Neuroprotective and Anti-inflammatory Properties of a Coffee Component in the MPTP Model of Parkinson's Disease

Abstract

Consumption of coffee is associated with reduced risk of Parkinson's disease (PD), an effect that has largely been attributed to caffeine. However, coffee contains numerous components that may also be neuroprotective. One of these compounds is eicosanoyl-5-hydroxytryptamide (EHT), which ameliorates the phenotype of α-synuclein transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation. Here, we sought to investigate if EHT has an effect in the MPTP model of PD. Mice fed a diet containing EHT for four weeks exhibited dosedependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed. Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with EHT treatment. The neuroinflammatory response to MPTP was markedly attenuated, and indices of oxidative stress and JNK activation were significantly prevented with EHT. In cultured primary microglia and astrocytes, EHT had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharideinduced NFκB activation, iNOS induction, and nitric oxide production. EHT also exhibited a robust antioxidant activity in vitro. Additionally, in SH-SY5Y cells, MPP + -induced demethylation of phosphoprotein phosphatase 2A (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by EHT. These findings indicate that the neuroprotective effect of EHT against MPTP is through several mechanisms including its antiinflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of PP2A. Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD.Kang-Woo Lee and Joo-Young Im contributed equally to this work.

Therapeutic benefits of a component of coffee in a rat model of Alzheimer's disease

“…Levels of PP2A methylation are controlled by a balance between the activities of two highly conserved, PP2A-specific, enzymes: a methyl transferase, PPMT, that transfers methyl groups from S-adensylmethionine to the PP2A carboxy terminus; and a methyl esterase, PME, that demethylates PP2A. EHT was initially identified as a component in coffee extracts that inhibited the PP2A demethylation reaction (Lee et al 2013). Dramatic increases in PP2A demethylation have been observed in brains from AD patients (Sontag et al 2004).…”

“…Pharmacokinetic studies delivering [ 3 H]-EHT intraperitoneally revealed that this compound crosses the blood brain barrier achieving levels sufficient to inhibit PP2A demethylation, indicating its feasibility for proof of concept studies (Lee et al 2011). EHT was identified as the major PP2A demethylation inhibitor in coffee (Lee et al 2011) and was reported to be effective in preclinical studies (Lee et al 2011; Lee et al 2013). …”

“…Synthetic EHT exhibited the same ability to support PP2A activity as EHT isolated from coffee. Dietary supplementation with synthetic EHT exhibited neuroprotective efficacies in mouse models for Parkinson’s disease (Lee et al 2011; Lee et al 2013). Here we report the beneficial effects of chronic dietary supplementation with EHT on PP2A activity, abnormal tau hyperphosphorylation, accumulation of intraneuronal Aβ and cognitive performance in a rat model for AD.…”

The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson's Disease: Involvement of Reactive Oxygen Species/Nuclear Factor-κB/Nuclear Transcription Factor Related to NF-E2

“…GSH and GSSG were measured in the substantia nigra and cerebral cortex by using a GSH assay kit (Cayman) with enzymatic recycling, as previously described (39). Absorbance was measured at 405 nm.…”

Caffeine administration prevents retinal neuroinflammation and loss of retinal ganglion cells in an animal model of glaucoma

“…Caffeine, by blocking A 2A R, is able to prevent synaptotoxicity, excitotoxicity and neuronal loss18192021. In addition, it has also been reported that caffeine has anti-inflammatory properties in the CNS22, namely by attenuating microglia-mediated neuroinflammation23.…”