No clue if this would help in stroke. Go ask your doctor.
Enhancement of the liver’s neuroprotective role ameliorates traumatic brain injury pathology
Contributed
by Bruce D. Hammock; received January 26, 2023; accepted May 19, 2023;
reviewed by Fernando Gomez-Pinilla, Andrew A. Pieper, and Naomi Sayre
Significance
To
date, no effective treatments are available for traumatic brain injury
(TBI). Here, we identified the neuroprotective role of the liver in TBI.
Hepatic sEH (soluble epoxide hydrolase) activity was specifically
altered following TBI and negatively correlated with the plasma levels
of 14,15-EET (-epoxyeicosatrienoic acid). Hepatic sEH manipulation
bidirectionally modulated TBI-induced neurological deficits by
regulating the generation of A2 phenotype astrocytes. Peripheral
14,15-EET rapidly crossed the blood–brain barrier. Moreover, 14,15-EET
mimicked the neuroprotective effects of hepatic Ephx2 deletion,
whereas 14,15-epoxyeicosa-5(Z)-enoic acid blocked the neuroprotective
effects of hepatic sEH ablation following TBI. These results highlight
the neuroprotective role of the liver in TBI and suggest that targeting
this neuroprotective role may represent a promising therapeutic strategy
for TBI.
Abstract
Traumatic
brain injury (TBI) is a pervasive problem worldwide for which no
effective treatment is currently available. Although most studies have
focused on the pathology of the injured brain, we have noted that the
liver plays an important role in TBI. Using two mouse models of TBI, we
found that the enzymatic activity of hepatic soluble epoxide hydrolase
(sEH) was rapidly decreased and then returned to normal levels following
TBI, whereas such changes were not observed in the kidney, heart,
spleen, or lung. Interestingly, genetic downregulation of hepatic Ephx2
(which encodes sEH) ameliorates TBI-induced neurological deficits and
promotes neurological function recovery, whereas overexpression of
hepatic sEH exacerbates TBI-associated neurological impairments.
Furthermore, hepatic sEH ablation was found to promote the generation of
A2 phenotype astrocytes and facilitate the production of various
neuroprotective factors associated with astrocytes following TBI. We
also observed an inverted V-shaped alteration in the plasma levels of
four EET (epoxyeicosatrienoic acid) isoforms (5,6-, 8,9-,11,12-, and
14,15-EET) following TBI which were negatively correlated with hepatic
sEH activity. However, hepatic sEH manipulation bidirectionally
regulates the plasma levels of 14,15-EET, which rapidly crosses the
blood–brain barrier. Additionally, we found that the application of
14,15-EET mimicked the neuroprotective effect of hepatic sEH ablation,
while 14,15-epoxyeicosa-5(Z)-enoic acid blocked this effect, indicating
that the increased plasma levels of 14,15-EET mediated the
neuroprotective effect observed after hepatic sEH ablation. These
results highlight the neuroprotective role of the liver in TBI and
suggest that targeting hepatic EET signaling could represent a promising
therapeutic strategy for treating TBI.
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