Pramipexole inhibits astrocytic NLRP3 inflammasome activation via Drd3-dependent autophagy in a mouse model of Parkinson’s disease

Abstract

Inflammation is one of the pathogenic processes in Parkinson’s disease (PD). Dopamine receptor agonist pramipexole (PPX) is extensively used for PD treatment in clinics. A number of studies show that PPX exerts neuroprotection on dopaminergic (DA) neurons, but the molecular mechanisms underlying the protective effects of PPX on DA neurons are not fully elucidated. In the present study, we investigated whether PPX modulated PD-related neuroinflammation and underlying mechanisms. PD model was established in mice by bilateral striatum injection of lipopolyssaccharide (LPS). The mice were administered PPX (0.5 mg·kg−1·d−1, i.p.) 3 days before LPS injection, and for 3 or 21 days after surgery, respectively, for biochemical and histological analyses. We showed that PPX administration significantly alleviated the loss of DA neurons, and suppressed the astrocyte activation and levels of proinflammatory cytokine IL-1β in the substantia nigra of LPS-injected mice. Furthermore, PPX administration significantly decreased the expression of NLRP3 inflammasome-associated proteins, i.e., cleaved forms of caspase-1, IL-1β, and apoptosis-associated speck-like protein containing a caspase recruit domain (ASC) in the striatum. These results were validated in LPS+ATP-stimulated primary mouse astrocytes in vitro. Remarkably, we showed that PPX (100–400 μM) dose-dependently enhanced the autophagy activity in the astrocytes evidenced by the elevations in LC3-II and BECN1 protein expression, as well as the increase of GFP-LC3 puncta formation. The opposite effects of PPX on astrocytic NLRP3 inflammasome and autophagy were eliminated by Drd3 depletion. Moreover, we demonstrated that both pretreatment of astrocytes with autophagy inhibitor chloroquine (40 μM) in vitro and astrocyte-specific Atg5 knockdown in vivo blocked PPX-caused inhibition on NLRP3 inflammasome and protection against DA neuron damage. Altogether, this study demonstrates an anti-neuroinflammatory activity of PPX via a Drd3-dependent enhancement of autophagy activity in astrocytes, and reveals a new mechanism for the beneficial effect of PPX in PD therapy.

BAG3 promotes autophagy and suppresses NLRP3 inflammasome activation in Parkinson’s disease

“…The regulatory effect of autophagy on inflammation is a recent discovery. Enhancing autophagy in an inflammatory environment can significantly inhibit inflammation and protect dopaminergic neurons in PD ( 16 , 39 , 40 ). Based on one of our previous studies and the important role of BAG3 in autophagy ( 10 ), we hypothesized that BAG3 regulates PD pathology by regulating autophagy in PD-related inflammation and validates the specific molecular mechanism.…”

“…Mice in groups I and III received an equal volume of negative AAV. We used previously reported methods to build a LPS-induced PD model ( 16 ). Three weeks later, mice in groups III and IV were treated with LPS (5 µg dissolved in 1 µL saline) in the bilateral striatum (1 µL/site, respectively) by stereotaxic injection according to the coordinates at (I) AP +1.18 mm, ML ±1.5 mm, DV −3.5 mm; (II) AP −0.34 mm, ML ±2.5 mm, and DV −3.2 mm from bregma.…”

“…To explore the effect of BAG3 on neuroinflammation and dopaminergic neuronal damage in a PD model, we used According to our previous study, the expression level of inflammation was highest at 3 days after LPS injection and the loss of dopaminergic neurons in substantia nigra was higher after 21 days (16). Therefore, we detected expression of inflammatory cytokines after 3 days after LPS injection, and expression of TH and Iba1 in the substantia nigra and striatum after 21 days (Figure 4A).…”

“…It is suggested that the increase of NLRP3 inflammasome is a key part of neuroinflammation induced by microglia. We have reported that pramipexole suppresses neuroinflammation in PD models through Drd3-dependent autophagy ( 16 ), which prompted us to explore whether BAG3 could modulate PD-related neuroinflammation through autophagy.…”

Polyvinylpyrrolidone-Capped Copper Oxide Nanoparticles-Anchored Pramipexole Attenuates the Rotenone-Induced Phenotypes in a Drosophila Parkinson’s Disease Model

“…The condition is characterized by decreased level of dopamine (DA) due to the progressive degeneration of the dopaminergic neurons in the substantia nigra pars compacta of the midbrain . It leads to motor symptoms, such as bradykinesia, akinesia, muscle stiffness, and difficulty in walking and coordination, and nonmotor symptoms like autonomic dysfunction, hyposmia, rapid eye moment, sleep behaviors, and cognitive changes. , The neuropathological hallmark of PD is the accumulation and aggregation of the overexpressed α-synuclein protein in striatal neurons called Lewy bodies, and they are responsible for the degeneration of dopaminergic neurons . Increased oxidative stress is indeed considered to be involved in the death of nigral cells .…”