What are Aminobutyric Acids?

Aminobutyric acids belong to a group of nonproteinogenic amino acids, consisting of a butyric acid molecule attached to an amino group. They include three isomers: α-aminobutyric acid (AABA), β-aminobutyric acid (BABA), and γ-aminobutyric acid (GABA). GABA is the most commonly studied and is the major inhibitory neurotransmitter within the central nervous system. The widespread expression of GABA across the central nervous system makes this chemical messenger critical for survival while engaging in a broad range of functions. Generally, GABA exerts inhibitory effects on cells, acting to lower the ability of nerve cells to receive, generate, or transmit chemical messenger signals to other nerve cells1. AABA has been previously linked to pediatric metabolic diseases, such as Reye’s syndrome, whereas BABA is a natural plant product that increases resistance to plant diseases. BABA has not been shown to have an association with human disease2.

GABA synthesis occurs through the action of glutamate and two isoforms of glutamic acid decarboxylase enzymes, GAD65 and GAD67. The active form of vitamin B6, pyridoxal phosphate, aids in the synthesis of GABA by binding GABA to its target receptors. Once synthesized, GABA is metabolized by GABA transaminase enzymes, which convert it into succinic semialdehyde and glutamate. This process, known as the GABA shunt, transforms GABA and 2-oxoglutarate into succinic semialdehyde and glutamate. Succinic semialdehyde is then oxidized to succinate, which enters the tricarboxylic acid (TCA) cycle1.

Impairments of GABAergic neurons or GABA receptor functioning have been associated with various neurological and mental health conditions, such as epilepsy, anxiety, and depression1. GABA is also synthesized in many peripheral organs, such as the heart, liver, and stomach, and alterations in systemic GABA levels can significantly impact metabolic, gastrointestinal, and cardiovascular health.

Aminobutyric Acid and Neuroscience

GABA neurons play a major role in regulating excitatory-inhibitory balance in concert with glutamate, the brain’s major excitatory neurotransmitter. GABA binds to GABA receptors located throughout the mammalian brain, including critical regions such as the basal ganglia, cerebral cortex, and hippocampus. As the principal inhibitory neurotransmitter in the central nervous system, GABA acts on either ligand-gated ion channels (GABAA or GABAC receptors) or metabotropic receptors (GABAB), leading to an increase in chloride conductance and/or inhibitory downstream signaling cascades. GABA, GABA metabolism, and the modulation of neuronal excitability in the central nervous system has been investigated in a variety of neurological and neurometabolic diseases including anxiety1, Alzheimer’s disease3, depression4, and epilepsy5.

GABA can accumulate in the cerebral spinal fluid (CSF) due to a mutation in 4-aminobutyrate aminotransferase (ABAT), resulting in GABA-transaminase deficiency, a rare neurodevelopmental and neurometabolic disorder. Untargeted metabolomics has been used to examine GABA-transaminase deficiency, a rare neurodevelopmental and neurometabolic disorder caused by mutations in GABAT that results in the accumulation of GABA in the brain. This study found that GABA-transaminase deficiency is associated with a complex metabolic profile in cerebrospinal fluid, and identified several potential biomarkers for the disorder. The study also found that anti-seizure medications can impact the accuracy of diagnosis, and that 2-pyrrolidinone and succinimide may be useful clinical screening biomarkers for GABA-transaminase deficiency6.

Aminobutyric Acid and Metabolic Health

Metabolic disorders such as obesity and type-2 diabetes are characterized by significant impairments in pancreatic β-cell function, resulting in insulin deficiency and adverse effects on glucose metabolism. Interestingly, recent data have implicated GABA signaling originating from peripheral tissues in modulating glucose regulation, obesity, and diabetes.

For example, one study performed in healthy mice demonstrated that oral intake of GABA increased β-cell mass, leading to a modest enhancement in insulin secretion and glucose tolerance. However, GABA treatment in high-fat-fed mice failed to rescue β-cell function and glucose intolerance7, suggesting other mechanistic complexities involved in GABA-mediated glucose regulation in the pancreas.

In addition to the importance of glucose regulation in metabolic disorders, adipose tissue inflammation is another key factor that links obesity to other downstream metabolic complications. Given that GABA also plays a role in regulating adipose tissue function, one report demonstrated that GABA administration in high-fat fed mice reduces obesity-induced adipose tissue macrophage infiltration and enhances insulin activity8.

Aminobutyric Acid and Liver Health

Sepsis, hepatic encephalopathy, and associated complications contribute to approximately 50% of deaths in intensive care units, and a considerable amount of research has been dedicated to understanding mechanisms within the liver and other peripheral organs. While many investigations have focused on peripheral organs and liver disease, recent research has attributed sepsis and systemic inflammation to central nervous system dysfunction and alterations in GABA concentrations.

Hepatic encephalopathy occurs when liver-derived pro-inflammatory cytokines cross the blood-brain barrier, initiating a cascade of inflammatory responses in brain cells. This results in upregulation of central GABAergic signaling, ultimately leading to exacerbated brain damage. The less studied GABA isomer, AABA, has also been implicated in the development of sepsis. Indeed, plasma levels of AABA are significantly increased in sepsis patients and could represent an early biomarker for a transition into more severe outcomes9. Other studies have demonstrated that AABA treatment in a mouse model of liver damage-induced sepsis reduces disease severity by promoting epigenetic modifications of macrophage-associated inflammatory genes and reprogramming of metabolic pathways10.

Aminobutyric Acid and Gastrointestinal Health

The link between gastrointestinal health, the microbiome, and the brain has gained considerable attention for its therapeutic potential for a number of mental health and neurological disorders. Notably, recent reports have revealed that several gut-derived bacteria produce neuroactive metabolites, including GABA. Collectively, these reports provide evidence for the augmentation of GABA-producing bacteria as a potential therapeutic for both gastrointestinal and mental health disorders11.

For instance, one report showed that oral administration of a specific Bifidobacterium strain that produces GABA significantly reduces visceral hypersensitivity in a rat model of abdominal pain12. Taken together with other reports demonstrating GABA’s analgesic properties, these data suggest a potential avenue for GABA-producing bacteria as a therapeutic option for ameliorating microbiome-associated ailments like irritable bowel syndrome.

Decreases in microbiome diversity have been recently linked to debilitating neurological disorders. Interestingly, one study found that individuals with schizophrenia exhibit alterations in the gut microbiome, with unique bacterial taxa associated with schizophrenia severity. Moreover, this report found that schizophrenic fecal microbiome transplant into germ-free mice resulted in excitatory-inhibitory imbalance, manifested as increased levels of GABA in key brain regions and the display of schizophrenic behaviors13.

Researchers have identified certain foods that contain lactic acid-associated bacterial strains that produce GABA, including fermented foods (e.g., yogurt, cheese, fermented rice germ) and probiotics that increase GABA production14. However, whether dietary GABA crosses the blood-brain barrier in sufficient amounts to produce health benefits is under investigation.

Aminobutyric Acid and Cardiovascular Health

Considering the widespread expression of GABA in many organs and the peripheral nervous system, GABA also plays a role in modulating cardiovascular health, particularly in regulating blood pressure and cardiovascular immune function. Specifically, signaling through GABA(A) ion channels expressed in the heart and aorta has been shown to exhibit protective effects against atherosclerosis, a common outcome of brain ischemic injury.

Plaque macrophages are key immune cells involved in atherosclerosis development. Impairments in these cells result in the formation of foam cells, one of the most dangerous components of atherosclerotic plaque. To demonstrate the protective effects of GABAergic signaling, one in vitro study administered GABA and a GABA receptor agonist, topiramate (a commonly used anticonvulsant), to human monocyte-derived macrophages. Results found that upregulation of GABA signaling decreases pro-inflammatory cytokines and cholesterol, and prevents foam cell formation15.

GABA has been demonstrated to have a role in blood pressure regulation by decreasing high blood pressure and enhancing baroreflex sensitivity. Research has indicated that GABA possesses ACE inhibitor properties, which further contribute to its blood pressure-lowering effects16. Moreover, supplementation with GABA has been observed to reduce blood pressure in individuals with mild hypertension17. GABA’s ability to modulate the balance between the sympathetic and parasympathetic nervous systems suggests its potential therapeutic value in the prevention and management of hypertension.

Aminobutyric Acid, circadian rhythms, and sleep

The inhibitory role of GABA has led many researchers to focus on its role in regulating circadian rhythms and sleep. In general, the sedative properties of GABA have led to the development of several drugs (e.g., barbiturates and benzodiazepines) that decrease wakefulness. However, the influence of GABAergic signaling on circadian rhythms is complex and remains under investigation18.

The action of GABA receptor agonists and their impact on sleep has been shown to depend on which GABA receptor subtype is targeted (i.e., GABAA, GABAB, GABAC receptors). For instance, GABAA has binding sites for barbiturates and benzodiazepines. These GABAA receptor agonists decrease waking, increase slow-wave sleep, and enhance an intermediate stage between slow-wave and paradoxical sleep. In contrast, GABAC receptors have higher sensitivity than GABAA and GABAB receptors. However, GABAC agonists and antagonists are not clinically available and are currently under examination for their novel therapeutic potential in alleviating poor sleep, insomnia symptoms, epilepsy, and narcolepsy19.

Aminobutyric Acid and drug development

GABA has been extensively studied in pharmaceuticals and drug development. Indeed, GABA’s inhibitory effects have greatly contributed to epilepsy management and are a major component in sedative drugs for anxiety treatment. Over the last 50 years, benzodiazepines and barbiturates have been utilized as anxiolytics, hypnotics, and anticonvulsants20. However, these GABA receptor agonists are not without side effects, and more recent research has aimed to improve GABA-dependent pharmaceuticals.

For instance, while benzodiazepines are fast and effective anxiolytics, long-term usage is limited by the development of tolerance and withdrawal symptoms. In an effort to develop alternatives, one report examined novel ligands for translocator protein (18 kD). Results found that in rodents, activation of translocator protein (18 kD) not only enhanced GABA neurotransmission but also reduced panic attacks in the absence of sedation and tolerance development21.

GABA pathways have also been implicated in the regulation of pain, and targeting this system is a focus for the development of effective analgesics. Indeed, one report demonstrated that activation of spinal GABAA receptors significantly reduces inflammatory and neuropathic pain in mice without the side effects of sedation, motor impairment, and tolerance development22.

Aminobutyric Acid in Research

As of June 2024, there are 103,265 citations for GABA and 73,142 citations for aminobutyric acid in research publications (excluding books and documents) on Pubmed. The vast number of publications linking this metabolite to a broad range of physiological functions suggests that any research program seeking to better understand neurological, metabolic, gastrointestinal, cardiovascular, and liver health may benefit from quantitative analysis of aminobutyric acids. Considering the importance of aminobutyric acids in biological functions, preclinical research may also benefit from aminobutyric acid quantification to further the understanding of biomarkers, diagnosis, drug development, and disease monitoring.

Referencias

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