Tetrahydrobiopterin modulates the behavioral neuroinflammatory response to an LPS challenge in mice

Vancassel S(1), Fanet H(2), Castanon N(3), Monchaux De Oliveira C(3), Cussotto S(3), Capuron L(3).

Author information:
(1)University of Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, Bordeaux,
France. Electronic address: .
(2)University of Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, Bordeaux,
France; OptiNutriBrain, International Associated Laboratory (NutriNeuro
France-INAF Canada), Quebec City, Canada.
(3)University of Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, Bordeaux,
France.

Tetrahydrobiopterin (BH4) is a necessary cofactor for the synthesis of
monoamines from essential amino-acids, phenylalanine, tyrosine and tryptophan.
The BH4 synthesis pathway is induced by inflammatory factors but highly
regulated processes maintain levels in a physiological range. However, BH4
activity can be durably altered in inflammation-related pathologies, such as
certain types of depression, potentially involving impairment of dopaminergic
neurotransmission. The purpose of this study was to investigate the response of
the brain BH4 pathway to the inflammatory stimulus induced by lipopolysaccharide
(LPS) in mice. Brain expression of genes related to BH4 synthesis, levels of
BH4, changes in L-aromatic amino acid precursors of monoamines and dopamine
levels were determined. As secondary aim, the effect of acute BH4 supply under
the inflammatory challenge was tested on these parameters and on the expression
of inflammatory cytokines. Mice were also submitted to the sucrose preference
test and to the open-field in order to asses hedonic and locomotor responses to
LPS, in addition to their modulation by BH4 supply. The LPS challenge resulted
in decreased striatal DA levels and increased Phenylalanine/Tyrosine ratio,
suggesting reduced BH4 activity. BH4 supply was effective to increase striatal
BH4 levels, to restore the LPS-induced decreased in DA levels in striatum and to
dampen the LPS-induced expression of inflammatory cytokines. At the behavioral
level, BH4 supply was able to restore the loss of locomotor response to
amphetamine in the LPS treated mice, suggesting a modulation of the dopaminergic
neurotransmission. These data suggest that BH4 can be considered as a potential
add-on molecule, helping to maintain or restore dopaminergic neurotransmission
in neuroinflammatory conditions..

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