Parkinson Epilepsy Flashcards
characterized by
progressive and irreversible loss of neurons from
specific regions of the brain
Neurodegenerative disorders
Examples of prototypical neurodegenerative
disorders: (4)
Parkinson disease
Huntington’s disease
Alzheimer’s disease (AD)
Amyotrophic lateral sclerosis (ALS)
loss of neurons from structures of the basal ganglia
results in abnormalities in the control of movement
Parkinson disease and Huntington’s disease
where the loss of
hippocampal and cortical neurons leads to
impairment of memory and cognitive ability
-Alzheimer’s disease (AD)
where muscular weakness results from the degeneration of spinal, bulbar, and cortical motor neurons
Amyotrophic lateral sclerosis (ALS)
2nd most common neurodegenerative disease (after Alzheimer’s disease) – Mean onset = 57 years of age – Affects 1-2% of population over 60 years of age • Disease progression is highly variable • Can be early onset in some cases
Parkinson Disease
Epidemiologic studies suggest increased risk of Parkinsons with
exposure to
pesticides, rural living, and drinking
well water
what can reduce risk of PD
reduced risk with cigarette smoking
and caffeine.
Four cardinal features of PD (4)
bradykinesia
muscular rigidity
resting tremor
impairment of postural balance
slowness and
poverty of movement
bradykinesia
stiffness and
resistance to limb movement
caused by increased muscle
tone
muscular rigidity
usually abates during voluntary movement
resting tremor
leads to disturbances of gait
and falling
impairment of postural balance
-characterized by severe loss of substantia nigra (SN) dopaminergic neurons -visible in brain sections as depigmentation of the SN in the midbrain.
Parkinson
It is estimated that approximately \_\_\_% to \_\_\_% of the SN dopamine cells are lost by the time a patient first presents for clinical evaluation, diagnosis, and treatment.
60
70
substantia nigra projects to two pathways
direct and indirect
the net effect of the ______ pathway is to excite motor cortex, and the net
effect of the _______ pathway is to
inhibit motor cortex.
direct
indirect
SN activity excites the direct pathway
(____ receptors) and inhibits the indirect
pathway (___ receptors)
D1
D2
reduces the excitation of motor cortex and its ability to generate commands for voluntary movement, resulting in the poverty of movement of Parkinsonian patients.
Loss of the nigrostriatal dopaminergic pathway
The loss of SN neurons puts a brake on the output of motor cortex, inhibiting
_______ motor commands from descending to the brain stem and spinal cord
As a result patients have difficulty initiating voluntary movements although involuntary, reflexive movements can be normal
voluntary
Neurons in CNS of PD patients have
abnormal accumulation of the protein called
α-synuclein
_______ protein accumulates inside
neurones forming inclusions called _________
α-synuclein
Lewy bodies
the unwanted product resulting from the planned synthesis of synthetic heroin.
MPTP (1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine)
Victims became almost completely immobile
(“frozen”), unable to blink and mute only
hours after injecting this drug.
MPTP (1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine)
produce Parkinson-like
symptoms in monkeys and has been used to
develop animal models for testing new
therapies for PD
MPTP
Dopamine receptors
G proteincoupled receptors (GPCRs)
The D1 and D5 receptors are members of the
D2-like family
activates adenylyl cyclase, increasing the intracellular concentration of the second
messenger cyclic adenosine monophosphate (cAMP)
Activation of D1-like family receptors coupled to the G protein Gαs
directly inhibits
the formation of cAMP by inhibiting the enzyme adenylate cyclase
D2-like family receptors coupled to the Gαi
Pharmacological Treatment of PD
• Goal =
Restore dopamine receptor function
Prodrug – immediate metabolic precursor of dopamine (DA) can cross the BBB while DA can not; 1-3% enters the brain
Levodopa
increase amount of
L-DOPA that reaches CNS
COMT inhibitors
may be given to patients who are taking levodopa
and are becoming resistant or having
fluctuations in levodopa effect
Dopamine receptor agonists
each dose of ________
effectively improves mobility for a period of time, but rigidity and akinesia
return rapidly at the end of the dosing interval.
levodopa
Increasing the dose of levodopa and frequency of administration can improve adverse effects, but this often is limited by the development of
dyskinesias, excessive
and abnormal involuntary movements.
•“On-off” Effect – fluctuations in clinical response to levodopa:
- “Off” = marked akinesia
- “On” = improved mobility but marked dyskinesia.
Conditions with PD-like symptoms
that result from other causes are
referred to as
parkinsonism
a natural alkaloid that
blocks vesicular transport of
monoamines, depletes stored
monoamines, including DA
Reserpine
drugs used in the treatment of schizophrenia
block the action of DA on its receptors
Antipsychotic drugs (neuroleptics)
•Patients who have received
neuroleptics for long periods of time
may develop
hyperkinetic disorder,
known as tardive dyskinesia
characterized by involuntary, purposeless movements affecting many parts of the body (abnormal movements of the tongue, mouth and masticatory muscles, choreoathetoid movements of the extremities)
Tardive dyskinesia
Drugs used in the treatment of nausea or vomiting (e.g., Compazine) or gastroesophageal disorders (e.g., metoclopramide) are also \_\_\_\_\_\_\_\_\_ agents
neuroleptic
the clinical manifestation of an abnormal and
excessive synchronization of a population of cortical neurons
Seizure
a tendency toward recurrent seizures unprovoked by any systemic or acute neurologic insult
Epilepsy
two or more unprovoked
seizures
Epilepsy
Epilepsy etiologies of seizures can be grouped into three categories
genetics
structural/metabolic
unknown course
Genetic etiology of epilepsy
Mutations in gene encoding a neuronal ion channel
Structural/Metabolic effects that may cause epilepsy
- trauma, tumors and other
- space-occupying lesions
- Certain drugs, withdrawal from alcohol or drugs, —metabolic disorders
- Vascular diseases
originate within networks limited to one cerebral hemisphere
and are usually associated with structural abnormalities of the brain.
•Focal seizures
arise within and rapidly engage networks distributed across both cerebral hemispheres and may result from cellular, biochemical, or
structural abnormalities that have a more widespread distribution
•Generalized seizures
disorders of neuronal excitability
epilepsies
occur when a large collection of neurons abnormally undergo
synchronous APs that produce stereotypical, involuntary spasms and alterations
in behavior
Seizures
Which factors can contribute to hyperexcitability of neurons?
- Increase excitatory post synaptic potentials (EPSPs)
- Decrease Inhibitory post synaptic potentials (IPSPs)
- Changes in voltage gated ion channels
- Alteration of local ion concentrations that favor depolarization
the principal fast (“classical”)
excitatory transmitters throughout
the CNS
Glutamate and possibly aspartate
the major inhibitory mediator in the brain, including being responsible
for presynaptic inhibition.
GABA
The mechanisms of action of anti-seizure drugs fall into three major categories:
- promoting the inactivated state of voltage-gated Na+ channels
- enhanced GABA–
mediated synaptic inhibition
3.inhibition of voltage-activated Ca2+ channels
Anti-seizure drugs
enhance Na+ channel inactivation thereby reducing the ability of neurons to fire AP at high frequencies
Several drugs inhibit seizures by enchansing
____-mediated synaptic inhibition through
an action at distinct sites of the synapse
GABA
Some _________ drugs act by reducing the
metabolism of GABA, resulting in increased
GABA concentration available for release
anti-seizure
inhibits the GABA reuptake
transporter, GAT-1, and reduces neuronal
and glial uptake of GABA
Tiagabine
activated at a much
more negative membrane potential (hence “low
threshold”) than most other voltage-gated Ca2+
channels expressed in the brain
T-type Ca2+ channels
The principal mechanism by which anti–
absence-seizure drugs act is by
inhibition of the
T-type Ca2+ channels
a common mechanism of action
among anti-seizure drugs, with anti-partial-seizure drugs inhibiting voltage-gated
Na+ channels and anti-absence-seizure drugs inhibiting voltage-gated Ca2+ channels
Inhibiting voltage-gated ion channels
Seizures can occur as an adverse effect of a large
number of drugs from different pharmacological
categories: (6)
antibiotics e.g. penicillins Immunosuppressant cyclosporine Overdose with tricyclic antidepressants Anesthetics e.g. propofol antineoplastic agents Abrupt withdrawal of therapy
recommended in protocols for bone
marrow transplantation
antineoplastic agents
