This slide is about Parkinson's diseases.(Basic Pathology & Toxicology)

1. Parkinson's Disease
&
Treatment
Presented by:
Rafiul Basher Rabby
Student of North South University

2. Introduction:
Parkinson's disease (PD) is a long-term degenerative
disorder of the central nervous system that mainly affects
the motor system.

3. It happens when nerve cells in the brain don't produce enough of a brain
chemical called dopamine.
With less and less dopamine, a person has less and less ability to regulate their
movements, body and emotions.

4. Symptoms
The symptoms of ‘Parkinson's disease’ is classified into three major groups:
1. Primary Motor Symptoms:
• Resting Tremor
• Bradykinesia
• Rigidity
• Postural Instability
2. Secondary Motor Symptoms:
• Freezing
• Micrographia
• Mask-like Expression
• Unwanted Accelerations

5. Additional secondary motor symptoms include those below:
• Impaired gross motor coordination
• Poverty of movement (decreased arm swing)
• Speech problems
3. Nonmotor Symptoms:
• Loss of sense of smell, constipation
• REM behavior disorder (a sleep disorder)
• Mood disorders
Other Nonmotor Symptoms:
• Depression
• Fear and anxiety
• Vision and dental problems
• Weight loss or gain
• Skin problems

6. The Stages of Parkinson's Disease:
Parkinson's Disease appears to have five different stages.
Parkinson's disease stages include:
1. Stage one:
During this initial phase of the disease, a person usually experiences mild symptoms, such as
tremors or shaking in a limb. During this stage, changes caused by Parkinson's, such as poor posture,
loss of balance, and abnormal facial expressions.
2. Stage two:
In the second stage of Parkinson's disease, the person's symptoms are bilateral, affecting both
limbs and both sides of the body.

7. 3. Stage three:
Stage three symptoms of Parkinson's disease can be rather severe and include the inability to walk
straight or to stand. There is a noticeable slowing of physical movements in stage three.
4. Stage four:
This stage of the disease is accompanied by severe symptoms of Parkinson's. Walking may still
occur, but it is often limited, and rigidity and bradykinesia (a slowing of movement) are often
visible.
5. Stage five:
In the last or final stage of Parkinson's disease, the person is usually unable to take care of himself
or herself and may not be able to stand or walk. A person at stage five usually requires constant
one-on-one nursing care.

8. Causes of Parkinson's disease
Parkinson's disease is a chronic, degenerative neurological disorder that affects one in 100 people over age 60.
There is no objective test, or biomarker, for Parkinson's disease, so the rate of misdiagnosis can be relatively high,
especially when the diagnosis is made by a non-specialist.
Prevalence of Parkinson's disease :
 Affect 200-300 per 100,000
 1,000,000 in US
 prevalence increases with increasing age
 10 per 100,000 at age 50
 200 per 100,000 at age 80

9. There are several factors that may contribute to the disease.
Genetics:
In the past 10 years, researchers have identified a number of rare instances
where Parkinson's disease appears to be caused by a single genetic mutation.
In these cases, the mutated gene is passed from generation to generation,
resulting in a great number of Parkinson's disease caseswithin an extended
family.Mutations in the LRRK2 gene are the greatest genetic contributor to
Parkinson's disease disovered to date.
Environmental factors:
On the opposite end of the continuum, in the early 1980s, a group of heroin users in California took drugs from a
batch contaminated with a substance called MPTP. After ingesting this chemical, the drug users were stricken
with a form of Parkinson's disease that was primarily, if not exclusively, "environmental" in origin.

10. Loss of dopamine:
Dopamine is a neurotransmitter chemical that aids
in passing messages between different sections of the
brain. The cells that produce dopamine are damage
in people with Parkinson’s disease . Without an adequate
Supply of dopamine the brain is unable to properly send &
receive messages. This disruption affects the body’s
ability to coordinate movement . It can cause problems
with walking and balance
Age and gender:
Aging also plays a role in Parkinson’s disease. Advanced age is the most significant risk factor for developing
Parkinson’s disease.
Scientists believe that brain and dopamine function begin to declines the body ages.This makes a person
more susceptible to Parkinson’s.
Gender also plays a role in Parkinson’s. Men are more susceptible to developing Parkinson’s than women.

11. Familyhistory: Having a parent or sibling with Parkinson's disease is thought to nearly double your risk of
developing the disease. Five to 10 percent of people who have Parkinson's disease also have a family
member with it.
Headinjury. There is evidence that people who have experienced head injuries that knocked them
unconscious may be at an increased risk of developing Parkinson's disease.
Factors That Protect Against Parkinson’s Disease
 Caffeine: People who consume more caffeine appear to have a reduced risk of developing
Parkinson's disease as opposed to those who only consume a little caffeine or none at all.
 Cigarette smoking.:A number of studies have found that people who smoke cigarettes are less
likely to develop Parkinson's disease than those who don't.

12. Complications of Parkinson's disease
 Cognitive problems.
 Problems with swallowing .
 Sleep Problems and sleep disorders .
 Constipation and bladder problems .
 Smell dysfunction
 Pain
 Depression and emotional changes
 Sexual dysfunction

13. Pathophysiology
 Loss of dopaminergic neurons in Substania
Nigra pars compacta and locus coeruleus
(symptoms will appear after 60% to 80%)
Presence of Lewy body
Lewy body stained strongly with antibodies
of Alpha- synuclein and other ubiquitinated
damaged proteins.
Cholinergic and Serotoninergic deficits
may account for some non-motor symptoms
(cognitive impairment/dementia and depression)

14. Parkinson’s disease associated with following functions-
Increased oxidative stress
Mitochondrial dysfunction
Protein aggregation
(alpha-synuclein)
Proteasomal dysfunction

15. Clinical Diagnostic criteria for Parkinson’s disease

16. PREVENTION
Since there is no known cause of this disease there are not any
prevention methods at this time. Beside this here is some basic
strategy to prevent Parkinson’s disease -
Regular physical checkups by physicians
Performing simple mental and aerobic exercises
 High fiber nutritious food
Caffeine , Tea
Antioxidants such as Vit C , Vit D
Non steroidal anti – inflammatory drugs (NSAIDs)

17. Treatment OF Parkinson’s Disease
The main aim of treatment in Parkinson's Disease is to minimize
symptoms. In early stage Pharmacological option for the treatment of PD
is multiple.
Current Treatment For PD
●Levodopa Drugs
●Dopamine Agonist
●MAO-B inhibitors
●Anticholinergics
●Amantidine

18.  Levodopa
It used to control the symptoms of Parkinson’s disease in all stages .It is also
called Dopamine replacement therapy.
How L-dopa works
●When taken by mouth, levodopa is absorbed into the blood from the small
intestine.
● Than it is converted into dopamine in the dopaminergic neurons by Dopa
decarboxylase.
●Since motor symptoms are produced by a lack of dopamine in the
substantia nigra, the administration of L-DOPA temporarily diminishes the
motor symptom.

20. Side Effects
1.nausea
2.vomiting
3. low blood pressure
4. dry mouth.
In some individuals it may cause confusion and hallucinations.
In the long-term, use of dopamine replacement can also lead to
1.Dyskinesias and
2.Motor fluctuations.

21. DOPAMINE AGONIST
●Used in early stage of PD to reduce symptoms .
●These were also used initially for individuals experiencing on-off fluctuations and
Dyskinesias as a complementary therapy to levodopa.
●When used in late PD they are useful at reducing the off periods.
●Effective in people those are younger than 60.
●They control disorders (such as compulsive sexual activity and eating, and
pathological gambling and shopping) even more strongly than levodopa.

22. Side Effects:
Drowsiness, Hallucinations, Insomnia, and Constipation.
MAO-B inhibitors
●MAO–B inhibitors (safinamide, selegiline and rasagiline) can help our nerve cells
make better use of the dopamine that we have.
●They blocked an enzyme called monoamine oxidase type B (MAO–B), which breaks
down dopamine in our brain. It increases the amount of dopamine.
●MAO-B inhibitors used as monotherapy improve motor symptoms.
●They are useful to reduce fluctuations between on and off periods.
Side Effect:
Headaches ,Aching joints , Indigestion , Flu-like symptoms
and Depression.
Anticholinergic
●Decrease the levels of acetylcholine to achieve a closer balance with Dopamine
Amantadine
●Used in early stage of PD
●Cause greater amount of dopamine to be released in brain

23. Surgery
Surgery is again being used in people with advanced PD for whom
drug therapy is no longer sufficient.
Rehabilitation
Regular physical exercise with or without physical therapy can be
beneficial to maintain and improve mobility, flexibility, strength, gait
speed, and quality of life.
Palliative care
Palliative care specialists can help with physical symptoms, emotional
factors.

24. Animal Models of PD
An adequate animal model of PD should
reproduce cardinal features of its human counterpart.

25. Why animal models?

26. List of Models Used
• Pharmacological Induced Models
• Reserpine (at High Dosages)
• Alpha-methyl-para-tyrosine
• Toxin Induced Models
• MPTP
• Methamphetamine
• Rotenone
• 6 OHDA
• Genetic Models
• PARK1
• PARK2
• PARK5

27. First Animal Model: Reserpine
• It was serendipitously discovered that high dosages of reserpine administered to
laboratory animals caused the development of tremors and bradykinesia (slowed
muscle response) and was the hallmark symptoms of Parkinson’s disease.
• It was recognized that dopamine is an independent neurotransmitter; previously
scientists had believed it to be solely a norepinephrine precursor.
• Then evolved the current understanding of Parkinson’s disease as the
consequence of dopaminergic neuron death and dopamine depletion in the brain
and of current treatment regimens based on dopamine replacement with
Levodopa.

28. Inducing Dopaminergic Cell Deaths in Mice

29. Mechanism of MPTP to Produce Parkinsonism Symptoms
MPTP, which kills dopaminergic (DAergic) neurons, is injected into the model.

30. Mechanism of MPTP to Produce Parkinsonism Symptoms

31. Figure Immunohistochemical visualization of mouse brain striatum samples from control
and MPTP treated mice.
Tyrosine hydroxylase expression was evaluated by immunofluorescence staining of a brain section from a control
untreated mouse (A) or a corresponding brain section from a mouse treated with 17 mg/kg MPTP (B).

32. What’s new in Parkinson’s Research?
How has Parkinson’s research evolved over the past ten year!!!
When first came to PDF, scientists were very focused on the idea of using
antioxidants to treat Parkinson’s disease. In fact, there were several large
clinical trials underway to test whether compounds such as creatine and
coenzyme Q10 could treat the disease by stopping a process called oxidative
stress. To everyone’s disappointment , these clinical trials failed. But there
remains hope for one potential treatment of this kind that works by raising
blood levels of an antioxidant called urate. As we go to press a phase 3
clinical trial that potential drug is getting underway. At about this time as the
antioxidant were going on, two independent lines of research changed the
focus of the field.

33. What’s new in Parkinson’s Research?
How confident should people feel about the state of PD science!!
Over the past ten years progress may have been difficult to see- there were only a handful
of new drugs approved. But behind the scenes, scientists have made progress in
understanding how PD develops and how to stop it. More importantly ,scientists have built a
strong pipeline filled with novel compounds that tackle PD symptoms and some that may
even halt the disease itself.

34. Statistics of Parkinson disease
Some pertinent facts about Parkinson’s include:
•Parkinson’s affects up to 1 million people in the U.S
•Doctors diagnose as many as 60,000 new cases each year.
•Parkinson’s strikes 50 percent more men than women.
•The average age of onset is 60
•Early onset PD, beginning before age 50. accounts for (5-10)%of cases.
•15-25 percent of people with Parkinson’s have a relative with the disease.
•Risk for people related to someone with Parkinson’s increase 2-5 percent
•Symptoms of Parkinson’s may progress over period longer than 20 years

35. Statistics of Parkinson disease

36. References
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530193/
• http://www.cell.com/action/showFullTextImages?pii=S0896-
6273%2803%2900568-3
• https://www.hindawi.com/journals/bmri/2012/845618/tab1/
http://www.pdf.org/parkinson_research_new
https://www.floridahospital.com/parkinsons-disease-pd/statistics-parkinsons-
disease-pd