ].
The study of water-immersion restraint strain (WIRS) induced stress (in
mice) resulting in memory impairments showed amelioration by
betaine[23 ]. This improvement
could be inhibited by antagonists of BGT-1, GABAA, and
GABAB receptors. Also, the betaine treatment post-WIRS,
significantly decreased the expression of GABA transaminase (GABA-T),
the enzyme responsible for breaking down GABA when not needed. GAT1,
GAT3, and BGT-1 expressed in astrocytes regulate GABA
levels[33 ], and inhibition of
GABA-T also increases GABA levels in synaptic
cleft[34 ]. As betaine is
transported by BGT-1 and decreases GABA-T expression, betaine could be
asserting its positive effects by changing GABA levels in the CNS. Thus,
betaine does not work only as a substrate of BGT-1, but it could also
interact largely with the entire GABAergic system.
In psychology, social defeat is seen as a form of stress that could
cause depression, anxiety, PTSD
etc[35 ]. The resilience
against such stress can be mediated by adaptive changes in neural
circuits of neurotransmitters (like GABA) and molecular
pathways[36 ]. Anhedonia is one
of the main symptoms of stress-related disorders. While studying the
role of brain-gut-microbiota axis in such disorders, it was found that
the mice subjected to chronic social defeat stress (CSDS), when given
betaine supplementation showed resilience to anhedonia. This indicates
that betaine supplementation could be used as a prophylactic nutrient to
prevent or minimize the relapse by stress in patients of such
psychiatric disorders[37 ].
Neuroprotective role against Alzheimer’s and
dementia
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease
that is characterized by progressive impairment of cognition, memory,
and intellectual functions. So far, there have not been many approved
agents that ameliorate cognition and the overall function of AD
patients, and different therapeutical approaches have been developed. It
is known that the amyloid-ß (Aß) aggregation play an essential role in
neuronal degeneration in AD; hence, it is an important biomarker in
AD-like pathologies[38 ]. Aß is
generated by amyloid precursor protein (APP) via sequential cleavage
from ß- and γ-secretases. The generation and deposition of Aß has been
associated with altered oxidative stress, inflammation, tau
phosphorylation and synaptic dysfunction, contributing to the
progression of the disease and eventually leading to death. Also, the
increased levels of Hcy have been associated with the onset of AD, along
with
hyper-homocysteinemia[39 ].
As betaine is an effective methyl donor to convert Hcy to methionine, a
therapeutic approach is being developed to use betaine supplementation
to target increased Hcy and cascade the AD progression. Chai et al have
shown that betaine supplementation ameliorates AD-like Hcy-induced
memory deficits, enhances long-term potentiation, and increases
dendritic branch numbers and density of dendritic
spines[40 ]. It also attenuated
the tau phosphorylation and Aß accumulation by altering APP
processing[40 ,41 ].
In a study, Sun et al demonstrated that subjects treated with betaine
supplementation showed amelioration in cognitive deficit resulting in
better recall of words, improved visual-spatial capacity etc.
[42 ]. Their results showed
betaine supplementation (200 μg/kg for a month) reverses Aß accumulation
and stimulates the regulation of memory-related protein (NR1, NR2A, and
NR2B). Overall, betaine has been suggested to be an effective
therapeutic tool to treat AD and could be combined with other drugs to
provide a successful therapy.
Vascular dementia (VaD) is the other most common type of dementia in
aged people after AD and lacks effective therapy. Chronic cerebral
hypoperfusion (CCH) is thought to be the primary reason behind cognitive
impairment in VaD patients. A study of betaine administration in rats
showed that memory deficits induced by CCH were
ameliorated[43 ]. The
CCH-induced synaptic protein loss was restored and oxidative stress was
suppressed by betaine. This experimental evidence yet suggests a
therapeutical application of betaine in neurodegenerative
disease[43 ].
Protective role against
Parkinson’s
Parkinson’s disease (PD) would be the second most prevalent
neurodegenerative disease (only after AD) characterized by uncontrolled
muscular activity, an increase in the metabolic concentrations of
sulphate and nitrate compounds, a decline in dopamine levels due to
neuronal degeneration, and sleep disturbance. In PD patients, oxidative
stress in the brain is evident and this stress causes oxidative
damage[44 ].
The dopaminergic drug laevo-3-4-dihydroxyphenylalanine (Levodopa, LD)
reduces the effects of PD effectively and is prescribed prominently.
However, LD administration also increases plasma levels of
Hcy[45 ]. To cross the
blood-brain barrier and to avoid peripheral toxicity, LD is administered
with a dopa decarboxylase inhibitor such as benserazide, which by
catechol-o-methyltransferase elevates Hcy levels further. The clinical
and experimental trials in PD patients show that a high accumulation of
Hcy could contribute to accelerated neurodegeneration and the onset of
atherosclerotic and neuropsychiatric
symptoms[46 ,47 ].
Hence, such treatment overall poses a risk of hyper-homocysteinemia in
PD patients leading them towards other neurodegenerative diseases such
as AD and dementia[48 ].
Alirezaei et al studied the effects of betaine administration on
oxidative stress and increased Hcy levels induced by LD/benserazide
treatment of PD patients[49 ].
They demonstrated the neuroprotective qualities of betaine against
LD-induced oxidative stress in the brain tissues of rats. Betaine could
elevate antioxidant levels and decrease lipid peroxidation and Hcy
levels. Also, the inhibitory effects of betaine on the neurotoxic nitric
oxide in microglial cells show the effectiveness of betaine as a
therapeutic against neurodegenerative diseases and suggests that betaine
would be useful for reducing NO-dependent inflammation in the
brain[50 ].
Rotenone is an inhibitor of mitochondrial complex I, breaks ATP
production and by enhancing the production of mitochondrial ROS causes
apoptosis, inducing neurotoxicity. It is widely used as a model of the
pathogenesis of PD. Neuronal cell death is one of the major factors
behind cognitive decline in AD and PD. It was demonstrated that betaine
performs neuroprotective effects against rotenone-induced neurotoxicity
in PC12 cells[51 ]. The
increasing oxidative stress and inflammation in the brain can cause
brain ischemia and ischemic stroke. The betaine treatment of PC12 cells
(with oxidative stress induced by H2O2)
resulted in decreased pro-inflammatory cytokine production and reduced
oxidative stress[52 ]. Betaine
also increased the expression of antioxidative enzymes and nonenzymatic
genes. These results showcase how betaine can and should be considered
as a protector against oxidative stress and neurodegeneration.
A therapeutic agent for
Schizophrenia
Schizophrenia has always had sleep dysfunction as one of its primary
descriptions[53 ]. The sleep
pressure, the driving force of the homeostatic process, builds up during
wakefulness and dissipates when asleep. Sleep pressure and sleep
disturbance are associated with onsets for patients with psychosis. It
is shown that with increasing high sleep pressure, specific metabolomic
alterations occur like decreased levels of betaine in the whole
brain[54 ]. Hence, betaine is
proposed as one of the biomarkers for the diseases and treatments
associated with sleep deprivation.
The neurons in schizophrenic brains tend to undergo gross morphological
changes. The neuronal morphogenesis-related traits are significantly
alleviated by a high-betaine diet, suggesting that betaine through a
neuroprotective mechanism could be effective for refractory
Schizophrenia patients[55 ].
Also, in CHDH (a gene for betaine synthesis) deficient mice the remnants
of schizophrenia-related molecular perturbations in the brain were
recorded. It was shown that betaine supplementation induced improvements
in cognitive performance dependent on genetic
background[56 ]. With such
results, betaine has been recommended as a psychotherapeutic for
patients with schizophrenia.