Parkinsons, pathophysiology, genetic factor, environmental factor, stages, free radicle theory

1. PARKINSON’S DISEASE
-PATHOPHYSIOLOGY
MAYUR KALE
DEPARTMENT OF PHARMACOLOGY
SKBCOP, KAMPTEE

2. Parkinson’s
Disease:

3. Types of Parkinson's Disease
• parkinsonism with no external
identifiable cause
Primary or
idiopathic
• Environmental factors
Secondary or
acquired
• Several dominant and recessive
genes
Hereditary
parkinsonism
• primary parkinsonisms which
present additional features
Parkinson plus
syndromes

4. Symptoms
1. Motor symptoms: (Primary)
 Resting Tremor
 Hypokinesia, Bradykinesia
 Rigidity Uniform (lead-pipe rigidity)
Ratchety (cogwheel rigidity)
 Postural instability
Secondary Motor Symptoms
 Freezing
 Microphagia
 Mask like expression
 Unwanted accrelation

5.  Stooped posture, a tendency to lean forward
 Dystonia (uncontrolled muscle contraction)
 Impaired fine motor skill and motor coordination
 Akathisia (restlessness)
 Speech problems, such as softness of voice or slurred
speech caused by lack of muscle control

6. Non Motor Symptoms
Autonomic Domain
 Dysphagia (difficulty in swallowing)
 Hypersalivation
 Impaired gastrointestinal motility
 Bladder disturbances
 Diaphoresis (excessive abnormal sweating)
 Sexual dysfunction
 Xerostomia (dryness of mouth)
 Constipation

7. Neuropsychiatric
 Depression (up to 50%)
 Anxiety, including panic attacks
 Dementia (20%-80%)
 Psychosis (<10% of untreated patients; 15%-40%
receiving PD medications)
 Confusion or delirium
 Apathy (Lack of intrest)

8. Sleep disorders
 Insomnia
 Restless legs and periodic limb movement
 Rapid-eye movement behavior disorder (30%)
 Sudden-onset sleep

9. Stages of PD
 Stage one Mild symptoms affect only one side of the body.
 Stage two Symptoms affect both sides of the body, with posture
and gait changes.
 Stage three Body movements are slow, and balance is impaired.
 Stage four Symptoms are severe and disabling, muscles become
rigid, the patient can't live alone, and walking is limited.
 Stage five Wheelchair-bound or bedridden, the patient needs
constant care.

10. Pathophysiology
Parkinson's
Disease
Impaired
Dopamine
Metabolism
Genetic Factor
Dominant
Inheritance
Recessive
Inheritance
Environmental
Factor
Synthetic
Neurotoxin
Insecticides
Herbicides
Fungicides
Free radical Theory
Neurotropic Factor
Drug induced Parkinson's
Disease

11. 1. Impaired Dopamine Metabolosm
 MAO induced neurotoxicity
 Magnese neurotoxicity
 Auto-oxidation of Dopamine

12. 2. Genetic Factor
Dominant
Genes in PD
SNCA
LRRK 2
(PARK8)
Recessive
Genes in PD
PARK2
(Parkin)
PINK1
(PARK6)
DJ-1
(PARK7)

13. SNCA gene
encodes the protein
alpha-synuclein
the main
component of
Lewy bodies
modulate
dopamine
synthesis and
uptake
regulates the
release of
neurotransmitters
at the presynaptic
terminal

14. LRRK 2 (PARK8)
 The LRRK 2 gene encodes for a protein called dardarin.
 One segment of the dardarin protein contains a large amount
of an amino acid called leucine.
 Proteins with leucine-rich regions appear to play a role in
activities that require interactions with other proteins, such as
transmitting signals or helping to assemble the cell’s
structural cytoskeleton.
 Other parts of the dardarin protein are thought to be involved
in protein-to-protein interactions
 Pathogenic mutations in LRRK2 seem to be associated with
an increase, rather than a loss, of kinase activity, and that
kinase activity appears to be necessary for neurotoxicity.

15. RECESSIVE PARK2 (Parkin)
The PARK2 gene
provides instructions for making a protein called parkin
which plays a role in the breakdown of unneeded proteins
It does this by tagging damaged and excess proteins with
molecules called ubiquitin.
Ubiquitin serves as a signal to move unneeded proteins into
specialized cell structures known as proteasomes

16. PINK1 (PARK6)
Park7
provides instructions for making the
DJ-1 protein
 Help to protect cells, from oxidative stress
 serve as a chaperone molecule that helps fold
newly produced proteins

17. 3. Neurotropic Factor (GDNF)
 In the CNS, Glial Cell Derived Neurotropic Factor
maintain the survival and activity of DA-ergic
neurons in the midbrain and motor neurons of the
cornu anterius medullae spinalis.

18. Synthetic Neurotoxin
MPTP
Insecticides
-Permethrin
- beta-HCH
Herbicides
-Paraquat
- 2,4-
dichlorophenoxyacetic
acid
Fungicide
-Maneb
Environmental
factor
3. Environmental Factor

19. 4. Free Radical Theory
Progressive Disease
Metabolic Reaction
Formation of Free
radicals
Engulf by enzyme
Progressively
decresed in level of
enzyme
Increased ROS
Neurodegeneration

20. 5. Drug induced Parkinson’s Disease
Potential Risk Medication
1. High Risk
a. Dopamine D2-receptor blockers Neuroleptics, Anti-emetics
b. Antihypertensive agents associated with DIP by
reducing dopamine levels
Reserpine
2. Intermediate Risk
a. Calcium channel blockers with Flunarizine, cinnarizine
b. Certain anticonvulsants Valproate
3. Lower risk
a. Antihypertensives Diltiazem, captopril
b. Antiarrhythmic Amiodarone, procaine
c. Immunosuppressants Cyclosporine, tacrolimus
d. Antidepressants Fluoxetine
e. Hormones Levothyroxine

21.  Neuroleptic: (Haloperidol & others) Block D-2 receptor
 Anti-emetics: (Metoclopramide)-Block D-2 receptor
 Calcium channel blocker: (cinnarizine and flunarizine)
Possible mechanism is
- D2 blockade
- inhibition of energy-dependent vesicular uptake of dopamine
- mitochondrial damages

22. Antiepileptic:
Possible mechanism is
- Defective function of mitochondrial enzyme
a. Nicotinamide adenine dinucleotide (NADH)
b. Coenzyme Q10
c. reductase (complex one)
- Excessive GABAergic activity in the basal ganglia

23. Thank You………
Nothng is in our control but
the action is….