Title:Tetrahydrobioterin (BH4) Pathway: From Metabolism to Neuropsychiatry
Volume: 19
Issue: 5
Author(s): H. Fanet, L. Capuron, N. Castanon, F. Calon and S. Vancassel*
Affiliation:
- INRAe, Nutrition and Integrated Neurobiology, UMR 1286, Bordeaux,France
Keywords:
tetrahydrobiopterin (BH4), guanosine-triphosphate-cyclohydrolase-1 (GCH1), cofactor, monoamines, depression,
Alzhemier, Parkinson.
Abstract: Tetrahydrobipterin (BH4) is a pivotal enzymatic cofactor required for the synthesis of
serotonin, dopamine and nitric oxide. BH4 is essential for numerous physiological processes at periphery
and central levels, such as vascularization, inflammation, glucose homeostasis, regulation
of oxidative stress and neurotransmission. BH4 de novo synthesis involves the sequential activation
of three enzymes, the major controlling point being GTP cyclohydrolase I (GCH1). Complementary
salvage and recycling pathways ensure that BH4 levels are tightly kept within a physiological
range in the body. Even if the way of transport of BH4 and its ability to enter the brain after peripheral
administration is still controversial, data showed increased levels in the brain after BH4
treatment. Available evidence shows that GCH1 expression and BH4 synthesis are stimulated by
immunological factors, notably pro-inflammatory cytokines. Once produced, BH4 can act as an anti-
inflammatory molecule and scavenger of free radicals protecting against oxidative stress. At the
same time, BH4 is prone to autoxidation, leading to the release of superoxide radicals contributing
to inflammatory processes, and to the production of BH2, an inactive form of BH4, reducing its
bioavailability. Alterations in BH4 levels have been documented in many pathological situations,
including Alzheimer's disease, Parkinson's disease and depression, in which increased oxidative
stress, inflammation and alterations in monoaminergic function are described. This review aims at
providing an update of the knowledge about metabolism and the role of BH4 in brain function,
from preclinical to clinical studies, addressing some therapeutic implications.