The Fight against Parkinsonism - Essay Example

“MPTP and Its Role in Toxic Parkinsonism” Mohammed Ali, Pope John Paul II, Michael J. Fox. These three men who are known and respected in the fields of boxing, religion and show business, respectively seem to have nothing in common. To the common people, they seem to be worlds apart in their way of life, from their beliefs to their everyday dealings, yet, all of them share a common ground: Parkinson’s Disease. Parkinson’s Disease (PD) is a “progressive neurodegenerative disorder, which is globally distributed, affecting all cultures and races” (European Parkinson’s Disease Association). It affects more than 6 million people worldwide. In Europe, there is an “overall prevalence (per 100 population) in persons 65 years of age and older was 1.8, with an increase from 0.6 for those age 65 to 69 years to 2.6 for those 85 to 89 years” (de Rijk, et.al, 21). The degeneration of the substantia nigra of the basal ganglia coupled with intracytoplasmic inclusions known as Lewy bodies is the pathological characteristic seen in patients afflicted with PD. “The primary biochemical defect is the loss of striatal dopamine” which is the neurotransmitter produced by the neurons in the pars compacta of the substantia nigra (Braddom, 1164). The basal ganglia “assist in the regulation of voluntary movement and the learning of motor skills” (Snell, 320). It also functions in the initiation of movements. It is because of this that patients present primarily (Last Name) 2 with motor affectations with the cardinal signs for PD which include bradykinesia (characterized by a slowness and sudden pause in movement), resting tremors (uncontrolled shaking or movement), muscular rigidity (stiffness) and postural instability. The specific cause for Parkinson’s disease is still unknown. Genetic factors such as defects in or mutations of several genes are known to cause PD, but these mutations actually result in only a very small number of cases of PD, in as little as 5% of the total number of PD cases. The two most important genes are “called parkin (autosomal recessive) and LRRK2 (autosomal dominant). Other genes that, when mutated, are known to cause PD include alpha-synuclein, DJ-1, PINK-1, and UCHL-1” (American Parkinson Disease Association). Envirionmental factors, such as exposure to toxins like pesticides/herbicides, industrial chemicals, trace metals, cyanide and carbon monoxide, are also thought to be a likely cause of Parkinson’s Disease. ‘The most compelling evidence for an environmental factor in PD relates to the toxin 1,2,3,6-methyl-phenyl-tetrahydropyridine (MPTP)” (Olanow & Tatton, 124). In the late 1940’s, MPTP was first tested for its possible therapeutic use tested as a possible anti-parkinsonian agent. Conversely, the drug was abandoned soon after the 6 humans given the drug developed PD symptoms and 2 of them died (myDr.com). The surge in the numbers of the MPTP-induced Parkinsonism came in the 1980’s when it was being sold in the streets as synthetic heroin. The case study done by (Ballard, Tetrud & Langston, 949) wherein the subjects, seven patients in total, developed permanent chronic and severe parkinsonism after repeatedly injecting MPTP intravenously. MPTP is able to cross the blood-brain barrier and react with the enzyme monoamine oxidase (MAO) (Hauser et.al). The interactions of MPTP with monoamine oxidase (MAO) was studied by Singer, Salach, Castagnoli & Trevort in 1986. (785) (Last Name) 3 l-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a thermal breakdown product of a meperidine-like narcotic. The nigrostriatal toxicity is not due to MPTP itself but to one or amore oxidation products resulting from the action of monoamine oxidase (MAO) on this tertiary allylamine. Both MAO A and B catalyse the oxidation of MPTP to the 1-methyl-4-phenyl-2,3-dihydropyridinium species (MPDP+), which undergoes further oxidation to the fully aromatic 1-methyl-4-phenylpyridinium species (MPP+). These bio-oxidations are blocked by selective inhibitors of MAO A and B. Additionally, MPTP, MPDP+ and MPP+ are competitive inhibitors of MAO A and B. The A form of the enzyme is particularly sensitive to this type of reversible inhibition. Both MAO A and B also are irreversibly inactivated by MPTP and MPDP+, but not by MPP+. This inactivation obeys the characteristics of a mechanism-based or suicide process. The inactivation, which is accompanied by the incorporation of radioactivity from methyl-labelled MPTP, is likely to result from covalent modification of the enzyme. Fig. 1: MPTP Conversion to MPDP and MPP+ (Adapted from Goodman, Louis Sanford, Alfred Gilman, and Alfred Goodman Gilman. Goodman and Gilmans The Pharmacological Basis of Therapeutics. New York: Pergamon Press, 1990.) Recent studies show that MAO B has a greater affinity than MAO A for MPTP. MPP+ enters the dopaminergic cells of the nigrostriatal system via the dopamine reuptake system and is concentrated within mitochondria by a specific energy-dependent (Schapira, Cooper, Dexter, Clark, Jenner & Marsden, 823) which then causes a mitochondrial complex I defect of the (Last Name) 4 oxidative phosphorylation/electron transport chain. These result in increased oxygen free radicals which can contribute to oxidative stress. Currently, oxidative stress is gaining the most support as the possible cause of Parkinson’s Disease. Oxidant stress and consequent cell death could develop when there is an increased dopamine turnover, resulting in excess peroxide formation, a deficiency in glutathione (GSH), thereby diminishing the brain’s capacity to clear H2O2 and an increase in reactive iron, which can promote OH formation (Olanow & Tatton, 127). Oxidative stress, in vitro, can lead to aggregation of -synuclein and proteosomal dysfunction (Fauci, et.al, 2553). Alpha-synuclein, which is deposited in the neuronal body, neuronal processes, astrocytes and oligodendroglial cells, form round lamellated eosinophilic cytoplasmic inclusions, the Lewy bodies (LBs), which is the hallmark of the disease (Agamanolis). These Lewy bodies cause neuronal damage and eventually, neuronal death or apoptosis. A mitochondrial complex I defect could also lead to cell damage through free radicals generated directly at this site or by way of a compensatory increase in respiration at complex II. It is noteworthy that MPTP toxicity can be attenuated by free radical scavengers and by coenzyme Q, a redox component of the mitochondrial respiratory chain that accepts electrons from complex I or II (Olanow & Tatton, 130). These mechanisms by which the neurotoxin MPTP causes Parkinsonism are aggravated because the affected neuron is not able to eliminate the said toxin. As a result, irreversible damage is done to the substantia nigra. and none was not cured by any medications. The fight against Parkinson’s Diseases is still waging on and further researches are being done as to the know its definite cause. However, one cannot discount the influence of environmental factors and the deleterious effects of MPTP to cause Parkinsonism. Therefore, prevention by avoiding exposure to MPTP and toxins which have similar structure or effects and proper information dissemination is the key to avert any hazardous consequences. (Last Name) 5 Works Cited Agamanolis, Dimitri. Degenerative Diseases. August 2007. 23 November 2008 < http://neuropathology.neoucom.edu/chapter9/chapter9dPD.html>. American Parkinson Disease Association (APDA). Patient Information: Risk Factors and Protective Factors. 25 Oct 2006. 23 November 2008 < http://www.apdaparkinson.org /User1ND/DetailedInfo.aspx?url=RiskFactors.htm> Ballard PA, JW Tetrud, and JW Langston. "Permanent Human Parkinsonism Due to 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP): Seven Cases." Neurology. 35. 7 (1985): 949-56. Braddom, Randall L., and Ralph M. Buschbacher. Physical Medicine and Rehabilitation. Philadelphia: Saunders, 2000. de Rijk MC, et al. "Prevalence of Parkinsons Disease in Europe: A Collaborative Study of Population-Based Cohorts. Neurologic Diseases in the Elderly Research Group." Neurology. 54. 11 (2000): 21-3. European Parkinson Disease Association (EPDA). The Global Declaration on Parkinsons Disease. 03 April 2007. 23 November 2008 . Fauci, Anthony S., and Tinsley Randolph Harrison. Harrisons Principles of Internal Medicine. New York: McGraw-Hill, Medical Pub. Division, 2008. Goodman, Louis Sanford, Alfred Gilman, and Alfred Goodman Gilman. Goodman and Gilmans The Pharmacological Basis of Therapeutics. New York: Pergamon Press, 1990. (Last Name) 6 Hauser, Robert A., Pahwa, Rajesh, Lyons, Kelly E., McClain, Theresa A. Parkinsons Disease. 17 May 2007. 23 November 2008 < http://www.emedicine.com/NEURO/topic304.htm>. MyDr.com. Parkinson’s Disease: MPTP and Drug-Induced Parkinson’s. 23 July 2007. 23 November 2008 < http://www.mydr.com.au/default.asp?Article=3299>. Olanow CW, and WG Tatton. "Etiology and Pathogenesis of Parkinsons Disease." Annual Review of Neuroscience. 22 (1999): 123-44. Schapira AH, JM Cooper, D Dexter, JB Clark, P Jenner, and CD Marsden. "Mitochondrial Complex I Deficiency in Parkinsons Disease." Journal of Neurochemistry. 54. 3 (1990): 823-7. Singer TP, JI Salach, Castagnoli N Jr, and A Trevor. "Interactions of the Neurotoxic Amine 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine with Monoamine Oxidases." The Biochemical Journal. 235. 3 (1986): 785-9. Snell, Richard S. Clinical Neuroanatomy for Medical Students. Philadelphia: Lippincott Williams & Wilkins, 2001. Read More