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

General
Emmanuel Geoffroy was a French botanist and explorer, who travelled to French Guiana in the late 19th century. The object of his search was to find latex bearing trees but he became distracted by the practices of the forest Indians who made an extract from the roots of the Robinia nicou plant (now called Lonchocarpus nicou) and put it in water to catch fish by poisoning them. Geoffroy named the poison nicouline. It is now known as Rotenone and has been discovered in a wide variety of other plants. It was subsequently developed commercially as a piscicide, insecticide and pesticide and is also known as Tubatoxin and Praderil. Its chemical name is hexahydro-2-isopropenyl-8,9-dimethoxychromeno[3,4-b]furo(2,3-h)chromen-6-one. The formula is C23H22O8

It is currently sold as a universal pest killer in gardens and for ridding chickens of parasites and is commonly called Derris Dust.

Bristol University has produced a good clear language description of the product.

There is some evidence that Rotenone can induce Parkinson's Disease in humans, but it is not high on the list of potential environmental toxins as it decomposes rapidly naturally and the human metabolism has defensive screens, which inhibit its progression to the substantia nigra. It is one of the few pesticides approved for use by organic farmers.

What is exciting about Rotenone is that, when it is administered in quantities to laboratory rats, it produces a form of Parkinson's Disease which very closely models that found in humans. This has been described by Canon et al (2009) and Telford (2010). (see separate topic - Rotenone Model)

Research
Tain et al (2009) have initiated PD in fruit flies with PINK1 and PARK2 by the application of Rotenone. They then treated these models with Rapamycin.  This had the effect of reversing the PD symptoms.

All published sources on Rotenone and Parkinson's Disease (including some that are quoted here) are unanimous about the way in which the toxin works. It inhibits the production of NADH Dehydrogenase, also known as Complex 1. This is one of a chain of enzyme molecules involved in the metabolism of oxygen into ATP by mitochondria. It has an important role, since ATP is the fuel that drives all animal cells.

However this hypothesis has recently been the subject of study by Choi et al (2011)

They started by knocking out an essential component of Complex 1 called Ndufs4 in the mitochondria of healthy mice. In theory the mice should have experienced dopaminergic cell death and begin to exhibit PD symptoms. Instead they remained stubbornly healthy. If Rotenone was administered subsequently, only then did PD symptoms develop. The team then tried another Complex 1 inhibitor, piericidin A, with the same result. The inference was that Rotenone was killing neurons in some other way.

Research then concentrated on another property of Rotenone, its ability to destroy microtubules. Microtubules are molecular ‘railway tracks’ that run the length of a neuron’s axons. These can be over a metre long in adult humans. Normally there is continual traffic up and down the microtubule. Specially adapted molecules haul mitochondria, neurotransmitters. Proteins and waste products from around the cell's nucleus to the synapses and back again. When Rotenone destroys the tracks, untransported cargoes pile up around the cell’s nucleus (Lewy bodies?) and the cell cease to function. The team then treated mouse neurons with colchizine, an unrelated microtubular destructive agent and it produced the same effect as Rotenone. Finally they treated neurons with a microtubule stabilising drug called taxol. This had the effect of insulating them against the effect of Rotenone.

The work may have identified a new therapeutic target for Rotenone-induced PD and may have significance for other forms of PD.

Taxol is a compound which was isolated from the bark of the Pacific yew tree Taxus brevifolia in 1971 by Monroe E. Wall and Mansukh C. Wani and found to have microtubule protective properties. It was developed commercially by Bristol-Myers Squibb (BMS) and the generic name was changed to paclitaxel. The BMS compound is sold under the trademark TAXOL. In this formulation, paclitaxel is dissolved in Cremophor EL and ethanol, as a delivery agent. A newer formulation, in which paclitaxel is bound to albumin, is sold under the trademark Abraxane.

Paclitaxel is now used to treat patients with lung, ovarian, breast cancer, head and neck cancer, and advanced forms of Kaposi's sarcoma. Paclitaxel is also used for the prevention of restenosis.