Parkinson's disease is a progressive neurological disorder caused by the loss of dopamine-producing neurons in the substantia nigra. The primary symptoms include tremors, stiffness, slow movement, and impaired balance. Dopamine is critical for normal motor function, and Parkinson's results from over 80% loss of dopamine neurons in the substantia nigra. This leads to decreased dopamine in the striatum and disrupts the direct and indirect pathways between the basal ganglia and motor cortex. Current treatments aim to replace dopamine or stimulate its receptors in the striatum.

1. Parkinson’s Disease
PRESENTED BY: GUIDED BY:
Prafulla Chandra Tiwari Mr. Rupesh Gautam
M.Pharm (1st sem) Lecturer
Pharmacology Jaipur College of pharmacy

2. PARKINSON'S DISEASE (PD)
Clinical Overview. Parkinsonism is a
clinical syndrome consisting of four
cardinal features: bradykinesia
(slowness and poverty of movement),
muscular rigidity, resting tremor (which
usually abates during voluntary
movement), and an impairment of
postural balance leading to
disturbances of gait and falling .

3. Etiology
The most common cause of
parkinsonism is idiopathic PD, first
described by James Parkinson in 1817
as paralysis agitans, or the "shaking
palsy." The pathological hallmark of PD
is a loss of the pigmented,
dopaminergic neurons of the
substantia nigra pars compacta, with
the appearance of intracellular
inclusions known as Lewy bodies.

4. Progressive loss of dopamine-
containing neurons is a feature of
normal aging; however, most people
do not lose the 70% to 80% of
dopaminergic neurons required to
cause symptomatic PD.

5. Pathophysiology. The primary deficit in
PD is a loss of the neurons in the
substantia nigra pars compacta that
provide dopaminergic innervation to
the striatum (caudate and putamen).

6. The current understanding of the
pathophysiology of PD can be traced
to neurochemical investigations that
demonstrated a reduction in the
striatal dopamine content in excess of
80%.

7. The current understanding of the
pathophysiology of PD can be traced
to neurochemical investigations that
demonstrated a reduction in the
striatal dopamine content in excess of
80%.

8. This paralleled the loss of neurons from
the substantia nigra, suggesting that
replacement of dopamine could
restore function. These fundamental
observations led to an extensive
investigative effort to understand the
metabolism and actions of dopamine
and to learn how a deficit in dopamine
gives rise to the clinical features of PD.

9. Dopamine Synthesis and Metabolism.
Dopamine, a catecholamine, is
synthesized in the terminals of
dopaminergic neurons from tyrosine
and stored, released, and metabolized

11. Dopamine Receptors.
The actions of dopamine in the brain
are mediated by a family of
dopamine-receptor proteins
. Two types of dopamine receptors
were identified in the mammalian brain
using pharmacological techniques: D1
receptors, which stimulate the synthesis
of the intracellular second messenger
cyclic AMP, and D2 receptors, which
inhibit cyclic AMP synthesis as well as
suppress Ca2+ currents and activate
receptor-operated K+ currents.

12. The five dopamine receptors can be
divided into two groups on the basis of
their pharmacological and structural
properties . The D1 and D5 proteins
have a long intracellular carboxy-
terminal tail and are members of the
class defined pharmacologically as D1;
they stimulate the formation of cyclic
AMP and phosphatidyl inositol
hydrolysis.

13. The D2, D3, and D4 receptors share a
large third intracellular loop and are of
the D2 class. They decrease cyclic AMP
formation and modulate K+ and Ca2+
currents. Each of the five dopamine
receptor proteins has a distinct
anatomical pattern of expression in the
brain.

14. The D1 and D2 proteins are abundant in
the striatum and are the most
important receptor sites with regard to
the causes and treatment of PD. The D4
and D5 proteins are largely extrastriatal,
whereas D3 expression is low in the
caudate and putamen but more
abundant in the nucleus accumbens
and olfactory tubercle.

15. Neural Mechanism of Parkinsonism.
Considerable effort has been devoted
to understanding how the loss of
dopaminergic input to the neurons of
the neostriatum gives rise to the clinical
features of PD .

16. The basal ganglia can be viewed as a
modulatory side loop that regulates the
flow of information from the cerebral
cortex to the motor neurons of the
spinal cord.

17. The basal ganglia can be viewed as a
modulatory side loop that regulates the
flow of information from the cerebral
cortex to the motor neurons of the
spinal cord

19. The neostriatum is the principal input
structure of the basal ganglia and
receives excitatory glutamatergic input
from many areas of the cortex. Most
neurons within the striatum are
projection neurons that innervate other
basal ganglia structures..

20. A small but important subgroup of
striatal neurons consists of interneurons
that connect neurons within the
striatum but do not project beyond its
borders. Acetylcholine and
neuropeptides are used as transmitters
by these striatal interneurons

21. The outflow of the striatum proceeds
along two distinct routes, termed the
direct and indirect pathways. The
direct pathway is formed by neurons in
the striatum that project directly to the
output stages of the basal ganglia, the
substantia nigra pars reticulata (SNpr)
and the globus pallidus interna (GPi);
these, in turn, relay to the
ventroanterior and ventrolateral
thalamus, which provides excitatory
input to the cortex.

22. The indirect pathway is composed of
striatal neurons that project to the
globus pallidus externa (GPe). This
structure, in turn, innervates the
subthalamic nucleus (STN), which
provides outflow to the SNpr and GPi
output stage.

23. The dopaminergic neurons of the
substantia nigra pars compacta (SNpc)
innervate all parts of the striatum;
however, the target striatal neurons
express distinct types of dopamine
receptors

24. The striatal neurons giving rise to the
direct pathway express primarily the
excitatory D1 dopamine receptor
protein, whereas the striatal neurons
forming the indirect pathway express
primarily the inhibitory D2 type.

25. Thus dopamine released in the striatum
tends to increase the activity of the
direct pathway and reduce the
activity of the indirect pathway,
whereas the depletion that occurs in
PD has the opposite effect.

26. TREATMENT OF PARKINSON'S DISEASE