Download Heroin and Parkinson`s

HEROIN AND PARKINSON’S
DISEASE
Brendan Sudbury, John Iovino, Matthew Bell, Michael Zangari
PHM142 Fall 2016
Instructor: Dr. Jeffrey Henderson
CASE STUDY
• Patients in the California Bay Area went from relatively normal individuals to
“frozen” in stature (Form and Langston, 2016)
• These patients had the symptoms of severe Parkinson's Disease;
bradykinesia, rigidity, tremor, flexed posture, loss of postural reflexes, and
drooling (Gupta, 2011)
• It was determined all of these individuals were heroin users, and received
their heroin from the same source
• Instead of heroin these individuals injected MPPP, a derivative of Demerol,
and MPTP, a by product from the reaction (Form and Langston, 2016)
Image retrieved from Form and Langston, 2016.
• From this incidence has emerged the use of MPTP-induced parkinsonism in
primates as an animal model for the study of Parkinson's Disease (Deik et al.,
2012)
PARKINSON’S DISEASE
• 2nd most common neurodegenerative disease
• Old age is a huge risk factor
• Don’t fully understand yet how aging puts people at risk
• Symptoms:
• Resting tremor
• Rigidity
• Bradykinesia
• Postural instability
• Motor impairments
CLASSIC PARKINSON'S DISEASE VERSUS
MPTP INDUCED PARKINSONISM
Classical Parkinson’s Disease
• Progressive loss of dopaminergic neurons in
the substantia nigra pars compacta. This leads
to the depletion of the striatal dopamine
• Presence of Lewy Bodies which are
accumulations of alpha-synuclein and
ubiquitin
Image retrieved from: https://www.rndsystems.com/resources/articles/alpha-synuclein-based-modelstudying-parkinsons-disease-pathology
MPTP Induced Parkinsonism
• Unlike classical Parkinson's disease, MPTP does not
induce the formation of Lewy bodies
• Selective nigral dopaminergic neuronal damage
thought to be induced by the toxic effects of
inhibiting the mitochondria (Fornai, F. et al., 2004)
Image adapted from: http://veganpaleoflux.com/mitochondria/
MPTP (L-METHYL-4-PHENYL-1,2,3,6TETRAHYDROPYRIDINE)
• MPTP is a byproduct in the production of synthetic heroin, MPPP (Gupta, 2011)
• MPTP leads to a severe loss of pigmented nerve cells in the substantia nigra pars compacta
(Langston et al., 1984)
• MPTP in it’s active form can also leads to decreased release of dopamine from these nerve cells
(Langston et al., 1985)
• Easily crosses the BBB due to high lipophilicity (Philippens, 2008)
Image retrieved from Form and Langston, 2016.
• MPTP is converted to it’s active form MPP+ via
the enzyme MAO-B (Philippens, 2008)
• MPP+ can be transported into dopaminergic
neurons via the Dopamine receptor (DAT)
(Philippens, 2008)
• Leads to specificity towards dopaminergic cell
• MPP+ major mechanism of pathology is through
inhibition of Complex 1 in the ETC of the
mitochondria (Cleeter et al., 1992)
• Prevention of energy production
Image retrieved from Form and Langston, 2016.
MPTP AND OXIDATIVE STRESS
• Inhibition of complex I of the ETC prevents the
oxidation of NADH
• Inhibition of the mitochondria gives rise to
reactive oxygen radicals and oxidized iron, which
have been strongly implicated in the pathology of
Parkinson’s disease (Sian, J. et al., 1999)
• Dopamine is an unstable molecule that undergoes
auto-oxidation to form dopamine quinones and
free radicals (Dias,V. et al., 2014)
• This process is catalyzed by MPP+, which can lead
to subsequent neuronal membrane damage
Image retrieved from Sian, J. et al. 1999
TREATMENT: MAO-B INHIBITORS
•
With no cure for Parkinson’s, drugs which suppress symptoms are a patient’s best choice for improving quality of
life.
•
Selegiline and rasagiline (Riderer and Laux, 2011)
•
Suicide Inhibitors
•
Selective for MAO-B
•
Only newly synthesized MAO-B are functional. Recovery time ~ 30-40 days. (Riederer and Laux, 2011)
•
The result: Reduced dopaminergic neuron breakdown via MPTP pathway.
Image retrieved from Sian, J. et al. 1999
FUTURE CONSIDERATIONS: LINKING PD
TREATMENT TO HEROIN ADDICTION?
• Heroin is capable of generating abnormally high stimulation of dopamine.
• With chronic use, the body responds to these abnormally high levels by increasing the number of inhibitory autoreceptors
on dopamine neurons. (Kosten and George, 2002)
• The result: more heroin is needed to produce the desired euphoric effect.
• If heroin use is suddenly halted, dopamine deprivation ensues… (Kosten and George, 2002).
• The biochemical reason why withdrawal symptoms occur.
• Possible Solution
• Could administering drugs typically used to treat Parkinson’s symptoms help addicts with overcoming withdrawal?
SUMMARY
• Heroin Parkonsinism
•
No Lewy body presence
•
MPTP is found in synthetic heroin as a byproduct of the Demerol analogue, MPPP
•
MPTP is converted to MPP+ by MAO-B enzyme
•
MPP+ can enter dopamine neurons in the substantia nigra pars compacta via the dopamine
transporter (DAT)
•
MPP+ can inhibit Complex 1 of the ETC inhibiting the production of ATP
•
•
Receives electrons from NADH and pumps proton to create the proton gradient for
the ATP synthase for the production of energy for the cell
Can also cause oxidative stress and destroy cell membranes
Treatment
•
MAO-B inhibitors such as seligiline will inhibit the conversion of MPTP to MPP+, essentially
preventing the inhibition of Complex I, leading to less oxidative stress on the dopaminergic
neurons.
REFERENCES
•
Cleeter, M. W. J., Cooper, J. M., & Schapira, A. H. V. (1992). Irreversible inhibition of mitochondrial complex I by 1‐methyl‐4‐phenylpyridinium:
evidence for free radical involvement. Journal of neurochemistry, 58(2), 786-789.
•
Deik, A., Saunders-Pullman, R., & San Luciano, M. (2012). Substance abuse and movement disorders: complex interactions and comorbidities.
Current drug abuse reviews, 5(3), 243-253.
•
Dias, V., Junn, E., Mouradian, & Maral, M. (2013). The role of Oxidative stress in Parkinson’s disease. Journal of Parkinson’s Disease, 3(4), 461–491.
•
Form, C., & Langston, W. Mind your P’s and T’s: How tainted drugs revolutionized Parkinson’s research.
•
Fornai, F., Lenzi, P., Gesi, M., Ruffoli, R., Ferrucci, M., Lazzeri, G., … Oliver M Schlü Ter §. (2004). Parkinson-like syndrome induced by continuous
MPTP infusion: Convergent roles of the ubiquitin- proteasome system and -synuclein.
•
Gupta, M. D. (2011). Synthetic Heroin-Induced Parkinsonism. Jefferson Journal of Psychiatry, 4(2), 11.
•
Kosten T and George, T. (2002). The Neurobiology of Opioid Dependence: Implications for Treatment. Addiction Science and Clinical Practice
1(1): 13-20.
•
Langston JW, Forno L, Rebert CR, et al: Selective nigral toxicity after systemic administration of MPTP in the squirrel monkey. Brain Res
292:390- 394, 1984
•
Langston JW, Langston EB, Irwin I: MPTP-induced Parkinsonism in human and non-human primates-clinical and experimental aspects. Acta
Neurol Scand 70(Suppl. 100):49-54, 1985
•
Philippens, I. H. (2008). Non-human primate models for Parkinson's disease. Drug Discovery Today: Disease Models, 5(2), 105-111.
•
Riederer, P and Laux, G. (2011). MAO Inhibitors in Parkinson’s Disease. Experimental Neurobiology 20(1): 1-17.
•
Sian J, Youdim MBH, Riederer P, et al. (1999). MPTP-Induced Parkinsonian Syndrome. In: Siegel GJ, Agranoff BW, Albers RW, et al., editors.
Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven.