1. Introduction
2. Lithium increases Dopamine
3. the epigenetic effects of Accutane
4. Lithium Restores Gene Transcription
5. Dose is Key
6. References

Introduction

Contrary to popular opinion lithium isn’t just a medication for the Manic and Psychotic, in fact, it’s in your water (at very very low doses). The World Health Organisation even recognises it as an essential mineral. Despite its long history as an antipsychotic, recent research has uncovered new and intriguing effects of this trace metal on brain health and epigenetics. Remarkably, lithium supplementation may also provide benefits for those experiencing adverse effects from Accutane treatment, which will be discussed in this article.

Lithium its traditionally thought to work only as an antipsychotic, suppressing excitatory neurotransmitters such as dopamine and glutamate whilst also increasing the inhibitory neurotransmitter GABA. However the reality is far more complex. Recent data has shone light onto a broad array of additional neuroprotective effects, such as enhancing brain derived neurotrophic factor and reducing oxidative stress. [1]

Although lithium is still tainted with the stigma of being a potent ‘zombifier’, suppressing cognition and mood – this couldn’t be further from the truth. A 2009 meta-analysis found that healthy subjects treated with lithium experienced no ill effects on any of the tested cognitive domains, and only minor effects on affective disorder patients. [2]

At lower supplemental doses, lithium paints and even rosier picture, with evidence for improved cognition at ‘sub-therapeutic doses’ (although these studies are typically performed on those with some mild cognitive impairment). [3]

Lithium increases Dopamine

It is true that at therapeutic doses lithium (>1000mg for humans) can decrease dopamine in some regions of the brain, but in other it can significantly enhance it. For example, a study in rats found that 10meq/kg, lithium increased striatal dopamine by 56%. The striatum is a region of the brain that is critical for the reward system, co-ordinating motivation, decision making and reward perception. This effect was normalised 24h after the injection. [4]

An additional study in rats found that a treatment of 74mg/kg of lithium carbonate for 12 days followed by a two day withdrawal period increased the dopamine in the striatum by 99%, however this increase was accompanied by decreases in hypothalamus, hippocampus and pons-medulla. [5] In a model of Parkinson’s low dose lithium helped to increase the number of dopaminergic neurons in the substantia nigra compared to controls.

Lithium has an opposing effect on many of the pro-apoptotic proteins that are increased during Accutane treatment such as Bcl-2 and p53. In one study, lithium treatment of cerebellar brain cells stimulated a 5 fold reduction in the ratio of p53 target Bcl-2 mRNA. [6] As outlined over previous articles, Accutane initiates programmed cell death (apoptosis) in a number of tissues throughout the body, including the gut, the brain, musculoskeletal system and hair. A diet high in lithium was found to completely prevent the loss of striatal dopamine and tyrosine hydroxylase in a model of Parkinson’s, which was attributed to it’s anti-apoptotic effects via suppression of p53. [7]

Lithium’s effects on the D2 dopamine receptor are particularly profound. After only 6 days of lithium feeding, researchers observed a 3-fold increase in D2 mRNA, with enhanced transcription rate. The researchers also found an increased sensitivity to stimulants following these 6 days. [8] D2 is one of the receptor regulated by retinoids and may be subject to aberrations following Accutane treatment, as I’ve outlined in this article.

the epigenetic effects of Accutane

Epigenetics is the field of genetics that explains how gene expression can be altered without changing the underlying genetic code directly. Epigenetic mechanisms can essentially switch genes on and off in a lasting manner, and thereby influence an organism’s traits and behaviour. Two twins sharing the same genes can experience vastly different health outcomes based on their exposure to epigenetic agents. There are two primary forms of epigenetic modification: DNA Methylation and Histone Modification.

Epigenetic modifications refer to alterations in how genes can be transcribed to take effect in the body. An analogy I’ve come up with to help make this easy to understand is to consider your genome as being like a book. Individual pages in the book could be thought of as genes. When a gene is transcribed, it’s like reading from a particular page and copying it out by hand.

DNA methylation can be a particularly enduring form of epigenetic modication, which makes the gene less accessible to transcriptional machinery. In this analogy methylation marks are like sticky tabs covering words in the page making it difficult (or impossible) to copy out the page – and so the gene can’t be transcribed and translated into protein. So, the gene is said be to less ‘expressed’.

modified from original byAnnabelle L. Rodd, Katherine Ververis, and Tom C. Karagiannis, CC BY-SA 4.0, via Wikimedia Commons

Chromatin is a complex of DNA and protein that makes the DNA more compact, helping to regulate gene expression. When Chromatin is tightly bundled it’s less accessible to transcriptional machinery less gene transcription takes place. In this state it is referred to as heterochromatin. The oppose case is where it’s more open and available for gene transcription where it’s referred to as Euchromatin.

When the chromatin is open and relaxed, or tightly closed, depends on Histone modifications. Acetyl groups can attach themselves to histone tails to encourage an open chromatin structure and therefore enhance gene transcription. However, these acetyl groups can also be removed by an enzyme call HDAC (Histone Deacetylase). Substances that can inhibit HDAC are referred to as HDACi’s (Histone Deacetylase inhibitors) and can help relieve the lasting repression of particular genes.

The effect of Accutane on methylation is complex and occurs in two distinct stages. Initially Accutane causes dysregulation of enzymes that maintain a healthy methylation status, particularly DNMT1 and DNMT3. During the course of an Accutane suppression of DNMT1 leads to demethylation events of certain genes and are subsequently over-expressed.

A microarray analysis found that during an Accutane treatment 402 gene promoters became demethylated and 88 became hypermethylated. The process of de-methylation of certain gene promoters might in fact be the mechanism by which retinoids force differentiation, particularly in relation to NOS1. [9] Whilst some genes experience enhanced transcription, others are repressed through hypermethylation.

Significantly, one of the genes subject to this transcriptional regulation was MYCN. This gene plays a pivotal role in the regulation of the WNT/β-catenin pathway, which appears to be highly relevant in the aetiology of PAS (read more). Once Accutane has been withdrawn, there is a very strong and sudden re-methylation. A study on mRNA expression patterns found that following a washout phase there remained no hypomethylated targets, but potentially 9156 repressed targets via hypermethylation.

This analysis also found significant results pointing towards to WNT/β-catenin pathway [10] Following this burst of intense of re-methylation, it’s possible that many of the gene targets marked for repression could continue to be aberrantly repressed. Given the role the Wnt/β-catenin pathway plays in acne pathogenesis, [11] it’s possible that this explains how Accutane is so effective in permanently remediating severe cystic acne.

Lithium Restores Gene Transcription

Lithium occupies a special place in pharmacology because as well as being a mood stabiliser, it also has hypomethylating effects acting as an HDACi. This appears to be a feature that’s common to mood stabilisers, as Valproic acid also enhances gene expression through similar mechanisms.

Lithium not only enhances gene expression both by the removal of methyl marks at gene promotors (for example at the BDNF promotor), but also by promoting global acetylation of the H3 histone.[12] This mirrors the repressive action of retinoids on the H3 histone, which are known to place repressive methyl marks such on the lysine H3K9. [13] [14]

The effects of lithium on acetylation of the H3 histone can be rapid, after just 30mins there is an increase in the global H3 acetylation level in the amygdala, allowing for enhanced gene transcription through open chromatin structure. The diverging epigenetic effects of Lithium and retinoids centres on their opposing action on the β-catenin. Whilst retinoids suppress β-catenin, Lithium enhances it. When β-catenin is suppressed, TCF/LEF binds to HDAC1 and HDAC2 subsequently reducing the acetylation at the promoters of Wnt-dependent genes, repressing gene transcription. [15] [16][17]

Many of lithium’s brain-boosting effects can be attributed to its action on the Wnt/β-catenin pathway, which is also fundamental to the action of Accutane throughout the body (read more). Lithium has been found to increase cytoplasmic levels of β-catenin, essentially having the opposite effect of Accutane. Lithium acts as an agonist of the canonical Wnt signalling pathway by inhibiting GSK3-β activity, thereby releasing β-catenin from the destruction complex. [19] This leads to the typical β-catenin proliferation effects, particularly relevant in the brain, where it induces neurogenesis in the hippocampus.

In fact, neuroimaging has demonstrated that lithium accumulation in the hippocampus is responsible for the larger hippocampal volumes observed in patients treated for bipolar disorder. Chronic high-dose lithium treatment in human hippocampal cultures increases the generation of progenitor cells, neuroblasts, and neurons. [20] The proliferative effect of lithium on hippocampal cells is the direct opposite of Accutane’s effect. The effect on Accutane on hippocampal stem cell proliferation has even been implicated in changes to memory formation during treatment (read here).

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