0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

TEL.14 – Manipulation of serotonin transmission on behavioural and neurochemical deficits…
opportunity to evaluate the role of serotonin on PHE-dependent cognitive
deficits.
Moreover, accumulated evidences indicate that even mildly elevated
blood PHE levels promote cognitive deficits involving the pFC. Indeed,
frontal/executive skills, (working memory, abstract reasoning, problem solving,
planning ability, sustained attention, inhibitory control, mental flexibility)
appear to be deficient in early-treated PKU [Diamond et al. 1997; Huijbregts
et al. 2002; Leuzzi et al. 2004; Smith et al. 2000; White et al. 2002], and in
early-treated adolescents deficits in pFC-dependent functions appear to correlate
with current blood PHE concentrations [Diamond 1994; Schmidt et al.
1994; Weglage et al. 1996; Welsh et al. 1990]. These data support the hypothesis
that the hyperphenylalaninemic condition has negative effects beyond
development, and suggest a direct interference of excess PHE on pFC functioning.
Fronto-cortical functioning is highly dependent on aminergic transmission.
Indeed, the pFC is innervated by dopaminergic, norepinephrinergic,
and serotoninergic afferents. Identification of mechanisms by which PHE
interferes with cortical aminergic systems could allow to identify complementary
therapies aimed to re-enable amine-dependent cognitive functions. There
is considerable evidence for a critical role of dopamine (DA) in working memory.
Therefore, it has been proposed that a deficient frontocortical DA transmission
is responsible for cognitive deficits in adult and adolescent earlytreated
PKU subjects [Diamond 1997]. Nevertheless, 5-HT is also widely distributed
throughout the pFC and act to modulate different types of pFCdependent
functions. Therefore, HPA-dependent cognitive disturbances might
involve fronto-cortical 5-HT transmission. PHE excess could interfere with 5-
HT metabolism by reducing brain availability of its amino acid precursor:
tryptophan. Indeed, one influent hypothesis suggests that in HPA brain, PHE
excess saturates brain-blood barrier carriers interfering with the access of
other amino acid to the brain [Pietz et al. 1999]. This hypothesis supports lifelong
dietary supplementation with tryptophan [Koch et al. 2003]. However,
previous data [Pascucci et al. 2002; 2008] do not show evidences of reduced
tryptophan availability in the HPA brain. Excess PHE can also interfere with
amine synthesis by inhibiting hydroxylase activity [Curtius et al.1981; Ogawa
and Ichinose 2006]. Such mechanism would reduce availability of 5-hydroxytryptophan
(5-HTP), the main rate limiting factor in 5-HT synthesis. The
demonstration of the second mechanism would, instead, support therapeutic
use of hydroxylated aminergic precursor, 5-HTP.
In this project, therapeutic effects of 5-HTP supplement will be evaluate
in two different sets of experiments: 1) in classical PKU, to investigate the use
of 5-HTP as alternative therapy to standard low-PHE diet; 2) in HPA, to investigate
5-HTP as support in different forms of HPA.
OVERALL OBJECTIVES
Overall objective of this project is the preclinical investigation of effects of
serotonin supply (by 5-hydroxytryptophan supplement) on cognitive functions
in phenylketonuria and mild hypeprhenylalaninemia.
2009 785