Caffeine reduces deficits in mechanosensation and locomotion induced by L-DOPA and protects dopaminergic neurons in a transgenic Caenorhabditis elegans model of Parkinson’s disease

Abstract

Context: L-DOPA is the first-line drug for Parkinson's disease (PD). However, chronic use can lead to dyskinesia. Caffeine, which is a known neuroprotectant, can potentially act as an adjunct to minimise adverse effects of L-DOPA. Objectives: This study determined changes in terms of neurodegeneration, locomotion and mechanosensation in Caenorhabditis elegans (Rhabditidae) strain UA57 overexpressing tyrosine hydroxylase (CAT-2) when treated with caffeine, L-DOPA or their combinations. Materials and methods: Neurodegeneration was monitored via fluorescence microscopy of GFP-tagged dopaminergic neurons in the head and tail regions of C. elegans. Meanwhile, mechanosensation and locomotion under vehicle (0.1% DMSO), L-DOPA (60 mM), caffeine (10 mM) or 60 mM L-DOPA þ 10 or 20 mM caffeine (60LC10 and 60LC20) treatments were scored for 3 days (n ¼ 20). Results: L-DOPA (60 mM) reduced CEP and ADE neurons by 4.3% on day 3, with a concomitant decrease in fluorescence by 44.6%. This correlated with reductions in gentle head (À35%) and nose touch (À40%) responses, but improved locomotion (20-75%) compared with vehicle alone. CEP and ADE neuron counts were preserved with caffeine (10 mM) or 60LC10 (98-100%), which correlated with improved mechanosensation (10-23%) and locomotion (18-76%). However, none of the treatments was able to preserve PDE neuron count, reducing the basal slowing response. Discussion and conclusions: Taken together, we show that caffeine can protect DAergic neurons and can reduce aberrant locomotion and loss of sensation when co-administered with L-DOPA, which can potentially impact PD treatment and warrants further investigation.

Caenorhabditis elegans provides an efficient drug screening platform for GNAO1-related disorders and highlights the potential role of caffeine in controlling dyskinesia

“…This effect is reversed by concomitant exposure to adenosine, suggesting a conserved caffeine-AR pathway in the nematode ( 68 ). Of note, administration of 10 m m caffeine (the same concentration used in our experiments) to C elegans protects dopaminergic neurons from neurodegeneration elicited by excessive biosynthesis of endogenous L-DOPA ( 43 ), and improve aberrant locomotion induced by L-DOPA in a transgenic C. elegans model of PD ( 44 ). Specifically, Manalo et al.…”

“…5B ). For these experiments, the lowest effective m m concentration has been used since 10 m m caffeine already proved to protect dopaminergic neurons from dopamine-induced neurodegeneration ( 43 ) and to reduce aberrant locomotion induced by L-DOPA in a transgenic C. elegans model of Parkinson’s disease [PD; ( 44 )]. Automated recordings of C. elegans trajectories highlighted the beneficial effect of caffeine (10 m m ) on the hyperactive crawling of goa-1 [S47G] and goa-1 [A221D] mutants as well as of animals lacking goa-1 ( Supplementary Material, Fig.…”

Deficiency in RCAT-1 Function Causes Dopamine Metabolism Related Behavioral Disorders in Caenorhabditis elegans

“…In addition, the difference in expression levels of cat-2 and bas-1 may cause the accumulation of L-DOPA, a precursor of dopamine synthesis that is produced by the actions of the products of these two genes. To test this hypothesis, we measured the intensity of dopaminergic neurons in R02D3.7 mutants, as exogenous L-DOPA has been reported to damage dopaminergic neurons [43][44][45]. We found that the fluorescence intensity of dopaminergic neurons was 30% less in R02D3.7(ok1745) mutants than in wild-type animals (Figure 4E, compare left panel vs. middle panel in Figure 4F).…”

Effect of altered production and storage of dopamine on development and behavior inC. elegans

“…31,32 In C. elegans, cat-2 overexpression is used as an endogenous model of L-DOPA exposure to replicate an increase in dopamine production; however, these animals show age-dependent dopaminergic neurodegeneration. 33,34 Taken together, previous studies have found that proper dopamine synthesis and sequestration is essential to maintaining neuronal health in C. elegans, and dysregulation of dopamine homeostasis can affect many behaviors in C. elegans including growth and reproduction.. In this study, we sought to determine whether endogenously increasing dopamine production through the overexpression of cat-2 could rescue the deficits identified in cat-1 null C. elegans.…”