Parkinson disease is the second-most
common progressive neurodegenerative
disorder that affects 2–3% of the
population ≥55 years of age.
In PD there is deficiency of dopamine in
Nigrostriatal dopamine pathway.
It is important to remember that,only
∼10% of PD cases are due to genetic
PD Characterized by cardinal features of
resting tremor, rigidity, bradykinrsia,
Dauer W et al. Neuron. 2003 Sep 11;39(6):889-909
Motor circuit in PD pathology
D2 receptor D1 receptor
VA & VL
•Reserpine works by inhibiting the vesicular monoamine transporter, VMAT2.
•Reserpine produces ~85% loss of dopamine in the SNpc.
>95% dopamine depletion in the striatum (2 h inj)
•Animals: Male NMRI mice (20–25 g)
•Inducer: Reserpine ( 5 mg/kg i.p)
•30 min prior to observation the test compounds are injected
• The animals are placed singly onto the floor of a Perspex container
• Horizontal movements are recorded for 10 min
• Record rearings and grooming episodes.
MPTP model in monkeys
•MPTP is indeed the gold standard for toxin-based animal models of PD.
•MPTP primarily causes damage to the nigrostriatal DA pathway with a
profound loss of DA in the striatum and SNpc
•Animals: rhesus monkeys( 5–8 kg)
•Dose: 10– 18 mg/kg i.v
•Time period : 5-8days
6-OHDA Induced models
• 6-OHDA does not efficiently cross the blood–brain barrier and so requires
direct injection into the brain.
6-OHDA unilaterally injected by using stereotaxic surgical
6-OHDA is taken up into the dopaminergic neurons via the
dopamine transporter, DAT
• 6-OHDA initiates degeneration through a combination of oxidative
stress and mitochondrial respiratory dysfunction.
• 6-OHDA readily oxidizes to form reactive oxygen species (ROS) such
Circling behavior in nigrostriatal
• Unilateral lesion of the dopaminergic nigrostriatal pathway in the rat by the
• Rat are rotates in a opposite direction (contralateral) when apomorphine, or L-
dopa is given.
• Rats rotate towards the lesioned side (ipsilateral) when amphetamine is
• Rotational behaviour is dependent upon the amount of DA receptor
stimulation, and the extent of DA denervation produced by the 6-OHDA lesion
• This test is used for the study of central dopamine function and the evaluate the
mode of action of new drugs on dopaminergic neuron
• Animals: Male Wistar rats (200–250 g)
• Anaesthesia: sodium pentobarbital(60 mg/kg i.p.)
• Toxin: 6-OHDA(8 μg)
Test compounds are
given i.p or sc. and
placed into the roto
Circling is recorded
over a 1 h period.
circling are determined
1mg/kg s.c. and
recording the rat’s
circling for 1 h
Percent change of
drug turns from
control & test turns
doses ED50 values
can be calculated
Determine the for
each subject is
mg/kg of D-
• Rotenone is the most intoxicating member of the rotenoid family and is
typically found in tropical plants.
• It is both an herbicide and insecticide having a half‐life of 3–5 days
• The most commonly administred by systemic route using osmotic pumps in
rats, (2–3 mg·kg-1/day)
• Rotenone is known to be a high-affinity specific inhibitor of complex 1 ,that
are involved in oxidative phosphorylation
Paraquat & Maneb model
(N,N dimethyl 4 4 bypiridinium)
‐ ‐ ‐ ‐
•paraquat (10 mg/kg i.p.)
•Maneb (30 mg/kg i.p.)
•Paraquat (PQ) is an herbicide that exhibits similar structure to MPP+
•Maneb preferentially act by inhibiting complex III of the mitochondrial respiratory
•PQ and Maneb have been shown to produce enhanced toxicity when combined
• PQ exerts its deleterious effect
through oxidative stress mediated by
redox cycling and generating reactive
Blanco-Ayala T et al. 2014 Jun 1;48(6):623-40.
α-synuclein expressed in the nervous system, where it is found in presynaptic
α-synuclein is a protein that, in humans, is encoded by the SNCA gene
Mutations of α syn, done by any of the substitutions A30P, A53T, and E46K
Mutations in a-synuclein increase the propensity for misfolding leads to
formation of lewybodies.
Koprich JB et al. Nature Reviews Neuroscience. 2017 Sep;18(9):515.
• The most frequent mutations are the G2019S and the R1441C
• Overexpression of wild-type LRRK2 in BAC transgenic mice induces
increased DA release in the striatum and motor hyperactivity
• BAC transgenic mice overexpressing R1441G mutant LRRK2 protein
showed age-dependent and progressive motor-activity deficits,
• LRRK2 KO mice are viable and have an intact nigrostriatal DA pathway
up to 2 years of age
• Mutated LRRK2 prompts the aggregation of a-synuclein
• Parkin is an E3 ubiquitin ligase and participates in the ubiquitin proteasome
• Combination with PINK1, parkin is directly involved in the mitochondria
• DJ-1 is a redox-sensitive molecular chaperones protein, localized in the
cytoplasm, which associates with mitochondria.
• DJ-1 KO mice are more sensitive to toxins and oxidative stress.
• DJ-1 overexpression was associated with increased protection against toxin-
MitoPark mouse model
Mitochondrial function is selectively disrupted by elimination of the
nuclear genome encoded mitochondrial Tfam gene
Mice survive to adulthood
and progressively show a PD
like motor deficts
Degeneration of nigrostriatal
L-dopa treatment normalizes motor deficits of MitoPark mice and its
efficacy weakens with age
• fruit fly Drosophila melanogaster has emerged as a suitable model for
studying mechanisms of PD-related neurodegeneration.
• the models exhibit motor deficits, manifest as a premature loss of climbing
ability when the flies are permitted to ‘escape’ from a vial housing them
(A53T or A30P )
premature loss of
climbing in 80%
30–50% loss of TH
• One-third of the cells that constitute the adult worm are neurones, of which
exactly eight are dopaminergic and are involved in motor activity
• Mutations within the gene leads to the typical decrease in locomotion (basal
slowing) i.e. reduction of bending frequency when near food(e.g. bacteria), to
• C. elegans is transparent and dopaminergic neurones can be easily observed in
live animals by driving the expression of green fluorescent protein.
• by over-expressing wild-type or mutant human a-synuclein (A53T or A30P)
display degeneration of dopaminergic neurons alongside loss of the basal
• over-expression of wild-type LRRK2 increased survival in response to
paraquat and rotenone indicating LRRK2 mutations may enhance vulnerability
• In zebrafish, dopaminergic neurons found in the posterior tuberculum of the
ventral diencephalon ascend towards the striatum.
• This altered dopaminergic activity is mirrored by reduced swimming,
indicative of bradykinesia,
• Overexpression of parkin protein protects the fish from cellular stress.
• Parkin KO causes a moderate (20%) loss of dopaminergic neurones, reduced
mitochondrial complex I activity and increased susceptibility to toxins
• PINK1 knockdown in zebrafish does not induce dopaminergic cell loss but,
instead, alters dopaminergic projections and induces locomotor deficits
• Pharmacological models are not effective for drugs used for repeated
• Toxin models are effective but they don’t show the formation of α-synuclein
aggregrates & lac of age dependent degradation of dopaminergic neuron.
• Genetic model of Parkinsons disease are effective but not showing the
neurodegeneration which is one of major hallmark of PD patiennts.
• Alternative models are more effective as compare to all model as they shows
all the symptomps occurred in PD patient .
• Selection of a suitable model which shows all the cardinal feature of PD is
effective for new drug development of parkinsons disease.
• Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag AE,
Lang AE. Parkinson disease. Nature reviews Disease primers. 2017 Mar 23;3:17013.
• Koprich JB, Kalia LV, Brotchie JM. Animal models of α-synucleinopathy for Parkinson
disease drug development. Nature Reviews Neuroscience. 2017 Sep;18(9):515.
• Blesa J, Trigo-Damas I, Quiroga-Varela A, del Rey NL. Parkinson’s Disease-
Associated Mutations Affect Mitochondrial Function. InMitochondrial Mechanisms of
Degeneration and Repair in Parkinson's Disease 2016 (pp. 139-158). Springer, Cham.
• Duty S, Jenner P. Animal models of Parkinson's disease: a source of novel treatments
and clues to the cause of the disease. British journal of pharmacology. 2011 Oct
• Blesa J, Przedborski S. Parkinson’s disease: animal models and dopaminergic cell
vulnerability. Frontiers in neuroanatomy. 2014 Dec 15;8:155.
• Dauer W, Przedborski S. Parkinson's disease: mechanisms and models. Neuron. 2003