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Altered glial-neuronal crosstalk: cornerstone in the pathogenesis of hepatic encephalopathy
Butterworth RF.. Neurochemistry international, 2010-03-27
Topic: Brain proteins, microglia and lab models
Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of liver failure, characterized neuropathologically by astrocyte swelling, microglial activation and Alzheimer Type II astrocytosis. Molecular studies in HE brain reveal altered expression of genes coding for key astroglial proteins including early losses of expression of GFAP and the glutamate transporter EEAT-2 with concomitant increases of the astrocytic/microglial mitochondrial benzodiazepine receptor (MBR). Decreased expression of EAAT-2 results in decreased glutamate transport and impaired cycling of glutamate-glutamine between astrocytes and neurons, as well as increased extracellular glutamate, activation of the NMDA receptor-mediated cGMP-NO signal transduction pathway, and nitration of tyrosine residues on key astroglial proteins such as glutamine synthetase (GS) and the MBR. GS is uniquely responsible for the removal of excess ammonia in brain. Ammonia-induced activation of MBR in astrocytes and/or microglia results in stimulation of the synthesis of neurosteroids such as allopregnanolone with positive allosteric GABA-A receptor neuromodulatory properties. Allopregnanolone concentrations are increased up to 7-fold in HE brain. Attenuation of microglial activation by minocycline results in a delay in onset of HE and prevents brain edema in liver failure. Mild hypothermia is likewise beneficial in acute liver failure resulting in normalization of extracellular brain glutamate and prevention of oxidative/nitrosative stress in experimental animals with HE resulting from either ischemic or toxic liver injuries.
Key findings
- Decreased expression of EAAT-2 results in decreased glutamate transport and impaired cycling of glutamate-glutamine between astrocytes and neurons, as well as increased extracellular glutamate, activation of the NMDA receptor-mediated cGMP-NO signal transduction pathway, and nitration of tyrosine residues on key astroglial proteins such as glutamine synthetase (GS) and the MBR.
- Ammonia-induced activation of MBR in astrocytes and/or microglia results in stimulation of the synthesis of neurosteroids such as allopregnanolone with positive allosteric GABA-A receptor neuromodulatory properties.
- Attenuation of microglial activation by minocycline results in a delay in onset of HE and prevents brain edema in liver failure.
Why it matters
This review describes altered astrocyte and microglia gene expression, glutamate handling and neurosteroid changes in hepatic encephalopathy brain. It is about liver failure-related brain changes and does not report a treatment, cure or prevention for Alzheimer's disease.
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Study details
- Evidence strengthLow
How this study scored 38/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Neurochemistry international) |
| Journal's citation record | 2 / 4 | Neurochemistry International: journal h-index 170 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2010 — within 20 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 4 / 7 | Cited 74 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 4.1 citations a year over 18 year(s) since 2010 |
| Impact for its field and year | 3 / 6 | Cited 4.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 5 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Roger F. Butterworth: h-index 81 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Université de Montréal: institution h-index 1,020 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 20350577) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 38 / 100 | — |
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May need a subscription Unpaywall, Europe PMC and OpenAlex found no free copy of the full text (checked 10 Oct 2026), so the publisher may charge for it. The PubMed abstract is free.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Butterworth, R. F. (2010). Altered glial-neuronal crosstalk: cornerstone in the pathogenesis of hepatic encephalopathy. Neurochemistry international. https://doi.org/10.1016/j.neuint.2010.03.012
Vancouver
Butterworth RF. Altered glial-neuronal crosstalk: cornerstone in the pathogenesis of hepatic encephalopathy. Neurochemistry international. 2010. doi:10.1016/j.neuint.2010.03.012. PMID: 20350577.
BibTeX
@article{butterworth2010-20350577,
author = {Butterworth, R. F.},
title = {{Altered glial-neuronal crosstalk: cornerstone in the pathogenesis of hepatic encephalopathy}},
journal = {Neurochemistry international},
year = {2010},
doi = {10.1016/j.neuint.2010.03.012},
pmid = {20350577},
url = {https://doi.org/10.1016/j.neuint.2010.03.012}
}
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