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Unlike opioids, nicotine, cannabinoids and other psychoactive chemicals, alcohol does not have specific binding receptors in the brain.
Most of the ethanol is oxidized in the liver by alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase 2 (ALDH2).
Alcohol removes two hydrogens through ADH to form acetaldehyde.
Acetaldehyde can cause DNA double-strand breaks and cause greater damage to the body.
Acetaldehyde then forms less toxic acetate under the action of ALDH2.
ALDH2 is located on human chromosome 12 and has both acetaldehyde dehydrogenase and esterase activities.
After the mutation of this gene, the enzyme activity is lost, causing a large amount of acetaldehyde to accumulate in the liver, causing uncomfortable reactions such as blushing after drinking.
Acetaldehyde, the intermediate metabolite of ethanol, can cause greater harm in the human body than ethanol itself.
Acetate is mainly used by astrocytes in the brain and can promote acute ethanol-induced poisoning in mice.
On March 22, 2021, Professor Zhang Li from the Institute of Alcohol Abuse and Alcoholism of the National Institutes of Health published an article revealing that astrocytes in the cerebellum mediate low-dose alcoholism through ALDH2.
The first author of the paper is Jin Shiyun, a doctor of anesthesia and perioperative medicine from the Second Affiliated Hospital of Anhui Medical University.
ALDH2 is enriched and expressed in cerebellar astrocytes in situ hybridization experiments found that ALDH2 is expressed in the cerebellum, thalamus, cortex, hippocampus, cerebellum and other brain regions of mice, and the expression is more abundant in the cerebellum.
In addition, in terms of neuron types, ALDH2 is mainly expressed on astrocytes.
Astrocytes in human cerebellar tissues are also enriched and express ALDH2.
After specifically knocking out ALDH2 in astrocytes, the acetate level decreased.
Compared with normal mice, the acetaldehyde concentration in peripheral blood and cerebellum tissue of all knock-out ALDH2 mice increased significantly after drinking alcohol.
After specifically knocking out ALDH2 on astrocytes, the concentration of acetaldehyde in peripheral and cerebellar tissues was no different from that of normal mice, but the concentration of alcohol metabolite acetate in peripheral and cerebellar tissues was significantly reduced.
The researchers found that the acetate level in the cerebellum of the mice increased significantly after half an hour after the alcohol was given.
However, this high level of acetate can be restored to normal levels in two cases.
The first is the effect of time.
One hour after alcohol administration, the acetate level of mice decreases to normal levels.
The second is the molecular effect of ALDH2: this increase disappeared after the specific knockout of ALDH2 in astrocytes, while the level of acetate still increased after specific knockout of ALDH2 in the liver.
These results indicate that ALDH2 derived from astrocytes in the central nervous system can regulate the level of alcohol metabolite acetate through the "invisible hand".
For a long time, it has been believed that acetate in the brain is mainly derived from alcohol metabolism in the liver, and acetate can enter the brain parenchyma through the blood-brain barrier.
However, the research in this article found that the central nervous system can directly regulate acetate.
Low-dose alcohol caused dyskinesia in mice.
Both female and male mice showed dyskinesia in the accelerated rotating rod experiment after giving low-dose alcohol or acetate.
But after specifically knocking out ALDH2 on astrocytes, there was no dyskinesia.
The researchers further injected the AAV5-GFAP-Cre virus into the cerebellar region of Aldh2 flox mice, using this viral strategy to specifically knock out ALDH2 on cerebellar astrocytes.
The mice did not show severe dyskinesia after giving low-dose alcohol.
Researchers found that acetate can significantly promote the synthesis of GABA.
In order to further determine whether the alcohol-induced sports injury is mediated by GABA, they injected GABA-A receptor antagonists or GABA-B receptor antagonists into the lateral ventricle of mice, which can significantly alleviate alcohol-induced motor incoordination.
This indicates that acetate mediates low-dose alcoholism through GABAergic signals.
In summary, this article reveals that ALDH2’s regulation of alcohol metabolite acetate has brain region (cerebellum) specificity and cell (astrocytic) specificity.
Acetate promotes the synthesis of GABA and GABA in the cerebellum.
The tonic inhibition causes symptoms of motor incoordination.
[References] 1.
https://doi.
org/10.
1038/s42255-021-00357-z The pictures in the article are all from the references
Unlike opioids, nicotine, cannabinoids and other psychoactive chemicals, alcohol does not have specific binding receptors in the brain.
Most of the ethanol is oxidized in the liver by alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase 2 (ALDH2).
Alcohol removes two hydrogens through ADH to form acetaldehyde.
Acetaldehyde can cause DNA double-strand breaks and cause greater damage to the body.
Acetaldehyde then forms less toxic acetate under the action of ALDH2.
ALDH2 is located on human chromosome 12 and has both acetaldehyde dehydrogenase and esterase activities.
After the mutation of this gene, the enzyme activity is lost, causing a large amount of acetaldehyde to accumulate in the liver, causing uncomfortable reactions such as blushing after drinking.
Acetaldehyde, the intermediate metabolite of ethanol, can cause greater harm in the human body than ethanol itself.
Acetate is mainly used by astrocytes in the brain and can promote acute ethanol-induced poisoning in mice.
On March 22, 2021, Professor Zhang Li from the Institute of Alcohol Abuse and Alcoholism of the National Institutes of Health published an article revealing that astrocytes in the cerebellum mediate low-dose alcoholism through ALDH2.
The first author of the paper is Jin Shiyun, a doctor of anesthesia and perioperative medicine from the Second Affiliated Hospital of Anhui Medical University.
ALDH2 is enriched and expressed in cerebellar astrocytes in situ hybridization experiments found that ALDH2 is expressed in the cerebellum, thalamus, cortex, hippocampus, cerebellum and other brain regions of mice, and the expression is more abundant in the cerebellum.
In addition, in terms of neuron types, ALDH2 is mainly expressed on astrocytes.
Astrocytes in human cerebellar tissues are also enriched and express ALDH2.
After specifically knocking out ALDH2 in astrocytes, the acetate level decreased.
Compared with normal mice, the acetaldehyde concentration in peripheral blood and cerebellum tissue of all knock-out ALDH2 mice increased significantly after drinking alcohol.
After specifically knocking out ALDH2 on astrocytes, the concentration of acetaldehyde in peripheral and cerebellar tissues was no different from that of normal mice, but the concentration of alcohol metabolite acetate in peripheral and cerebellar tissues was significantly reduced.
The researchers found that the acetate level in the cerebellum of the mice increased significantly after half an hour after the alcohol was given.
However, this high level of acetate can be restored to normal levels in two cases.
The first is the effect of time.
One hour after alcohol administration, the acetate level of mice decreases to normal levels.
The second is the molecular effect of ALDH2: this increase disappeared after the specific knockout of ALDH2 in astrocytes, while the level of acetate still increased after specific knockout of ALDH2 in the liver.
These results indicate that ALDH2 derived from astrocytes in the central nervous system can regulate the level of alcohol metabolite acetate through the "invisible hand".
For a long time, it has been believed that acetate in the brain is mainly derived from alcohol metabolism in the liver, and acetate can enter the brain parenchyma through the blood-brain barrier.
However, the research in this article found that the central nervous system can directly regulate acetate.
Low-dose alcohol caused dyskinesia in mice.
Both female and male mice showed dyskinesia in the accelerated rotating rod experiment after giving low-dose alcohol or acetate.
But after specifically knocking out ALDH2 on astrocytes, there was no dyskinesia.
The researchers further injected the AAV5-GFAP-Cre virus into the cerebellar region of Aldh2 flox mice, using this viral strategy to specifically knock out ALDH2 on cerebellar astrocytes.
The mice did not show severe dyskinesia after giving low-dose alcohol.
Researchers found that acetate can significantly promote the synthesis of GABA.
In order to further determine whether the alcohol-induced sports injury is mediated by GABA, they injected GABA-A receptor antagonists or GABA-B receptor antagonists into the lateral ventricle of mice, which can significantly alleviate alcohol-induced motor incoordination.
This indicates that acetate mediates low-dose alcoholism through GABAergic signals.
In summary, this article reveals that ALDH2’s regulation of alcohol metabolite acetate has brain region (cerebellum) specificity and cell (astrocytic) specificity.
Acetate promotes the synthesis of GABA and GABA in the cerebellum.
The tonic inhibition causes symptoms of motor incoordination.
[References] 1.
https://doi.
org/10.
1038/s42255-021-00357-z The pictures in the article are all from the references
