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While at present there are no substances that have proven neuroprotective properties for the treatment of Parkinson's, a number of substances and strategies are being researched with indications that it may be possible to slow down or halt the pathogenic process. A recent trial of Exendin-4, a drug already used for the treatment of diabetes, is an example of this. Almiles-Olmes, Iciar; Dickson, John; Kefalopoulou, Zinovia; Djamshidian, Atbin; Ell,Peter; soderlund,Therese; Whitton, Peter; Wyse, Richard; Isaacs, tom; Lees,Andrew; Limousin, Thomas and Foltynie (2013) Full Text J. Clin. Invest. doi:10.1172/JCI68295. Exenatide and the treatment of patients with Parkinson’s disease http://www.jci.org/articles/view/68295
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‘Neuroprotection’ can imply that there are therapies which inhibit neurodegeneration from taking place. Alternatively, in cases where someone has been diagnosed as having a neural deficit, it means that the condition can be prevented from worsening. Either way it presents the researcher with the problem of proving a negative, i.e. of showing that something which would otherwise have happened did not happen.
This can be avoided in tests in vitro or with fast breeding animal models, but can present difficulties in assessing humans
One way of doing this is to collect information on a large group of people, to monitor their health over an extended timescale, and to identify differences between those that acquire a degenerative condition and those that do not. Distinctions may be made for gender, ethnicity, age, nutrition, location, diet, genetics, medical history and lifestyle choices.
Another is to assemble cohorts of patients and controls and get them to complete questionnaires deigned to isolate significant differences between the two groups.
The results obtained by both methods are questionable, but gain strength when repeated studies show the same result.
If the risk to patients is deemed minimal research can proceed to Clinical Trials , where cohorts of patients are given controlled amounts of medication and the effect on their disease is measured against a second cohort given a placebo.
Introducing new therapies
The process of proving a new therapy generally follows a set sequence:-
- tests on cells in dishes (in vitro);
- tests on laboratory animals with induced forms of the target disease;(in vivo)
- tests on patients, generally involving larger and larger cohorts, with time to assess long term side effects and outcomes.
It is valuable if results can be corroborated at each stage by more than one independent project team.
Delays can occur for a number of reasons:-
- obtaining the necessary funding for each stage in the process;
- optimising the capabilities, experience and facilities of the laboratory;
- the priorities assigned to unrelated projects:
- maintaining continuity of staff and expertise.
Assuming that results arrive at a satisfactory outcome there are three more hurdles to overcome:-
- publishing the results in a peer-reviewed scientific journal. As a general rule the more prestigious is the journal, the more stringent the review criteria and the longer the lead time on publication.
- making a sound business case and carrying out a risk analysis by drug manufacturers in competition with other diseases.
- meeting the requirements of national drug licencing bodies,
Parkinson's Disease tends to fare badly in this process because:-
- There is no clinical diagnostic test for the disease.
- There are not enough diagnosed cases compared to other diseases to justify a large investment in research.
- The disease is idiosyncratic - patients have differing symptoms, rates of deterioration and varying responses to drugs, making 'one-size-fits-all' remedies harder to develop.
- palliative drugs such as levadopa, which have to be taken continually in large quantities,have a greater potential profit margin than drugs which might reverse the symptoms.
It is not surprising then that many a promising hypthesis does cross the therapeutic boundary from academic research to commercial production. Contributors to patient forums show frustration at the slow progress of research and a willingness to self-medicate or experiment with alternative medicine.
Of the recent research described in the following pages Rasagaline and Tolcapone have completed the research sequence and are prescribed. NSAIDs, Creatine and Vitamin D are available over the counter and Melatonin can be purchased via the internet.
Seidl and Potashkin Seidl,Stacey E. And Potashkin, Judith A. (2011) Full Text Front. Neurol. 2:68
The Promise of Neuroprotective Agents in Parkinson’s Disease
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221408/ evaluated a number of promising potential neuroprotective agents
Boll et al Boll, Marie Catherine; Zubeldia,Mireya Alcaraz and Rios, Camilo (2011) Full Text: Curr. Neuropharmacol. 9 (2) 350 -359 Medical Management of Parkinson’s Disease: Focus on Neuroprotection. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131725/?tool=pmcentrez summarized the current PD neuroprotection scene
Detail of individual agents are given in the following pages and readers are invited to update these as more research comes to light.
Yacoubian, Talene A. and Standaert, David G. Full Text Biochim. Biophys. 1792 (7) 676 – 687.
Targets for Neuroprotection in Parkinson’s Disease
Levy, Oren A.; Malagelada, Christina and Greene, Lloyd A. Full Text Apoptosis 14 (4) 478 – 500:
Cell death pathways in Parkinson’s disease: proximal triggers, distal effectors, and final steps
Yacoubian, Talene A. and Standaert, David G. Full Text Biochim. Biophys. Acta 1792 (7) 878 – 687:
Targets for Neuroprotection in Parkinson’s Disease
Surmeier, Dalton James Guzman, Jaime N.; Sanchez-Padilla, Javier and Goldberg, Joshua A. Full Text Antioxid. Redox. Signal. 14 (7): 1289–1301.
The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies
Kannappan, Ramaswamy; Gupta,Subash Chandra; Kim, Jye Hi,Reuter,Simone and Aggarwal,Bharat Bushan Full Text Mol. Neurobol. 44 (2) 142 - 159
Neuroprotection by Spice-derived Neutroceuticals: You are what you eat.
Mazzio, Elizabeth A.; Close, Fran and Soliman, Karen F. A. Full Text Int. Jnl. Mol. Sci. 12 (1) 506—569
The Biochemical Basis for Nutraceuticcal Strategies to Attenuate Neurodegeneration in Parkinson’s Disease.
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- Substances with possible neuroprotective properties:
- Caffeine,--Celastrol,--Co-Enzyme Q10,--Creatine,--DHA,--Exendin-4 (EX-4),--GDNF,--Glutathione (GSH),--GM1,--Isradipine,--Melatonin,--Minocycline,--Nicotine,--NSAIDs,--Phenylbutyrate,--Phytic Acid,--Probucol,--Quinoxaline,--Rasagiline,--Riboflavin,--Statins,--Tolcapone,--Urate & Uric Acid,--Vitamin D,--Vitamin E,--