0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

PFIZER.2 – Effects of the phosphodiesterase type X (PDE10) inhibitor on R6/2 mouse model of HD
The results of our studies with rolipram provide strong theoretical support
for the strategy of targeting CREB signaling to promote striatal and cortical
neuron survival in HD. However, these studies do not provide a direct path
to a therapy since there are no PDE4 inhibitors currently available for clinical
use, as these agents suffer from severe side effect liabilities. Thus, we have
turned to the investigation of another phosphodiesterase, PDE10A, which
may be a particularly promising target as a potential treatment for HD [Chappie
et al. 2009; Giampà et al. 2009]. PDE10A is highly expressed in the striatal
medium spiny neurons [Seeger et al. 2003; Coskran et al. 2006; Xie et al.
2006] vulnerable in HD, where it regulates both cAMP and cGMP signaling
cascades [Siuciak et al. 2006a; Siuciak et al. 2006b]. Notably, inhibition of
PDE10A with the highly specific inhibitor TP-10 results in a significant
increased in CREB phosphorylation in striatum [Schmidt et al. 2008]. A
recent study published by our group showed that TP-10 treatment in our rat
QA model resulted in a significant sparing of striatal neurons, on one hand,
and a parallel increase in activated CREB, on the other [Giampà et al. 2009].
Significantly, TP-10 treatment also produced a significant sparing of cortical
neurons in this model, either as a result of a primary neuroprotective effect on
striatal neurons or, possibly, by a more direct effect (see further discussion
below). These encouraging results lead us to continue our research by testing
whether the same neuroprotective effects could be achieved by TP-10 in the
well-established transgenic mouse model of HD, namely, Bates’ R6/2 mice
[Mangiarini et al. 1996].
EFFECT OF TP-10 TREATMENT ON THE R6/2 MICE:
RESULTS TO DATE
R6/2 mice and wild type littermate controls were treated daily with vehicle
or TP-10 beginning at 4 weeks of age through study termination. In the
R6/2 animals, TP-10 treatment increased survival time by approximately 10%.
However, the more significant finding is that TP-10 treatment almost completely
ameliorated the development of neurological deficits in the R6/2 mice
prior to death. Specifically, at 12 weeks of age, when R6/2 mice treated with
vehicle were fully symptomatic, R6/2 mice treated with TP-10 displayed
almost no hind paw clasping during tail suspension, no deficit in rotarod performance,
and no decrease in locomotor activity in an open field. This effect
of TP-10 treatment on neurological function was reflected in a significant
amelioration in brain pathology in the R6/2 mice. TP-10 treatment largely prevented
the gross decrease in brain volume, and the dramatic reduction in striatal
cell number and cell size that was characteristically observed in the vehicle
treated R6/2 animals. TP-10 treatment also significantly reduced the
degree of microglial activation that occurs in response to the mutant huntingtin-induced
brain damage.
In summary, results to date indicate that TP-10 treatment has a dramatic
therapeutic effect to prevent the loss of function caused by the Huntington’s
mutation in the R6/2 mice. In this grant renewal, we continue this investigation
with four Specific Aims. These are:
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