Of Primates and Parkinson's.
In their campaign against the new biomedical facility at Oxford SPEAK have repeatedly claimed that the results of non-human primate research to medical advancement. In particular SPEAK claims that experiments using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson's disease did not make any major contribution to the development of the Deep Brain Stimulation (DBS) technique for the treatment of Parkinson's disease (http://www.speakcampaigns.org.uk/PD.php/), and that the MPTP monkey model is a poor model for Parkinson's disease. The following essay will show why these claims are false.
Parkinson's disease is a degenerative disorder of the central nervous system that affects muscle control, and belongs to a group of conditions called movement disorders. It is often characterized by a debilitating tremor, muscle rigidity, and a slowing of physical movement , termed bradykinesia, that in extreme cases may lead to a loss of physical movement, termed akinesia. The disease is caused by the loss of neurons located in a region of the brain known as the substantia nigra pars compacta that secrete the neurotransmitter dopamine. Low levels of dopamine leads to changes in the activity of other nuclei within the basal ganglia, a group of nuclei in the brain associated with motor functions which also includes the striatum and subthalmic nucleus. This in turn inhibits neuronal activity in the thalamus and disrupts neuronal activity in the motor cortex that causes the symptoms of Parkinson's disease.
Parkinson's disease is the most common cause of parkinsonism, a group of disorders that share common symptoms and pathophysiology. Parkinsonism may result from brain injury, disease of exposure to toxins. In what became known as "The case of the Frozen Addicts"1 heroin users presented at various Northern California emergency rooms with symptoms indistinguishable from those of Parkinson's, caused by the presence of MPTP in their drug supply. It was soon demonstrated that MPTP induces a specific loss of substantia nigra neurons that mimics the degeneration seen in Parkinson's disease2. MPTP has an identical effect on monkeys and while parkinsonism induced by MPTP is not usually permanent the MPTP monkey has since proved to be an excellent, if not exact, experimental model for Parkinson's disease.
Fifty years ago the only treatment available for Parkinson's disease was lesioning of different targets within the basal ganglia. The frequent permanent complications and limited effectiveness of this surgery made the identification of alternative treatments highly desirable. The first major breakthrough came in the mid 1950's when Arvid Carlsson, while working on rabbits and mice treated with the parkinsonism inducing drug reserpine, discovered the that dopamine was an important neurotransmitter in it's own right, not just a precursor of norepinephrine as had previously been thought, and was present at high levels in the basal ganglia3,4. He observed that parkinsonism was associated with a reduction in dopamine levels and further that the symptoms of parkinsonism could be alleviated by treatment with the dopamine precursor L-Dopa (Levodopa). When other researchers including Oleh Hornykiewicz, building on Arvid Carlsson's work, demonstrated that depletion of dopamine was a feature of Parkinson's disease in humans in the early 1960's5,6 L-Dopa began to be used to treat Parkinson's disease. The importance of the work done Arvid Carlson received official recognition when he was awarded the Nobel Prize in Physiology or Medicine in 2000.
L-Dopa is a highly effective drug for the treatment of Parkinson's disease, its effects are vividly depicted in the film Awakenings, and remains to this day the most widely used drug for the treatment of Parkinson's disease. As a consequence of this surgery almost disappeared as a method for treating Parkinson's disease. Unfortunately several years later it was found that the intensive long-term treatment with L-Dopa required to treat Parkinson's disease caused side effects such as hyperactivity and uncontrollable movement in many patients, and a gradual reduction in sensitivity to L-Dopa that in turn leads to a requirement for ever higher doses7. The development of new drugs such as the dopa decarboxylase inhibitors, dopamine agonists and monoamine oxidase B inhibitors, that are usually used alongside L-Dopa, helped to reduce these problems but nevertheless from the late 1970's there was a resurgence in neurosurgery to treat Parkinson's disease. Thalamotomy of the thalmic nucleus ventralis intermedius (VIM) was effective in alleviating tremor and to a lesser extent rigidity but had no effect on akinesia.
Deep Brain Stimulation
It was while performing a thalamotomy of the VIM at Grenoble that Alim-Louis Benabid accidentally discovered that high-frequency electrostimulation of VIM was enough to shop the tremor associated with Parkinson's disease8. Between 1987 and 1993 Prof. Benabid and his colleagues treated 87 patients with deep brain stimulation (DBS) of the VIM which mimicked the effect of thalamotomy in suppressing tremor without having an effect on rigidity and akinesia9 . Nevertheless DBS of the VIM was a significant advance over thalamotomy as it could be applied to both sides of a patients brain and had the advantage of a lower rate of complications than thalamotomy and immediate reversibility if any complications did occur.
While the Grenoble group were undertaking their initial trials of DBS of the VIM, several groups were undertaking research using the MPTP monkey model that demonstrated the pivotal role of the sub-thalamic nucleus (STN) in the mechanisms central to parkinsonism10,11. In particular in 1991 Tipu Aziz and colleagues showed that thermcoagulative lesioning, a standard neurosurgical technique, could when applied to the STN relieve tremor as effectively as thalamotomy, but in addition also alleviated rigidity and akinesia11. The importance of this discovery was immediately recognized by the Grenoble group and following successful studies of the effect of electrostimulation of the STN in the MPTP monkey model12 they carried out trials of DBS of the STN in patients suffering from severe Parkinson's disease13. DBS of the STN combined all the benefits observed with the DBS of the VIM with alleviation of rigidity and akinesia13. In addition to this almost one third of patients who underwent DBS of the STN were able to stop taking L-Dopa and most the remainder were able to reduce the dosage significantly, thereby helping to avoid the development of resistance to L-Dopa and the unpleasant side effects associated with high doses of L-Dopa14. DBS of the STN immediately became the method of choice when treating Parkinson's with surgery and has now been performed successfully on over 20,000 Parkinson's patients around the world.
Deep brain stimulation of the sub-thalamic nucleus is not an appropriate treatment for many Parkinson's sufferers so research on new treatments continues. In recent years there has been considerable interest in the potential for gene therapy to be used to treat Parkinson's disease15. Since there is no single Parkinson's disease gene scientists are studying a number of potential targets, but in all cases such research is heavily reliant on the use of animal models.
One promising approach is to express glutamic acid decarboxylase, the enzyme that catalyzes the synthesis of the neurotransmitter GABA, in the excitatory glutamatergic neurons of the STN thereby inducing inhibitory neurotransmission in the STN and alleviating the symptoms of Parkinson's disease. This approach was been tested successfully and optimized in the 6-hydroxydopamine (6-OHDA) rat and MPTP monkey models of parkinsonism16,17, before entering clinical trials in human. The results of the phase I clinical trials have recently been released and indicate that this therapy is safe and also produces a significant improvement in motor function in Parkinson's patients18.
It is too early to say for certain whether or not gene therapy will become another valuable weapon against Parkinson's in the armory of medicine, but the initial results certainly look promising.
The claim by SPEAK that deep brain stimulation "...has nothing whatsoever to do with animal experiments" is a blatant lie, as is their claim that Prof. Tipu Aziz "...has in the past claimed that the treatment of deep brain stimulation given to Parkinson sufferers owes everything to his research on monkey brains". The truth is that the huge progress made in treating Parkinson's disease over the past half century has depended equally on both animal experimentation and clinical studies of human, neither approach would by itself have yielded such great dividends. If SPEAK doubt this they should ask themselves why scientists such as Alim-Louis Benabid and Oleh Hornykiewicz, who made important discoveries by studying human patients, also carry out research using animal models of parkinsonism.
It is perhaps fitting to end with a quotation from a recent review7 of deep brain stimulation:
"The knowledge of the functional changes of basal ganglia activity in the parkinsonian state as it emerged from extensive experimental studies on animal models has provided the theoretical basis for surgical therapy in PD. The 6-hydroxydopamine (6-ODHA) rat model and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of PD provided powerful research tools for uncovering the pathophysiology of changes in functional basal ganglia activity in PD.
Sorin Breit, Jorg B. Shultz, Alim-Louis Benabid (2004)"
1. Langston J.W., Palfreman J. "The Case of the Frozen Addicts." Vintage Books, New York, 1996.
2. Smeyne R.J., Jackson Lewis V. "The MPTP model of Parkinson's disease." Molecular Brain Research, Vol. 134, pp. 57-66 (2005).
3. Carlsson A., Lindqvist M. Magnussen T. "3.4-Dihydrophenylalanine and 5-hydroxytryptophan as reserpine antagonists." Nature, Vol. 180, pp. 1200 (1957).
4. Carlsson A. "The occurrence, distribution and physiological role of catecholamines in the nervous system." Pharmacological reviews, Vol. 2.2, pp.490-493 (1959).
5. Barbeau A., Murphy G.F., Sourkes T.L. "Excretion of dopamine in diseases of basal ganglia." Science, Vol. 133, pp. 1706-1707 (1961).
6. Hornykiewicz O. "Dopamine (3-hydroxytryamine) in the central nervous system and its relation to the Parkinson syndrome in man." Dtsch Med. Wochenschr. Vol. 87, pp. 1807-1810 (1962).
7. Breit S. Schulz J.B., Benabid A.L. "Deep brain stimulation." Cell and Tissue Research, Vol. 318, pp. 275-288 (2004).
8. Benabid A.L., Pollak P., Louveau A., Henry S. "Combined (thalamotomy and stimulation
stereotactic surgery of the VIM thalmic nucleus for bilateral Parkinson disease." Applied Neurophysiology, Vol. 50, pp. 344-346 (1987).
9. Benabid A.L, Pollak P., Seigneuret E., Hoffmann D., Gay E., Perret J. "Chronic VIM thalmic stimulation in Parkinson's disease, essential tremor and extra-pyramidal dyskinesias" Acta Neurochirurgica. Supplementum., Vol. 58, pp. 39-44 (1993).
10. Bergman H., Wichmann T., DeLong M.R. "Reversal of experimental parkinsonism by lesions of the subthalamic nucleus." Science,Vol. 249, pp. 1436-1438 (1990).
11. Aziz T.Z., Peggs D., Sambrook M.A., Crossman A.R. "Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate" Movement Disorders, Vol.6, No. 4, pp. 288-292.
12. Benazzouz A., Gross C., Feger J., Borad T., Bioulac B. "Reversal of rigidity and improvement in motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys." The European Journal of Neuroscience, Vol. 5, pp. 382-389 (1993).
13. Limousin P., Pollak P., Benazzouz A., Hoffmann D., Broussolle E., Perret J.E., Benabid A.L. "Bilateral subthalamic nucleus stimulation for severe Parkinson's disease." Movement Disorders, Vol. 10, pp. 672-674 (1995).
14. Benabid A.L., Koudsie A., Benazzouz A., Vercueil L., Fraix V., Charbardes S., LeBas J.F., Pollak P. "Deep brain stimulation of the corpus luysi (subthalamic nucleus) and other targets in Parkinson's disease. Extension to new indications such as dystonia and epilepsy" Journal of Neurology, Vol. 248. Suppl. 3, pp. 37-47 (2001).
15. During M.J., Leone P. "Targets for gene therapy of Parkinson's disease: growth factors, signal transductio, and promoters." Experimental Neurology, Vol. 144, pp. 74-81 (1997).
16. Luo J., Kaplitt M.G., Fitzsimons H.L., Zuzga D.S., Liu Y., Oshinsky M.L., During M.J. "Subthalamic GAD gene therapy in a Parkinson's disease rat model." Science Vol. 298, pp. 425-429 (2002).
17. Emborg M.E., Carbon M., Holden J.E., During M.J., Ma Y., Tang C., Moirano J. Fitzsimons H., Roitberg B.Z., Tuccar E., Roberts A., Kaplitt M.G., Eidelberg D. "Subthalamic glutamic acid decarboxylase gene therapy: changes in motor function and cortical metabolism." Journal of Cerebral Blood Flow and Metabolism, Electronic publication 2006.
18. Neurologix Press Release, 25th September 2006 (http://www.eurekalert.org/pub_releases/2005-09/bm-nap092305.php).