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.