Neuroprotection of Exendin-4 by Enhanced Autophagy in a Parkinsonian Rat Model of α-Synucleinopathy

Abstract

Glucagon-like peptide-1 (GLP-1) receptor stimulation ameliorates parkinsonian motor and non-motor deficits in both experimental animals and patients; however, the disease-modifying mechanisms of GLP-1 receptor activation have remained unknown. The present study investigated whether exendin-4 (a GLP-1 analogue) can rescue motor deficits and exert disease-modifying effects in a parkinsonian rat model of α-synucleinopathy. This model was established by unilaterally injecting AAV-9-A53T-α-synuclein into the right substantia nigra pars compacta, followed by 4 or 8 weeks of twice-daily intraperitoneal injections of exendin-4 (5 μg/kg/day) starting at 2 weeks after AAV-9-A53T-α-synuclein injections. Positron emission tomography/computed tomography (PET/CT) scanning and immunostaining established that treatment with exendin-4 attenuated tyrosine-hydroxylase-positive neuronal loss and terminal denervation and mitigated the decrease in expression of vesicular monoamine transporter 2 within the nigrostriatal dopaminergic systems of rats injected with AAV-9-A53T-α-synuclein. It also mitigated the parkinsonian motor deficits assessed in behavioral tests. Furthermore, through both in vivo and in vitro models of Parkinson's disease, we showed that exendin-4 promoted autophagy and mediated degradation of pathological α-synuclein, the effects of which were counteracted by 3-methyladenine or chloroquine, the autophagic inhibitors. Additionally, exendin-4 attenuated dysregulation of the PI3K/Akt/mTOR pathway in rats injected with AAV-9-A53T-α-synuclein. Taken together, our results demonstrate that exendin-4 treatment relieved behavioral deficits, dopaminergic degeneration, and pathological α-synuclein aggregation in a parkinsonian rat model of α-synucleinopathy and that these effects were mediated by enhanced autophagy via inhibiting the PI3K/Akt/mTOR pathway. In light of the safety and tolerance of exendin-4 administration, our results suggest that exendin-4 may represent a promising disease-modifying treatment for Parkinson's disease.

Exendin-4 stimulates autophagy in pancreatic β-cells via the RAPGEF/EPAC-Ca2+-PPP3/calcineurin-TFEB axis

“…Importantly, we provide confirmation that these pathways are conserved in adult human islets, supporting novel therapeutic approaches targeting this pathway to preserve a functional pancreatic β-cell mass in T2D. Given the accumulating evidence supporting the application of GLP1R agonists for the treatment of other disease states, including other metabolic diseases and numerous neurological disorders [ 64 ] via mechanisms involving autophagy [ 61 , 65 , 66 ], these findings could have implications beyond the treatment of T2D.…”

“…pathways are conserved in adult human islets, supporting novel therapeutic approaches targeting this pathway to preserve a functional pancreatic β-cell mass in T2D. Given the accumulating evidence supporting the application of GLP1R agonists for the treatment of other disease states, including other metabolic diseases and numerous neurological disorders [64] via mechanisms involving autophagy [61,65,66], these findings could have implications beyond the treatment of T2D. Statistical analysis was performed using a two-way ANOVA followed by Bonferroni's post-hoc test *P < 0.05, **P < 0.01, ***P < 0.005 effect of GLT; ^P < 0.05, ^^P < 0.01, ^^^P < 0.005 effect of overexpression.…”

L-dopa-Dependent Effects of GLP-1R Agonists on the Survival of Dopaminergic Cells Transplanted into a Rat Model of Parkinson Disease

“…The 6-OHDA lesioned rat does not replicate all the features of Parkinson's disease, and the neuroprotective effects of GLP-1R agonists may not be as evident in α-synuclein based models of PD. Some studies show a neuroprotective effect similar to that shown in the 6-OHDA lesioned rat [29,66,67] whilst others illustrate an increase in α-synuclein accumulation which could promote its toxic effects in some regions of the brain [68]. Post mortem studies have demonstrated a relatively slow accumulation of α-synuclein in grafted cells [69,70] and whilst this is not currently thought to lead to major issues with graft function, it would be prudent to verify effectiveness of GLP-1R agonists in this scenario.…”

Dexmedetomidine alleviates early brain injury following traumatic brain injury by inhibiting autophagy and neuroinflammation through the ROS/Nrf2 signaling pathway

“…As shown in the study by Zhao et al ( 25 ), DEX increases autophagy, decreases reactive oxygen species (ROS) production and apoptosis and then eliminates damaged mitochondria in a lipopolysaccharide-induced acute kidney injury model through the PI3K/AKT/mTOR pathway. The AKT/mTOR signaling pathway is generally acknowledged as the most important regulatory pathway in autophagy ( 26 , 27 ). ROS regulate the NFE2L2 (nuclear factor, erythroid derived 2, like 2) pathway, transcriptionally activates hypoxia-inducible factor (HIF-1) and p53 and then promotes autophagy ( 28 , 29 ).…”