Progress and Prospects in Parkinson's Research/Causes/Toxins/Paraquat

Background
Paraquat was first synthesised in 1882 and was marketed as a herbicide in 1961 by ICI (now Zeneca). Its formula is N,N′-dimethyl-4,4′-bipyridinium dichloride. It has a similar molecular structure to MPTP. The Zeneca factory in Huddersfield,UK makes some 8,000 tonnes a year, most of which is exported. It is a very effective weedkiller if used properly, and is sold under a variety of tradenames including Weedol Pathclear, Crisquat; Dexuron; Esgram; Gramuron; Para-col; Pillarxone; Tota-col; Toxer Total; PP148; Cyclone; Gramixel; Gramoxone; and AH 501.r.  It kills plants by inhibiting photosynthesis, but becomes biologically inactive upon contact with the soil. Its uses include land clearance, defoliation and as a desiccant.

In its undiluted state it is very toxic. Death by heart, kidney and respiratory failure occurs within 30 days of ingesting half a teaspoonful and there is no antidote. For this reason it was banned by Finland, Sweden, Austria, Norway and Hungary, and its use is restricted in the USA, but this did not stop America from spraying Mexican marijuana fields with it in the 1970s. The European Union approved the use of paraquat in 2004, but annulled the directive authorizing its use in 2007 following court action by Sweden, Denmark, Austria, and Finland.

One of its uses in Third World countries is committing suicide (76% of suicides in Trinidad in 1990/91). Taking a single swig of undiluted Paraquat and spitting it out immediately is fatal.

2007

Miller published a detailed refutation of the PD case against paraquat. One of his main arguments was that because of the fierce nature of Paraquat toxicity most researchers induced PD in laboratory animals by direct injection of Paraquat into the substantia nigra. Miller argued that this negated the efficacy of the blood brain barrier in keeping out the toxin. He also observed that any inflammatory substance injected in this manner would have the same effect.

2009

His case was supported by the findings of Bartlett et al who attempted to induce PD through the application of Paraquat to Macaque Rhesus monkeys. Their conclusion was:-

"'This acute exposure study found that paraquat is excluded from the brain by the blood brain barrier and thus does not readily support the causative role of paraquat exposure in idiopathic Parkinson's disease.'"

2011

Tanner et al made a positive association between Parkinson’s Disease and Paraquat (and Rotenone) by cluster analysis.

Roede et al found that Maneb and Paraquat used in combination were particularly toxic.

Singhal et al demonstrated that silymarin and melatonin offer nigrostriatal dopaminergic neuroprotection against Maneb and Paraquat-induced PD (in rats) by the modulation of oxidative stress and apoptotic machinery.

Research
2011

Littlejohn et al found that male mice were much more susceptible to Paraquat induced PD than female mice.

Mangano et al found that the application of granulocyte macrophage colony stimulating factor (GM-CSF) inhibited the neurodegenerative effects of Paraquat.

Yin et al exposed different varieties of recombinant inbred mice to Paraquat injection and measured the rate and extent of the onset of dopamine neuron loss in the substantia nigra. They found that there were marked and consistent variations according the genetic make-up of the mice. Their conclusions state:-

"“This is the first study to report genetically-based differences in susceptibility to PQ neurotoxicity and to understanding individual differences in vulnerability to PQ neurotoxicity and its relation to PD in humans.”"

Kwon et al found that DJ-1 null gene cells resisted Paraquat toxicity. Their conclusions state:-

"“DJ-1 null cells showed reduced complex I activity, which was partially rescued by ectopic DJ-I expression. In summary, our results suggest that DJ-1 is critical to maintain mitochondrial complex I and complex I could be a key target in interaction of paraquat toxicity and DJ-1 for giving rise to PD.”"

2012

Lee, Pei-Chen et al enrolled 357 incident idiopathic PD cases and 754 population controls from 2001 to 2011 in central California. Participants were asked to report all head injuries with loss of consciousness for >5 minutes. Paraquat exposure was assessed via a validated geographic information system (GIS) based on records of pesticide applications to agricultural crops in California since 1974 and ambient pesticide exposure within 500 m of residences and workplaces were recorded.

They observed a 2-fold increase in risk of PD for subjects who reported a Traumatic Brain Injury (TBI),  and a weaker association for paraquat exposures. However, the risk of developing PD was 3-fold higher in study participants with a TBI and exposure to paraquat than those exposed to neither risk factor.