Sitagliptin and liraglutide reversed nigrostriatal degeneration of rodent brain in rotenone-induced Parkinson’s disease

Abstract

The present study investigated the possible relationship between pro-inflammatory cytokines and programmed nigral neuronal death in rotenone model of Parkinson's disease (PD). Sitagliptin and liraglutide efficacy to inhibit the inflammatory-apoptotic degenerative process were investigated, too. The experimental PD were induced in male albino rats by ten subcutaneously injections of rotenone (3 mg/kg/day, s.c). All treatment drugs were administered for 16 days after induction of Parkinson rat's model. Sitagliptin and liraglutide were administered in three different dose levels (10-20-30 mg/kg, p.o), (25-50-100 μg/kg, s.c), respectively. Cylindrical and catalepsy tests were used to detect the optimum dose response of each drug. Sitagliptin (30 mg/kg/day, p.o) and liraglutide (50 μg/kg, s.c.) showed statistically significant (p ≤ 0.05) effect on behavioral activity. Where both doses improved the motor performance significantly in comparison with other doses in both cylindrical and catalepsy tests. Furthermore, they reversed rotenone-induced nigral neuronal loss, associated with marked decrease of pro-inflammatory cytokines: interleukin (IL)-1β, IL-6, transforming growth factor (TGF)-β1, together with a significant increase of striatal dopamine, nigral glial cell line-derived neurotrophic factor (GDNF), and tyrosine hydroxylase positive (TH+) cells. Moreover, the pro-apoptotic environment in nigrostriatal tissues was abrogated significantly, as the pro-apoptotic protein Bax decreased along with the anti-apoptotic protein Bcl-2 increased. In conclusion, sitagliptin and liraglutide represent a promising strategy to mitigate the progression of PD by their anti-inflammatory, anti-apoptotic neurotrophic and neurogenic mechanistic activities.

Liraglutide improves cognitive impairment via the AMPK and PI3K/Akt signaling pathways in type 2 diabetic rats

“…Under certain circumstances, autophagy is a stress adaptation that inhibits apoptosis and prevents cell death; however, in other cellular settings it constitutes another pathway of cell death. The results of the present study demonstrated that a low dose of liraglutide may be sufficient to reduce the expression of caspase-3 and Bax, and to increase the expression of Bcl-2, thus resulting in the reduction of apoptosis, which is similar to the results of a previous study by Badawi et al (39). According to the results of the present study, administration of liraglutide may activate autophagy while suppressing apoptosis.…”

The novel protective effects of loganin against 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity: Enhancement of neurotrophic signaling, activation of IGF‐1R/GLP‐1R, and inhibition of RhoA/ROCK pathway

“…For example, exendin-4, a GLP-1 agonist, attenuated dopaminergic neuronal loss in MPTPinduced mouse model of PD by attenuating inflammatory and oxidative insults (Kim et al, 2009). Another GLP-1 agonist, liraglutide, a drug that is on the market as a treatment for type 2 diabetes, reversed nigrostriatal degeneration through anti-inflammatory, antiapoptotic, and neurotrophic mechanistic activities in PD-like rats induced by rotenone (Badawi, Abd El Fattah, Zaki, & El Sayed, 2017). Moreover, intrathecal injection of loganin in rats has been reported to attenuate formalin-induced tonic pain in an Ex9-39-reverse manner, suggesting the activation of spinal GLP-1R involved in the antinociceptive effects of loganin (Gong, Fan, Ma, Xiao, & Wang, 2014).…”

Drug Repurposing in Parkinson’s Disease

“…Lixisenatide (an incretin mimetic like exenatide, based on the structure of exendin-4) and liraglutide, dulaglutide and albiglutide (based on the structure of human GLP-1 and termed GLP-1 analogues). In PD models, data exists for liraglutide and lixisenatide which have similarly demonstrated neuroprotective effects in animal-toxin models of PD, preventing MPTP-, 6-OHDA-and rotenone-induced dopaminergic cell loss and motor impairments which were associated with reduction in pro-apoptotic signalling,pro-inflammatory cytokine production and promotion of neurotophic factors such as GDNF[129][130][131][132].…”