Dopamine receptor agonist stimulates neurogenesis & leads to functional recovery in Parkinsonian rats

A study published today in the Journal of Neuroscience shows that a drug which mimics the actions of dopamine can stimulate neurogenesis and lead to the recovery of motor functions in a rat model of Parkinson’s Disease (PD).

PD is characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra (meaning ‘black substance’; the cells produce melanin and so are coloured black). The axons of these cells form the nigrostraital pathway, which is involved in the production of movement, and the death of these cells leads to the classical Parkinsonian symptoms of  tremors, stiffness and impaired balance and coordination.

One approach researchers have taken in trying to develop treatments for PD is to transplant embryonic stem (ES) cells or neural progenitors into the brain, in the hope that they will differentiate into dopaminergic neurons which can replace those that have degenerated. This approach has proved to be technically difficult, and many are ethically opposed to the use of ES cells.

Christopher Eckman and Jackalina Van Kampen, of the Mayo Clinic College of Medicine in Jacksonville, Florida, used a different approach. They injected the dopamine D3 receptor agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) into the ventricles of rats by 2-, 4- or 8-week continuous infusion.

Injections of bromodeoxyuridine (BrdU), which is incorporated into newly synthesized DNA, showed that 7-OH-DPAT stimulated endogenous stem cells in the rats’ brains to generate new dopaminergic neurons,  and injection of a fluorescent tracer showed that the cells extended their processes to the striatum.  

Approximately 28% of the newly-generated cells differentiated into dopaminergic midbrain neurons. Rats treated with 7-OH-DPAT for 8 weeks had 75% of the normal number of dopaminergic substantia nigra neurons, and recovered 80% of their motor functions; these effects were observed 4 months after treatment with the drug.

“This is the first study to show that endogenous neurogenesis can lead to recovery of function in an animal model of Parkinson’s disease,” says Dr. Eckman. “[7-OH-DPAT had] a profound behavioural effect…even after it ‘washed out’ of the system.”

7-OH-DPAT has never been used in humans, but two other drugs, pramipexole and ropinirole, have similar effects on dopamine receptors and have been approved for use in treating PD. Drs. Eckman and Van Kampen are now investigating the effects of these substances on neurogenesis, and are trying to determine if other drugs can stimulate genesis of the neurons that are lost in Alzheimer’s Disease and other neurodegenerative diseases. 

Neurosurgeon condones vivisection for cosmetics

In an interview in last Saturday’s Guardian, Tipu Aziz, a pioneering Oxford neurosurgeon, controversially condones the testing of cosmetics on animals.

Aziz developed the technique of deep brain stimulation to treat patients with Parkinson’s Disease. The condition is caused by degeneration of a group of neurons in a region of the midbrain called the substantia nigra (‘black substance’). These cells normally produce the neurochemical transmitter dopamine and are involved in the control of movement. The death of these cells causes the classical Parkinsonian symptoms of tremors and stiffness.

Deep brain stimulation involves implanting an electrode into the brain of Parkinson’s patients. Brain scans enable surgeons to guide the electrode to the region producing the electrical signals which cause the tremors. The electrode is connected by a wire which runs under the skin to a battery pack. Electrical signals produced by the electrode interfere with those causing the tremors, so that the symptoms are alleviated or cured altogether. According to Aziz, 40,000 people around the world have benefited from the technique.

Parkinson’s Disease was previously treated with the drug L-dopa, a chemical precursor from which dopamine can be synthesized. Replacing the dopamine that would normally be produced by the cells which have died can alleviate the symptoms of Parkinson’s, although not all patients respond to the treatment. Awakenings, starring Robert De Niro and Robin Williams, concerns the plight of the first patients to be treated with L-dopa.

In the 1980s, a student in California serendipitously developed a recreational drug by modifying the chemical structure of pethidine. The drug contained impurities which produced symptoms identical to Parkinson’s in those who took it.

Aziz experimented on monkeys to develop the deep brain stimulation method. First, he would administer the Parkinson’s-inducing drug to monkeys so that they developed symptoms of the disease. Then he would implant electrodes into the monkeys’ brains to try and treat the symptoms.

Because of the importance of animal experimentation in his work, Aziz is, of course, pro-vivisection. He has supported the proposed multi-million pound Biomedical Research Centre at Oxford, the building of which has been strongly opposed by animal rights activists. Aziz spoke to supporters of the Oxford labs after an invitation from Laurie Pycroft, the 16-year-old blogger who founded the pro-vivisection group Pro-Test.

Now, he has gone further to say that he sees nothing wrong with the testing of cosmetics on animals. “People talk about cosmetics being the ultimate evil,” says Aziz in The Guardian, “but beautifying oneself has been going on since we were cavemen.”

According to Aziz, Britain has achieved “a disproportionate amount of benefits by medical research using animals,” but it also has “probably the most violent and absurd animal rights movement in the world.”

He adds that he is sick of having his work misrepresented by “misinformed and sometimes illiterate anti-vivisectionists who adopt terrorist tactics,” and who have “undermined democracy.” His outspoken pro-vivisection views and criticism of animal rights activists is bound to make him a target for groups such as the Animal Liberation Front.

In the future, Aziz will be working on stem cell, viral and gene therapy to treat Parkinson’s Disease and other neurodegenerative disorders. “I have no problems with what I do,” concludes Aziz, because “I know it is right.”