Antihistamines and similar drugs could slow down Huntington's disease


Date:
June 9, 2020
Source:
eLife
Summary:
Scientists have described a potential new therapeutic strategy
for slowing down early-stage Huntington's disease.



FULL STORY ========================================================================== Scientists have described a potential new therapeutic strategy for
slowing down early-stage Huntington's disease in a new study published
today in eLife.


==========================================================================
The research in mice indicates that targeting the histamine H3 receptor
(H3R) - - a well-established drug target for other conditions such as
hay fever - - could help to prevent imbalances in dopamine signalling
that lead to brain- cell death and deficits in movement and memory.

"It was already well known that dopamine signalling goes away in
Huntington's disease, but we and other research teams have shown more
recently that dopamine receptors and histamine receptors are found
together and control signalling in the brain," explains lead author
David Moreno-Delgado, who was a Postdoctoral Research Scientist at the University of Barcelona, Spain, at the time the research was carried out,
and is now Biology Team Leader at NovAliX, Belgium.

"Because dopamine receptors are found in many normal cells throughout the central nervous system, we proposed that targeting dopamine signalling
through the histamine receptor might be a more effective strategy to slow
the progression of Huntington's disease." The team looked at whether
these protein partners are found together in mice with Huntington's
disease and could potentially be targets for treatment. They found that
at two- and four-months-old, both healthy mice and those with asymptomatic Huntington's disease have the dopamine D1 receptor (D1R)-H3R complex. But
when the team looked at older mice aged six- and eight-months-old, the
mice with Huntington's disease (now symptomatic) had completely lost
the D1R-H3R complexes. The individual receptors were still present,
but at the most advanced stage of the disease, these proteins were no
longer acting together as partners.

To confirm the role of the D1R-H3R complex, the team tested the effects
of an antihistamine drug called thioperamide on movement, learning and
memory in mice with Huntington's disease. Mice treated with thioperamide
were only as likely to fall as healthy mice of the same age, while those treated with saline were unable to maintain their balance. Moreover,
in a test of memory, the mice treated with saline showed no preference
for familiar objects, whereas those treated with thioperamide had no
such memory deficits.

The team next explored whether these results were due to the treatment preserving the D1R-H3R complexes. Studies of tissues from treated and
untreated mice showed that only the treated animals still had H3R/D1R
complexes at six and eight months of age. Moreover, when they treated mice
with Huntington's disease that had already reached seven months of age
(when these protein partners are no longer found together), thioperamide
had no effect on movement, learning or memory deficits. This confirms
that the protective effects of thioperamide occurs through the D1R-H3R complexes and that these need to be present for the drug to work.

Finally, the team looked at human brain tissue samples for the presence
of D1R- H3R complexes. They found that, in healthy individuals and
people with early- stage Huntington's disease, the D1R-H3R complexes
were present. By contrast, in people with more advanced disease, the
D1R-H3R complexes were almost absent.

"The imbalance of dopamine signalling in disease progression represents
a potential 'point of no return' for Huntington's disease patients as
it can eventually lead to nerve-cell dysfunction and death," explains
senior author Peter McCormick, Senior Lecturer at Queen Mary University of London, UK. "In this study we show that D1R/H3R complexes are found within
the brain at early- but not late-disease stages and that targeting these complexes could potentially slow the progression of early-stage disease.

"In addition, our data help explain previous studies attempting to target
H3R by showing the dependency on D1R/H3R complexes for these drugs to
work. This is important as there are multiple H3R compounds either in
the clinic or that have been through phase two and three trials that
could be opportunities for drug repurposing."

========================================================================== Story Source: Materials provided by eLife. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. David Moreno-Delgado, Mar Puigdelli'vol, Estefani'a Moreno, Mar
Rodri'guez-Ruiz, Joaqui'n Botta, Paola Gasperini, Anna Chiarlone,
Lesley A Howell, Marco Scarselli, Vicent Casado', Antoni Corte's,
Sergi Ferre', Manuel Guzma'n, Carmen Llui's, Jordi Alberch, Enric I
Canela, Silvia Gine's, Peter J McCormick. Modulation of dopamine D1
receptors via histamine H3 receptors is a novel therapeutic target
for Huntington's disease. eLife, 2020; 9 DOI: 10.7554/eLife.51093 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200609122920.htm

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