Abstract
The oral antidiabetic drug metformin is known to exhibit anti-inflammatory properties through activation of AMP kinase, thus protecting various brain tissues as cortical neurons, for example. However, the effect of metformin on the substantia nigra (SN), the main structure affected in Parkinson’s disease (PD), has not yet been studied in depth. Inflammation is a key feature of PD and it may play a central role in the neurodegeneration that takes place in this disorder. The aim of this work was to determine the effect of metformin on the microglial activation of the SN of rats using the animal model of PD based on the injection of the pro-inflammogen lipopolysaccharide (LPS). In vivo and in vitro experiments were conducted to study the activation of microglia at both the cellular and molecular levels. Our results indicate that metformin overall inhibits microglia activation measured by OX-6 (MHCII marker), IKKβ (pro-inflammatory marker) and arginase (anti-inflammatory marker) immunoreactivity. In addition, qPCR experiments reveal that metformin treatment minimizes the expression levels of several pro- and anti-inflammatory cytokines. Mechanistically, the drug decreases the phosphorylated forms of mitogen-activated protein kinases (MAPKs) as well as ROS generation through the inhibition of the NADPH oxidase enzyme. However, metformin treatment fails to protect the dopaminergic neurons of SN in response to intranigral LPS. These findings suggest that metformin could have both beneficial and harmful pharmacological effects and raise the question about the potential use of metformin for the prevention and treatment of PD.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder featuring the loss of the dopaminergic neurons in the substantia nigra (SN) and Lewy pathology, with a resultant alteration of the motor function that produces the loss of autonomy; cognitive function and mood are impaired (Marinus et al, 2018; Odin et al, 2018; Sojitra et al, 2018)
More compelling evidence supporting the involvement of neuroinflammation in PD pathogenesis relies on genome-wide association studies, which have found a genetic association with PD susceptibility in the human leukocyte antigen region (Nalls et al, 2014) and other polymorphisms related to the immune system including tumor necrosis factor (TNF), TNFR1, IL-1β, triggering receptor expressed on myeloid cells 2, IL-1 receptor antagonist and CD14 (Hirsch and Hunot, 2009; Rayaprolu et al, 2013)
We have evaluated the effect of metformin on microglia polarization, inflammasome activation, free radical production and main immune checkpoints, including CX3CL1/CX3CR1R and CD200/CD200R in response to LPS, FIGURE 5 | Effect of metformin and LPS on the expression of TNF-α (A), IL-1β (B), IL-6 (C), induced mRNA levels of nitric oxide synthase (iNOS) (D), Monocyte chemoattractant protein 1 (MCP-1) (E), CD200 (F), and CX3C chemokine receptor 1 (CX3CR1) (G) mRNAs in the SN of rats from the different treatments assayed, measured by RT-PCR
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder featuring the loss of the dopaminergic neurons in the SN and Lewy pathology (intracellular accumulation of α-synuclein and other proteins in the so-called Lewy bodies), with a resultant alteration of the motor function that produces the loss of autonomy; cognitive function and mood are impaired (Marinus et al, 2018; Odin et al, 2018; Sojitra et al, 2018). More compelling evidence supporting the involvement of neuroinflammation in PD pathogenesis relies on genome-wide association studies, which have found a genetic association with PD susceptibility in the human leukocyte antigen region (Nalls et al, 2014) and other polymorphisms related to the immune system including TNF, TNFR1, IL-1β, triggering receptor expressed on myeloid cells 2, IL-1 receptor antagonist and CD14 (Hirsch and Hunot, 2009; Rayaprolu et al, 2013) These studies highlight the importance of neuroinflammation-based animal models of PD, including those induced by injecting pro-inflammatory compounds such as thrombin (Carreño-Müller et al, 2003), tissue plasminogen activator (Villarán et al, 2009) or LPS within the SN (Castaño et al, 1998). It has been shown that subtoxic doses of LPS exacerbate disease progression in an animal model of PD (Godoy et al, 2008), supporting the hypothesis that brain inflammation may play a significant role in PD progression
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