White Paper by Wei (Adelyn) Tsai
Reviewed by: Greg Hollenbeck, Thia Hanania
Background
L-glutamine (L-Gln) is a ubiquitous amino acid in mammalian tissues involved in many functions (Chen & Herrup, 2015)(Fig.1). Unique to the brain, it is an important precursor of many neurotransmitters: the excitatory amino acids, glutamate (Glu) and aspartate (Asp), and the inhibitory amino acid, γ-aminobutyric acid (GABA)(Albrecht et al., 2010). It is involved in the Gln/Glu cycle, wherein Glu is synthesized into Gln in astrocytes, and Gln gives rise to Glu, GABA, or Asp in neurons (Bak et al., 2006)(Fig.2). Therefore, L-Gln homeostasis is specifically important for the balance of glutamatergic and GABAergic transmission, dysregulation of which leads to many neurologic and cognitive diseases.
Fig. 1 Functions of glutamine. Glutamine provides building blocks for DNA and protein synthesis. It provides cellular energy by entering the tricarboxylic acid cycle (TCA cycle). It is also the precursor of the major antioxidants, glutathione (GSH). Unique to the brain, glutamine is used to produce neurotransmitters glutamate and GABA (J. Chen & Herrup, 2015).
Fig. 2 Glutamine/Glutamate cycle. Glu released from the presynaptic neurons is transported to astrocytes, where it is converted to Gln by the enzyme glutamine synthetase. Gln is recycled to neurons to enable glutamate synthesis. In the neurons, Gln can be converted to GABA or Asp through a series of biochemical reactions (not shown)(Natarajan & Venneti, 2019).
Brain-health complaints
1) Alzheimer’s disease (AD)
Studies have found decreased Gln level in the brain in AD patients (Antuono et al., 2001; Hattori et al., 2002). This reduction may be responsible for AD pathology via several different mechanisms. As mentioned above, astrocytes are important in regulating Gln/Glu cycling. In AD, reactive astrocytes downregulate glutamine synthetase (GS), an enzyme catalyzing Gln formation from Glu and ammonia. Since Gln is the precursor of GABA, reactive astrocytes thus cause GABA depletion, which was found in AD patients reported by many previous studies (Ambrad Giovannetti & Fuhrmann, 2019). Importantly, glutamine supplementation could reverse the loss of GABAergic inhibition in mice (Ortinski et al., 2010). Gln is also protective against Aβ-induced neurotoxic effects and blocks the expression of indices of neurodegeneration in AD mice models (Chen & Herrup, 2012). A previous study reported blocking GS induced inflammation in glial cells (Palmieri et al., 2017) and that GS activity declined in AD patients (Smith et al., 1991), so supplementing L-Gln may be a possible treatment for chronic inflammation in AD patients (Chen & Herrup, 2015).
A few clinical studies reported the potential for Gln as AD treatment. In a Mendelian Randomization study using genetic variants strongly associated with Gln as the instrument, the circulating Gln shows a protective effect against AD (Adams, 2020). In a previous clinical trial, a nutritional supplement mainly containing glycine, glutamine, and niacin (5g, 4.92g was a mixture of glycine + Gln) were found to be able to increase growth hormone in healthy middle-aged and elderly subjects and individual increase of insulin-like growth factor 1 (IGF-1) was associated with improved memory and vigor (Arwert et al., 2003). Since using growth hormone-releasing hormone to increase growth hormone and IGF-1 was found to improve cognition in AD patients (Baker et al., 2012), L-Gln may be used to alleviate AD by releasing growth hormone in addition to the biological actions found in the preclinical studies.
2) Depression
Studies have shown changes to glutamine + glutamate (Glx) pool and thus aberrant glutamatergic systems in major depressive disorder (MDD) (Mathews et al., 2012). A 3 years follow-up study found the ratio of Gln to Glu was significantly higher in MDD patients at baseline compared to controls but this ratio decreased over 3 years in MDD patients. The reduction was also correlated with decreased severity of depression (Hashimoto et al., 2016). A review of proton magnetic resonance spectroscopy (1 H MRS) literature found reduced Glx levels in MDD (Yksel & Öngür, 2010). Thus, supplementing the brain with L-Gln may be beneficial to reset Gln/Glu homeostasis in depressive patients.
A few studies support this. Low levels of Gln and Glu caused hypoactive glutamatergic neurons in the medial prefrontal cortex of stress-induced depressive mice, and Gln supplementation increased glutamatergic neurotransmission and attenuated depressive behaviors (Son et al., 2018). Another study also showed direct infusion of L-Gln into the prefrontal cortex of mice reverse the depressive-like behavior induced by Gln/Glu cycle impairments (Lee et al., 2013). As early as the 1970s, Cocchi proposed the use of L- Gln as an antidepressant after seeing its antidepressant properties in 43 depressive adults (Cocchi, 1976). However, afterward, no clinical studies have been done to assess the effects of L-Gln in depressive patients. There are, however, reports about the use of Gln-containing supplements improved mood in patients undergoing marrow transplantation (Young et al., 1993) and reduced anxiety and depression in patients recovering from chronic illnesses (Jones et al., 2015).
3) Addiction
It is well known that glutamatergic and GABAergic systems are involved in addiction. Importantly, GABAergic neurotransmissions are blocked by many abusive drugs and chronic drug exposure reduces the inhibitory effects of GABAergic systems over time (Lüscher & Malenka, 2011). This leads to neural hyperexcitability during withdrawal, causing serious withdrawal symptoms such as anxiety and seizures (Clapp et al., 2008). A review of the magnetic resonance spectroscopy and positron emission tomography studies in drug addicts revealed changes to the GABA level in the brain (Moeller et al., 2016). Using L-Gln to treat addiction has been proposed since the 1950s. Rogers et al. first found Gln reduced voluntary alcohol consumption in rats (Rogers et al., 1955, 1956). Later they found 1g L-Gln administration reduced alcohol craving in patients (Rogers & Pelton, 1957). L-Gln could be acting by increasing GABA levels and thus increasing inhibitory control (Cocchi & Tornati, 1977). L-Gln was included in the neuronutrient SAAVE and Tropamine to increase the GABA level and gave it to addicted patients. Studies showed this type of therapy reduced withdrawal symptoms and facilitated recovery rate (Chen et al., 2004; Jukić et al., 2011). Another study using a neurotransmitter-precursor-supplement intervention that contained 50mg/kg/d L-Gln in detoxified heroin addicts also found alleviation of withdrawal and mood symptoms (D. Chen et al., 2012).
4) Brain injury
Gln depletion is associated with increased mortality in critically ill patients (Rodas et al., 2012), and Gln administration could improve the survival of these patients (Griffiths et al., 1997). In traumatic brain injury (TBI) patients, plasma Gln level was found to be low (van Rosmalen et al., 2015), suggesting that Gln supplementation may improve the clinical outcomes of brain injury patients as well.
Traumatic brain injury can induce inflammation, histopathological changes, and apoptosis in the intestine (Hang et al., 2003). In rat models of TBI, Gln was found to suppress intestinal inflammation by decreasing nuclear factor kappa B activity and pro-inflammatory cytokine expression (Chen et al., 2008). Furthermore, Gln also protected the intestinal mucosal structure and reduced mucosal apoptosis in these rats (Feng et al., 2008). Similarly, the beneficial effect of Gln was shown in a previous clinical trial. In this trial, combined probiotics (240ml fermented milk with probiotic strain Lactobacillus johnsonii) and glutamine (30g) in addition to the standard diet were given to brain injury patients in the intensive care unit (ICU). The diet containing probiotics and glutamine decreased the infection rate and shortened the stay these patients stayed in the ICU (Falcão De Arruda & De Aguilar-Nascimento, 2004). Since the integrity of the gastrointestinal tract is important to prevent immune response (Falcão De Arruda & De Aguilar-Nascimento, 2004), the effects of Gln on anti-inflammation and protection of intestine structure may explain why these patients had fewer infections. In another study, Gln was additionally added into the enteral nutrient fluid and patients given this enriched diet had reduced loss of lean tissue, improved nutrition status, shorter hospital stays, and accelerated recovery rate (Zeng et al., 2009).
Gln can be given via enteral and intravenous routes. However, enteral administration can significantly increase the metabolic conversion of Gln to Glu (Melis et al., 2005). Since most TBI patients have impaired blood-brain barrier (Price et al., 2016), increased plasma glutamate could worsen the excitatory-inhibitory imbalance (Glu and GABA imbalance) commonly seen in these patients (Guerriero et al., 2015). Therefore, more studies have used intravenous administration of Gln on brain injury patients. Importantly, two previous randomized trials demonstrated that intravenous Gln containing dipeptide, L-alanyl-L-glutamine, in clinically relevant dose (0.34g/kg & 0.75 g/ kg ) increased plasma and brain Gln levels but did not elevate plasma and cerebral Glu level in head trauma and TBI patients (Berg et al., 2006; Nägeli et al., 2014). Therefore, a dosage range from 0.34g/kg to 0.75 g/ kg may be appropriate for intravenous Gln for brain injury. Intravenous Gln containing dipeptide can also improve the clinical outcome of TBI patients. In a clinical trial, patients being administered with this Gln-containing therapy reduced mortality, length of stay in the ICU, lung infection, and gastrointestinal hemorrhage (Yang & Xu, 2007). This study showed again that intravenous Gln can be useful for brain injury patients.
Overall, L-Gln is an important neurotransmitter precursor and its imbalance underlies the causes of different neurological and neuropsychiatric diseases. Importantly, most of the recent clinical studies presented here used combined treatment in which L-Gln is included. Therefore, while supplementing with L-Gln may be useful to improve brain health, the exact neurologic benefits of taking L-Gln alone or with other supplements need further investigation.
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