Divergent Effects of Metformin on an Inflammatory Model of Parkinson’s Disease

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.

Metformin Protects From Rotenone–Induced Nigrostriatal Neuronal Death in Adult Mice by Activating AMPK-FOXO3 Signaling and Mitigation of Angiogenesis

“…In their studies, de Pablos and colleagues have used a week therapy with MTF (150 mg/kg, p.o., twice daily dosage) in an MPTP-induced PD model and a model of dementia and showed a neuronal harming action of MTF. Hence, a warning conclusion was released for the possibility of the pathogenic role of MTF in neurodegenerative conditions (Ismaiel et al, 2016;Tayara et al, 2018). Based on the data reported by Patil et al (2014), the neuroprotective role of MTF (500 mg/kg, p.o.)…”

Autophagy Activator Drugs: A New Opportunity in Neuroprotection from Misfolded Protein Toxicity

“…Hence, AMPK activators, shifting the energy balance toward reduction of ATP consumption, along with the enhanced mitophagy and prevention of α-synuclein aggregation, can act as possible PD-modifying drugs. Although no results from clinical trials with metformin in PD patients have so far been reported, there is preclinical evidence that AMPK activation in neurons is protective, and the treatment with metformin can ameliorate symptoms and pathology in animal models of toxin-induced PD [ 182 , 183 ]. In 2017, a pilot study on patients diagnosed with mild cognitive impairment or early AD showed that treatment with metformin improved executive function, learning and memory [ 184 ].…”

Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria

“…Metformin supplementation ameliorates the signs of stroke, cytokine levels, and neutrophil infiltration in the brains of mice subjected to medial cerebral artery occlusion by activating the AMPK pathway and inhibiting NF-κB signaling [146,147]. In contrast, in an inflammatory model of PD consisting of intranigral injection of LPS, metformin ameliorates microglial activation and cytokine secretion, but exacerbates the death of dopaminergic neurons [148]. These detrimental effects may arise from the fact that metformin is a weak inhibitor of the mitochondrial complex I [149], whose deficiency has been clearly linked to PD development [150].…”