Upregulation of the PI3K/AKT and Nrf2 Pathways by the DPP‑4 Inhibitor Sitagliptin Renders Neuroprotection in Chemically Induced Parkinson’s Disease Mouse Models

Parkinson’s
disease (PD) is one of the most common
progressive
neurodegenerative pathologies that leads to dopaminergic deficiency
and motor manifestations. Alpha-synuclein aggregation is a characteristic
hallmark of PD pathogenesis. These aggregates facilitate the formation
of Lewy bodies and degeneration. The epidemiological evidence demonstrates
a definitive association of diabetes with PD risk. Considering this,
many antidiabetic agents such as GLP-1 agonists and DPP-4 inhibitors
are being explored as alternative PD therapeutics. This study evaluated
the neuroprotective effect of the DPP-4 inhibitor sitagliptin mediated
by the PI3K/AKT and Nrf2 pathways in PD models. In silico studies were conducted to determine the binding affinity, stability,
and ADMET properties of DPP-4 inhibitors with target proteins. Sitagliptin
(15 mg/kg p.o.) was administered in rotenone (30 mg/kg p.o. for 28
days)-induced and MPTP/P (25 mg/kg i.p. MPTP and 100 mg/kg probenecid
i.p. twice a week for 5 weeks)-induced PD mouse (C57/BL6) models.
Neurobehavioral assessments were carried out throughout the study.
Biochemical (GSH, MDA), molecular estimations (AKT, Nrf2, PI3K, GSK-3β,
GLP1, CREB, BDNF, NF-κB, alpha-synuclein), histopathological
studies, and immunohistochemistry were carried out at the end of the
study. The in silico studies demonstrate better binding,
stability, and ADMET profile of sitagliptin with both target proteins.
Sitagliptin restored cognitive and motor deficits in both rotenone-
and MPTP/P-induced mouse models. There was upregulation of PI3K, AKT,
Nrf2, CREB, and BDNF levels and downregulation of GSK-3β, NF-κB,
and alpha-synuclein levels in both models after treatment with sitagliptin.
However, GLP1 levels were not significantly restored, indicating a
GLP1-independent mechanism. It also restored histopathological alterations
and TH+ neuronal loss induced by rotenone and MPTP/P. These findings
demonstrate that sitagliptin exhibits neuroprotective action mediated
by upregulation of the PI3K/AKT and Nrf2 pathways in rotenone and
MPTP/P mouse models of PD.