Parkinson's disease (PD) is a chronic
neurodegenerative disease, and there is no cure for it at present. Recent research has indicated a link between
type 2 diabetes mellitus (T2DM) and PD, which suggested that a treatment to improve
insulin resistance for T2DM may be useful for PD patients.
Glucose-dependent insulinotropic
polypeptide (GIP) belongs to the
incretin hormone family, which can promote
insulin release and improve
insulin resistance. Several GIP analogues have been developed as potential treatments for T2DM. In the present study, a novel long-lasting GIP analogue,
D-Ala2-GIP-glu-PAL, has been tested in an acute PD mouse model induced by four
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP)
intraperitoneal injections.
D-Ala2-GIP-glu-PAL treatment (25 nmol/kg ip.) for 7 days after
MPTP treatment improved the locomotor and exploratory activity of mice, and improved
bradykinesia and movement balance of mice.
D-Ala2-GIP-glu-PAL treatment also restored
tyrosine hydroxylase (TH) positive dopaminergic neuron numbers in the substantia nigra and TH levels in the striatum.
D-Ala2-GIP-glu-PAL also reduced the chronic
inflammation response as seen in astrocyte and microglia activation in the substantia nigra pars compacta (SNpc).
D-Ala2-GIP-glu-PAL reversed the reduction of synapse numbers (
synaptophysin levels), decreased the ratio of
growth factor and apoptosis signaling molecules Bax/Bcl-2, and improved the decrease of p-CREB(S133)
growth factor signaling in the substantia nigra. Therefore,
D-Ala2-GIP-glu-PAL promotes cell survival of dopaminergic neuron in the SNpc by activating the cAMP/PKA/CREB
growth factor second messenger pathway that also inhibits apoptosis. The present results demonstrate that
D-Ala2-GIP-glu-PAL shows promise as a novel treatment of PD.