What is GTA?
The triglyceride 1,2,3-triacetoxypropane is more generally known as triacetin, glycerin triacetate or 1,2,3-triacetylglycerol. It is the triester of glycerol and acetylating agents, such as acetic acid and acetic anhydride.[6]
It is safe?
It is an artificial chemical compound,[9] commonly used as a food additive, for instance as a solvent in flavourings, and for its humectant function, with E number E1518 and Australian approval code A1518. It is used as an excipient in pharmaceutical products, where it is used as a humectant, a plasticizer, and as a solvent.[10]
It has been considered as a possible source of food energy in artificial food regeneration systems on long space missions. It is believed to be safe to get over half of one's dietary energy from triacetin.[14]
GTA administration alone did not have any effect on locomotor activity (Fig. 5a, b)
Given the low toxicity of GTA and its Food and Drug Administration approval for human use, GTA represents a good candidate for use in the proposed acetate supplementation therapy for CD. Furthermore, GTA did not elicit any noticeable toxic effects and did not cause the overt gastrointestinal irritation associated with high doses of calcium acetate.
Triacetin was quickly metabolized to glycerol and acetic acid and these chemicals were not developmental toxins.
GTA increases HDAC mRNA content:
GTA administration elevated both HDAC1 (F1,20=5.01, p=0.049) and HDAC2 (F1,20=5.09, p=0.048) mRNAs (Fig. 6B). Cortical HDAC3 and HDAC4 mRNA abundance remained unaltered following GTA supplementation.
GTA facilitates Histone Acetylation:
These led us to evaluate the efficacy of GTA as source of metabolic acetate, in animal models of experimental psychosis (Chatterjee et al. 2011; 2012; Manahan-Vaughan et al. 2008), for its ability to maintain or facilitate basal acetylation of global histone targets as an alternative to using HDACi and in turn, alleviating associated behavioral phenotypes. Thus, the hypothesis underlying the GTA treatment strategy is based primarily on the previous knowledge that (i) GTA enhances the cellular Bacetate^ availability in the form of acetyl CoA in the brain tissues as one of the HAT substrates (Mathew et al. 2005) and (ii) long-term GTA treatment augments HAT activity (Soliman et al. 2012).
GTA restores histone H3/H4 acetylation in the hippocampus of chronic MK-801-treated mice
The GTA treated group and the GTA together with MK-801-treated group showed better ability to distinguish (recognition) between the familiar and the novel object with respect to the MK-801-treated group, as they spent significantly (P< 0.05) more time with the novel object than the familiar one.
Increased Histone Acetylation Accompanies Memory Formation:
The first indication that histone acetylation might be associated with memory formation was found when Levenson et al. (6) examined H3 and H4 acetylation 1 h and 24 h following contextual fear conditioning and latent inhibition, two paradigms of associative learning. H3 acetylation (on K14) was significantly increased in hippocampal area CA1 1 h (but not 24 h) after contextual fear conditioning, whereas no change was observed in overall H4 acetylation. Conversely, H4 acetylation was increased following latent inhibition but not following contextual fear conditioning. The results of this study conceptualized two important aspects of the connection between histone acetylation and memory formation. First, histone acetylation—and with it, structural changes of the chromatin—accompanies memory formation. Second, different learning paradigms are likely to elicit distinct epigenetic signatures in the brain. Numerous follow-up studies confirmed these findings in contextual fear conditioning (7, 21, 22), in other brain areas such as the prefrontal cortex (23) and the amygdala (24, 25), in other memory tasks such as eye-blink conditioning and object recognition (26), in other phases of a memory’s life such as consolidation and reconsolidation/extinction (23–25, 27, 28), and in organisms other than rodents, e.g., crabs (29). Although Western blot analysis or immunohistochemistry could detect such acetylation changes on a global scale, more refined studies using chromatin immunoprecipitation (ChIP) clarified that these changes do not occur indistinguishably throughout the chromatin but instead occur gene-specifically. That is, the acetylation changes associate with the promoter regions of learning and memory genes (e.g., zif268 and CREB), which, when hyperacetylated, show a concomitant increase in transcription (22, 23, 30, 31). Thus, histone acetylation increments favor gene expression programs that are necessary for memory formation.
Decreased Histone Acetylation Accompanies Memory Impairments:
Decreased Histone Acetylation Accompanies Memory Impairments Memory impairments are associated with several neurodevelopmental, neuropsychiatric, and neurodegenerative diseases such as Rubinstein-Taybi syndrome (RTS), Rett syndrome, Fragile X syndrome, schizophrenia, depression, addiction, Alzheimer’s disease (AD), Huntington’s disease, Parkinson’s disease, Friedreich’s ataxia, and amyotrophic lateral sclerosis. Stunningly, the majority of such disease-related memory impairments seem to be accompanied by decreased histone acetylation (2, 32), and even memory impairments associated with aging fall into this category (33). For the purpose of this review, we describe RTS and AD as examples of neurodevelopmental and neurodegenerative diseases, respectively, because these two disorders have the best-understood relationship between cognitive impairment and histone hypoacetylation. We refer the reader to recent reviews that cover the other aforementioned diseases (2, 34, 35) and to Related Resources for further information on this topic as it relates to stress-related disorders.
(Annu. Rev. Pharmacol. Toxicol. 2013. 53:311–30)
GTA increases NMDAR subunit expression in rats:
To explore the possibility that increased circulating acetate could influence NMDAR subunit expression, GluN subunits were measured in rats gavaged daily with GTA for 3 weeks. A significant increase of cortical GluN1 (F1,20=8.32, p=0.018), and GluN2B (F1,20=6.32, p=0.033) subunits were observed in GTA fed rats compared to controls (Fig. 5B).
Decreased expression of GluN subunits is associated with cognitive impairment, hyperactivity and schizophrenia:
GluN1(hypo) mice exhibited impairments on all tests of cognition that we employed, as well as reduced engagement in naturalistic behaviors, including nesting and burrowing. Behavioral deficits were present in both spatial and non-spatial domains, and included deficits on both short- and long-term memory tasks. Results from anxiety tests did not give a clear overall picture. This may be the result of confounds such as the profound hyperactivity seen in GluN1(hypo) mice.
A possible relationship between impaired memory function and a decrease in NMDA receptors (Kumar, 2015) during senescence has been proposed. Thus, a decrease in NMDA receptor protein expression in regions like the hippocampus occurs during senescence (Magnusson, 1998). This decrease involve a reduction in GluN1 (Gazzaley et al., 1996; Liu et al., 2008). Also, an age-related decrease in the expression of GluN2A and GluN2B occurs in the hippocampus (Sonntag et al., 2000; Zhao et al., 2009). This decrease occurs together with a change in the localization of GluN2B from the synapse to extrasynaptic sites (Potier et al., 2010). A reduction in glutamate uptake has been associated with extrasynaptic NMDA receptors at the hippocampal CA1 synapse of aged rats (Potier et al., 2010). Recently, it has been reported that activation of extrasynaptic NMDA receptors induces tau overexpression (Sun et al., 2016). Since, the GluN2B subunit is present (Rammes et al., 2017) in extrasynaptic NMDA receptors, it has been considered a potential target for the treatment of neurodegenerative disorders related to aging, such as AD. In this context, it is especially interesting that in AD Aβ oligomers interact with the exposed regions of the subunit GluN1 (see for example Amar et al., 2017).
Over the past 20 years, there has been a confluence of evidence from many research disciplines pointing to alterations in excitatory signaling, particularly involving hypofunction of the N-methyl-D-aspartate receptor (NMDAR), as a key contributor to the schizophrenia disease process.
Elevated levels of GluN2B receptors may increase cognition:
Both mice and rats that were engineered to over-express GRIN2B in their brains have increased mental ability. The "Doogie" mouse had double the learning ability on one measure of learning.[8][9]
In particular, the NMDAR–GluN2B subunit plays a critical role in experience-dependent synaptic plasticity associated with learning and memory (Kutsuwada et al., 1996; Ito et al., 1997; Tang et al., 1999; Kim et al., 2005; Akashi et al., 2009; Fetterolf and Foster, 2011). Animal studies show that the Glun2b subunit is required for neuronal pattern formation in general, and for channel function and formation of dendritic spines in hippocampal pyramidal cells in particular (Ito et al., 1997; Cull-Candy et al., 2001; Kim et al., 2005; Akashi et al., 2009). Transgenic overexpression of Grin2b in the forebrain of mice, and in the cortex and hippocampus of rats results in an increased activation of the NMDARs, with mice and rats showing a superior performance in various tests of learning and memory (Tang et al., 1999; Wang et al., 2009).
GTA increased NAA and ATP concentrations in the injured brain:
GTA treatment increased NAA levels in the injured hemisphere by approximately 29% compared with water-treated controls. In the animals examined 6 days after CCI injury, NAA levels were decreased an average of 33% in the water-treated animals. GTA treatment increased NAA levels in the injured hemisphere by an average of 23% relative to water-treated animals at this time point.
But it is probably not effective in the healthy brain:
NAA levels are not increased when acetate levels are increased as high as 17-fold in the brain.
NAA is a marker of general intelligence:
Decades of research have revealed that general intelligence is correlated with two brain-based biomarkers: the concentration of the brain biochemical N-acetyl aspartate (NAA) measured by proton magnetic resonance spectroscopy (MRS) and total brain volume measured using structural MR imaging (MRI).
Edited by William Sterog, 16 February 2021 - 11:59 PM.
