week 10: Parkinsons disease Flashcards
History of Parkinson’s disease = 1917, 1912, 1950
- 1817- James Parkinson defined “shaking palsy”, disorders characterised by:
“Involuntary tremulous motion, with lessoned muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forward, and to pass from walking to a running pace: The senses and intellects being uninjured.” - 1912- Friedrich Lewy described the presence of Lewy bodies as a pathological hallmark of PD
- 1950s- Carlsson observes that 80% of the dopamine in the brain is found in the basal ganglia and suggests a link between PD and the loss of basal ganglia dopamine
Parkinson’s disease occurs in which population?
- Occurs in ~0.3% of the population
- 1-3% of the elderly population (<65 years of age)
Parkinson’s disease - WHAT IS IT? CAUSED BY? = 4
- Progressive NEUROGENERATIVE DISORDER
- ‘Nigrostriatal dopaminergic’ pathway
- Significant CELL LOSS IN SUBSTANTIA NIGRA PARS COMPACTA
- Depletion of DOPAMINE
Symptoms of Parkinson’s Disease include: 5
- Rigidity
- Bradykinesia (slowness of movement)
- Postural instability
- Dysfunctional gait
- Tremors
What some NON-MOTOT SYMPTOMS OF PD?
- Non-motor symptoms are
COMMON and can occur at
ALL STAGES OF PD - ‘Neuropsychiatric symptoms’
- depression,
- anhedonia
- confusion
- dementia
- hallucinations, illusions, delusions,
attention deficit
- cognitive dysfunction
- anxiety, panic attacks, apathy - SLEEP DIORDERS
- restless legs and perioidic limb movements
- RM loss of atonia
- insomnia
- sleep-disordered breathing
- vivd dreaming
- REM Behaviour disorder
- excessive daytime somnolence - SENSORY SYMPTOMS
- Pain - primary PD realted central pain
- secondary pain
- fluctuation-related pain; wearing off, dyskinesia
- paraesthesia
- olfactory disturbance
- visual dysfunction = contrast sensitivity, colour vision
The relationship between LEWY BODIES AND PD = 3
- CELL LOSS IN SUBSTANTIA NIGRA PARS COMPACTA
- Loss of dopaminergic TERMINAL LOSS IN THE STRIATUM > DOPAMINE CELL LOSS IN SUBSTANTIA NIGRA PARS
3.Lewy bodies are clumps of abnormal protein particles that, for reasons that are not fully understood, accumulate in the brain.
Parkinson’s disease is caused by
- A-SYNCULEIN AGGREGATES
– Protein misfolding
– Oxidative stress
Parkinson’s disease is caused by….WHICH ARE FOUND IN WHICH SPECIFIC REGIONS OF THE NERVOUS SYSTEM? = 3
A-synuclein aggregates
Found in specific regions of the nervous system (e.g.):
- Basal ganglia
- Olfactory bulb
- Locus coeruleus
PD:
‘A-synuclein aggregates’ OCCUR IN OTHER NEUROLOGICAL DISORDERS = 3
- DOWN SYNDROME
- ALZHIEMERS DISEASE
- RAPID EYE MOVEMENT SLEEP DISORDER
(REM SLEEP DISORDER)
CAUSE OF PARKINSON’S DISEASE = 3
PROTEIN MISFOLDING
- PROETIN HOMEOSTASIS IS IMPAIRED IN PD
- PROTEIN SURVEILLANCE SYSTEMS DETECT ALTERED PROTEINS AND …STIMULATE THE REMOVAL AND ELIMINATION
- ‘A-SYNUCLEIN’ AGGREGATES IN PARTICULAR ‘AFFECT SURVEILLANCE SYSTEMS’
CAUSES OF PARKINSON’S DISEASE = OXIDATIVE STRESS
- Post-mortem analysis of PD TISSUES SHOWS SIGNS OF INCREASED OXIDATIVE STRESS
- INHIBITORS OF MITOCHONDRIAL COMPLEX 1 INDUCE PD FEATURES IN ANMALS
- INCREASE IN ‘REACTIVE OXIDATIVE’ SPECIES INDUCES WIDESPREAD ‘CELLULAR DAMAGE’
- OXIDATIVE SPECIES CAN COME FROM =
- MITOCHONDRIAL SOURCES OR
- DOPAMINE OXIDATON
What is the functional role of ALPHA-SYNUCLEIN?
- functional role not completely understood
- MAY BE IMPORTANT FOR
- REGULATION OF ACTIVITY-DEPENDENT MODULATION OF NIGROSTRIATAL DOPAMINE TRANSMISSION
- or LONG TERM REGULATION OF PRE-SYNAPTIC FUNCTION
Animal models of PD… Model broadly separated into?
- Several animal models mimic PD symptoms
- MODELS REPLICATE SUBSETS OF SYMPTOMS
MODELS BRADLY SEPARATED INTO
1. ‘TOXIN MODELS’
2. ‘GENETIC MODELS’
What is 6-Hydroxydopamine (6-OHDA) and how is it used in Parkinson’s Disease (PD) models? =5
- 1st animal of PD to model substantia nigra pars compacta dopaminergic cell death used
- 6-Hydroxydopamine (6-OHDA) is an ANALOGUE OF DOPAMINE
- Does NOT CROSS BLOOD BRAIN BARRIER
- INSERTED INTO TARGETED BRAIN REGIONS
- CONCENTRATION AND VOLUME CAN BE USED TO CONTROL THE SIZE OF THE LESION/ CELL DEATH
define what is STEREOTAXIC SURGERY? = 3
- Using ATLASES OF BRAIN ANATOMY IN RODENTS - SPECIFIC BRAIN REGIONS CAN BE TARGETED FOR MANIPULATION
- INJECTIONS INTO BRAIN REGIONS USING ‘FINE TIP GLASS PIPETTES’
- Allows for REPRODUCIBLE AND ACCURATE TARGETING
What are the behavioral effects of the 6-OHDA model in Parkinson’s Disease (PD) research, and how can these effects be assessed in rodents? = 3
- The 6-OHDA model causes an IMBALANCE OF DOPAMINE TRANSMISSION
- LEADING TO ALTERED ROTATIONAL BEHAVIOUR in RODENTS with a ‘UNILATERAL LESION IN THE NIGROSTRIAL PATHWAY’
- BEHAVIOUR assessed by ADMINISTERING DOPAMINE AGONIST (like apomorphine) or amphetamine, which INDUCES GREATER ROTATIONS in the rodents.
What is L-DOPA, and how is it used in the treatment of Parkinson’s Disease (PD)? = 4
- L-DOPA is a dopamine PRECURSOR and INDIRECT agonist for DA RECEPTORS, used for DOPAMINE REPLACEMENT THERAPY in PD.
- It is given in COMBINATION with ‘carbidopa’ or ‘benserazide’ to help L-DOPA REACH CNS.
- However, it DOES NOT effectively RELIEVE ALL PD SYMPTOMS
- LONG-TERM TREATMENT can LEAD to DYSKINESIA (involuntary movements).
What is amantadine, and how is it used in the treatment of Parkinson’s Disease (PD)? = 4
- Amantadine was originally used as an anti-influenza drug but also treats PD symptoms.
- It is the only drug to date with proven efficacy for treating L-DOPA-induced dyskinesia.
- Although its mechanisms of action are not completely understood,
- amantadine has MULTI-MODAL EFFECTS (DOPAMINERGIC AND GLUTAMATERGIC SYSTEMS)
How does amantadine affect the dopaminergic system in Parkinson’s Disease (PD) treatment? = 3
- ENHANCES dopamine transmission both PRE-AND POST - SYNAPTICALLY.
- It is believed to INCREASE THE RESPONSIVENESS and BINDING OF DOPAMINE TO D2 RECEPTORS
- MAY ALSO ALTER THE ACTIVITY OF MONOAMINE OXIDASE B
How does amantadine affect glutamatergic transmission in the treatment of L-DOPA-induced dyskinesia? = 3
- inhibits NMDA receptors, addressing the DYSREGULATION of GLUTAMINERGIC TRANSMISSION in the BASAL GANGLIA associated with ‘L-DOPA-induced dyskinesia.’
- no other anti-glutamatergic drug has shown equal efficacy,
- amantadine is often used as a REFERENCE DRUG when developing NEW ANTI-DYSKINESIA DRUGS
How are MAO-inhibitors used in the treatment of Parkinson’s Disease (PD), and what are their potential benefits? = 5
- MAO-inhibitors, which metabolize dopamine, noradrenaline, serotonin, and adrenaline,
- can be used in early PD diagnosis to DELAY NEED FOR for L-DOPA.
- They can also POTENTIATE the effect of L-DOPA.
- ‘Selegiline and rasagiline’ are IRREVERSIBLE INHIBITORS of MAO-B and
- may have NEUROPROTECTIVE PROPERTIES
What challenges are associated with a-synuclein therapies in Parkinson’s Disease (PD)?
- NEURONS SECRETE SMALL AMOUNTS of a-synuclein, leading to LIMITED ANTIBODY BINDING
- targeting the PROTEIN MISFOLDING that occurs INTRACELLULARLY is difficult,
What is Deep Brain Stimulation (DBS) and how is it used in the treatment of Parkinson’s Disease (PD)?
- Deep Brain Stimulation (DBS) involves implanting an electrode into the brain to electrically stimulate dopaminergic neurons
- typically in the
- Globus Pallidus or
- Subthalamic Nucleus.
3.A pulse generator implanted near the collarbone controls and induces electrical activity.
- The frequency of stimulation can be tailored to the individual.
- While DBS TREATS SYMPTOMS of PD, it does NOT STOP NERUAL DEGENRATION
Describe treatments of Parkinson’s Disease and their mechanism:
- – L-DOPA
- – Amantadine
- – Monoamine oxidase inhibitors
- – A-synuclein treatment
- – Deep brain stimulation
A-synuclein treatment
vaccines that target alpha-synuclein; the idea is that these vaccines will capture and remove the alpha-synuclein being passed between cells and thus stop or at least slow down Parkinson’s progression.
Explain the 6-OHDA model of Parkinson’s Disease
– Mechanisms
– Behaviour
Explain the 6-OHDA model of Parkinson’s Disease
– Mechanisms
– Behaviour
