CNS Disorders Flashcards
Lecture 1
Disorders of Demyelination and Ion Channel Dysfunction
What causes epilepsy?
Temporary abnormal CNS activity.
What are the possible symptoms of epilepsty?
Tonic and clonic convulsions. Loss of consciousness. Brain damage.
What are tonic convulsions?
Convulsions with prolonged muscle contraction.
What are clonic convulions?
Muscles alternate between relaxed and contracted.
What are the two symptomatic classes of epilepsy?
Focal syndromes - Localised abnormal CNS activity. Generalised - Abnormal activity in both hemispheres.
What are the two causative classes of epilepsy?
Idiopathic - No obvious cause. Mostly genetic in origin. Symptomatic - Neurological disturbance (Stroke damage/Head trauma/Tumour)
How is epilepsy diagnosed?
Medical history + Electroencephalography recordings.
How does an EEG work?
Measures cortical (surface) neuron activity between 2 electrodes. 16 electrodes used.
Describe a normal EEG pattern.
1-30Hz (Alpha = 8-13Hz; Beta = 13-30Hz).
How is overactivity indicated on an EEG?
Spikes
What are the limitations of EEG and how can they be overcome?
Measures only surface structure activity. PET/MRI scans can be used to measure activity in deeper regions.
What is the common cause of idiopathic epilepsy?
Mutations of sodium channels.
Give 2 examples of idiopathic epilepsy and the gene responsible.
Generalised Epilepsy with Febrile Seizures plus - SCN1A; Severe Myoclonic Epilepsy of Infancy - SCN1A.
What effect do mutations have on sodium channels? Give an example.
Slower inactivation of of sodium channels causing persistent current. Caused by substitution of GAL to QQQ at 879-881.
Describe the symptoms observed in Q54 mice.
Frozen posture at 3 months. Tonic-clonic seizures (grunts/trashing of limbs) and excess salivation when older. 75% die by 6 months (brain damage).
Describe the development of the hippocampus in Q54 mice.
Normal until seizures start - Severe neural loss.
What is BNFC?
Benign Neonatal Familial Convulsions.
What is the cause of Benign Neonatal Familial Convulsions.
Inherited mutations of ACh sensitive sodium (M-current) channel genes on chromosomes 8 and 20.
What are the symptoms of BNFC?
Brief generalised convulsions between 4th day and 3rd month of life. Later development normal but increased risk of epilepsy in later life.
What is the M-current?
Heteromultimeric voltage activated Potassium current.
What is the function of the M-current?
Regulates neuronal AP firing by decreasing excitability of neurones (Adaptation).
How is the M-current inhibited and what are the effects?
Activation of muscarinic receptors, Use of xE991 channel blocker. Increased excitability of a dissociated sympathetic neuron caused by the reduction in M-current. Sustained high firing frequency after depolarisation. No repolarisation.
Which genes are responsible for functional expression of the M-current?
KCNQ2/KCNQ3.
Describe the structure of a M-current channel subunit.
6TM domains. Incomplete 7th loop between S5 and S6.
What Is the M-current cycle?
Depolarisation (P(open) = low); High frequency stimulation; P(open) slowly increases causing the potassium current to broaden the AP; Frequency of firing decreases; Repolarisation (P(open) falls).
What is the effect of KCNQ2/3 mutations?
Decrease M-current amplitude by 20-30%. Neuronal hyperexcitability.
Give 4 examples disorders caused by mutations of M-current channels along with the mutation responsible.
Long QT Syndrome, Congenital Deafness - KCNQ1+KCNE1; Childhood-Onset Deafness - KCNQ3/4; Epilepsy - KCNQ2/3.
Give 3 examples of mutations in other channels and the disorders they cause.
GLRA1 - Startle Disease (Hyperekplexia); SCN4A (sodium channel) - Hyperkalemic periodic paralysis; SCN5A - Idiopathic Ventricular Fibrillation.
How does multiple sclerosis arise?
Axon demyelination leads to autoimmune responses against the damaged myelin.
What are the symptoms of multiple sclerosis?
Blurred vision, Muscle weakness/spasms, Loss of sensation.
What is the effect of multiple sclerosis on the CNS?
Breakdown of the blood-brain barrier at asymmetrical sites in the brain.
Explain the effects of demyelination on electrical properties of neurons.
Increased Cm due to thinning of insulator - causes longer time constant hence more current is required for depolarisation. Decreased Rm - shorter length constant - less EPSPs reach soma to form APs.
What are the effects of demyelination on physical properties of neurons?
Axon develops properties of an unmyelinated axon - Ion channels distribute uniformly. Slow, unreliable AP conduction. Longer AP/refractory periods blocks high frequency firing. Prone to spontaneous AP firing. Crosstalk.
Lecture 2
Cellular Mechanisms of Drug Action.
What is the composition of the CNS?
CNS = brain + spinal cord - bulk of CNS is neurons supporting glia and endothelial cells
Name three types of Glia cells
Schwann, astrocytes, oligodendrocytes
Primary target of Drugs?
Neurons
Give the two therapeutic uses of drugs in the CNS and give examples of their use in treatment
1.) Neurological: epilepsy, Parkinson’s, Alzheimers 2.) Psychotropic: anaesthetics, anxiolytics, antidepressants etc
Draw a quick sketch of the blood brain barrier
(should include a lumen, capillary, cleft and fenestra)
What does drug access to the brain require?
Carrier mediated transport or lipid solubility
General targets for the cellular basis of drug action?
Neurotransmission/Neuronal Function
GPCR (Alpha)q pathway?
Phospholipase C - Ins(1,4,5)P3 and dicylglycerol - Ca2+ and Protein kinase C
GPCR (Alpha)s/I pathway?
adenylyl cyclase - cAMP - protein kinase A
Give two ways the Neurotransmitter noradrenaline is removed and or undergoes degradation from the synapse cleft
Uptake 1: back into the synapse and repackaged into vesicles or breakdown via MAO Uptake 2: into neighbour glial cell and broken down by COMT
How is Acetylcholine removed from the synaptic cleft?
Breakdown by acetylcholinesterase
Other than Ionotropic and Metabotropic receptors what are other possible receptor targets?
Kinase- Linked receptors, Intracellular receptors (Not particularly well-developed CNS drug targets)
Breakdown of current drug targets by percentage static
Enzymes: 47%, GPCRs: 30% Ion Channels: 7%, Transporters: 4%
What are Hypnotics used to treat?
Treats Insomnia
What do Anxiolytics treat?
Treats anxiety
Most common Anxiolytic drug?
Benzodiazepines
Simple mechanism of Benzodiazepines on GABA(A) receptor
The anxiolytics is an agonist of the benzodiazepine site on the alpha1 or gamma2 subunit interface. This allows Cl- influx causing hyperpolarisation and thus inhibition
Other anxiolytics (Hint: For stress and overactivity of sympathetic nervous system)
Beta Blockers.
Two examples of Beta Blockers?
Propranol, Oxprenolol.
Define Epilepsy
Electircal disturbances in the brain leading to seizures- brief, chronically recurring, rapid onset
Cause of epilepsy?
Sodium channels stay open for too long, leading to hyper excitability of the neuron. Triggers excessive calcium release which can be neurotoxic
General treatment of Epilepsy?
Use-dependent block of Na+ channels: rapid firing means drug accumulation and blocked activity
Lecture 3
Antidepressants and Antipsychotics.
Use of GABA(A) receptor as Epilepsy treatment
Poorly-defined barbiturate site agonist, potentiate effects of GABA (inhibitory)
How to inhibit GABA breakdown in glial cells
Use Vigabatrin to reduce GABA- aminotransferase (stops GABA - succinic semialdehyde - succinate)
What is the Biological amine theory?
Depression caused by functional deficit of transmitters (originally noradrenaline) whilst mania due to excess. Evidence for 2-3 amines: NA, serotonin and dopamine
Depression: 3 Ways Drug treatment aimed at increase in neurotransmission
- Inhibit reuptake 2. Inhibit metabolism 3. Enhance release
Depression: What is used to inhibit reuptake?
Tricyclic antidepressants: eg. Receptor antagonists
Depression: What is used to inhibit metabolism?
Monoamine oxidase inhibitors (MAOIs) increases the amount for vesicular uptake and not degradation
Depression: What is used to enhance release?
Alpha 2 adrenoceptor antagonists(presynaptic receptors - regulate release (usually inhibit)
Depression: Why does clinical efficacy take weeks?
- Neuronal adaption 2. Neurogenesis
Characteristics of Amphetamine
Idirectly acting sympathomimetic - structurally related to noradrenaline. Sufficiently similar to NA to be take up by uptake 1 (although releases mainly cytosolic NA - not exocytosis
Clinical use of amphetamine?
CNS Stimulant in narcolepsy. Also used in ADHD
methylenedioxymethamphetamine
MDMA - ecstasy
Cocaine use
Local anaesthetic = state-depedent Na+ channel block *Powerful stimulant properties similar to amphetamines
Define Psychoses
Marked distortions of reality and disturbances in perception intellectual functioning, affect (mood) motivation and motor behaviour
Schizophrenia has two symptoms types what are they?
- positive: delusions and hallucinations, disorganised speech, bizarre behaviour 2. Negative: loss or decrease of normal function
Generally what are psychoses thought due to?
Overactivity of dopaminergic systems- particularly mesolimbic - associated with emotions and cognition (schizophrenia due to over activity of dopaminergic systems. Post-mortem studies show increased striatal D2 receptors)
What is the glutamate hypothesis regarding schizophrenia?
Compromised NMDA receptor function. Inhibits glycine uptake - studies with inhibitors of glycine transporter underway
Lecture 4
Opioids as Analgesic Drugs.
What are opioids used for?
Analgesia
What are the effects of Analgesia?
Nausea, hypnosis and drowsiness, mood changes mental clouding, GI motility and secretions decrease. Respitation and heart rate and pupil contriction decrease
What are the 3 types of opioid receptor?
Mu. Kappa. Delta.
Give an example of a non-selective opioid and its precursor.
Beta-endorphin; Preproopiomelanocortin.
Give an example of a delta-selective opioid and its precursor.
Leu-enkephalin; Preproenkephalin.
Give an example of a kappa-selective opioid and its precursor.
Dynorphin; Preprodynorphin.
Give 3 examples of a mu-selective opioids.
Endomorphin 1; Endomorphin 2; Morphine.
Describe the cellular mechanism of action of opioids.
Bind to opioid receptors (GiPCRs) which negatively control cAMP concentration. Beta/gamma subunits couple to ion channels.
What are the 3 main neuronal effects of opioids?
Inhibit postsynaptic excitability. Inhibit transmitter release. Modulate presynaptic AP firing.
What are the 3 main cellular effects of opioids?
Decrease in sodium channel conductance. Increase in potassium channel conductance. Decrease in calcium channel conductance.
How do opioids decrease sodium channel conductance?
Decrease cAMP. PKA not activated. No phosphorylation of sodium channels.
How do opioids increase potassium channel conductance?
Beta/gamma subunit positively regulates potassium channels by binding to them.
How do opioids decrease calcium channel conductance?
Presynaptic membrane hyperpolarised by increased potassium conductance. Less N-type VOCCs open.
What are the 3 mechanisms of increased drug tolerance?
Increased drug metabolising enzymes in liver. Altered number of receptors (insulin/BDNF). Conditioning via context of drug taking.
How does psychological drug dependence develop?
Dopamine release in nucleus accumbens (Part of pleasure centre).
What is used for morphine withdrawal? Why?
Biuprenorphine; Higher affinity. Less effective - eases withdrawal.
What is used to treat opioid overdose? Why?
Naloxone; High affinity antagonist.
Lecture 5
Parkinson’s Disease.
What are the symptoms of Parkinson’s Disease (PD)?
Tremor at rest; Muscular rigidity.
What are the two categoried of PD?
Parkinsonian syndromes. Symptomatic parkinsonism.
Describe the difference in brain activity between normal and PD brains?
Similar to lesions of basal ganglia and locus coeruleus.
Describe the damage of PD to basal ganglia.
Loss of 90% dopamine in SNpc. Degeneration of SNpc neurones. Loss of dopaminergic innervation of striatum. Abnormal increase in astrocytes (astrogliosis) (reverse causality).
What are dopamine receptors. Name the classes.
GPCR receptors. D1-5.
Describe D1 receptors.
G-alpha-s coupled - increase cAMP (Like D5).
Describe D2 receptors.
G-alpha-i coupled - Decrease cAMP; Increase potassium conductance (Beta/gamma). Like D3/4.
Describe D3 receptors.
G-alpha-i coupled - Decrease cAMP; Increase potassium conductance (Beta/gamma). Presynaptic. Inhibit DA release.
What are lewy bodies?
5-25um spheres of lipids, neurofilaments, alpha-synuclein, synphilin-1 and ubiquitin.
Where are lewy bodies found?
SNpc neuronal cytoplasm.
What are lewy bodies associated with?
PD and cell loss.
What is alpha-synuclein?
140aa protein with an amyloidogenic domain.
What causes familial PD?
Mutations in alpha-synuclein gene (SNCA). Mutations of genes coding for enzymes of the ubiquitin proteosomal pathway. Mutations in PINK1 (PTEN-induced putative kinase 1). Mutations in PARK7-DJ1.
Name 2 enzymes of the ubiquitin proteosomal pathway as well as their function, which are associated to PD.
PARK2 - E3 ubiquitin ligase. UchL1 - ubiquitin C-terminal hydrolase.
What are the roles of alpha-synuclein?
Negative regulation of DA neurotransmission. Regulation of synaptic vesicle pools. Involved in protection of terminals from injury. Trafficking ER/Golgi cargoes.
What can be deduced from build up of alpha-synuclein in lewy bodies?
Build up of toxic/damaged protein. May contribute to pathology. May be protective. Leads to cell death.
Describe the two cell death patterns that PD may cause.
Acute - Loss of a part of SNpc (caused by toxin) followed by normal cell death. Accelerated rate of cell death.
Why is PD hard to diagnose?
Cell death occurs 4-5 years before symptoms show - 50% cell loss.
Describe the neurotoxic properties of PD cell death.
Pre-fibrillar oligomers form pores disrupting organelle function. Misfolding in ER causes neuropathology.
What can be used as future treatment strategies for PD?
Modified aphla synuclein.
What is the focus of current PD therapies? Why?
DA deficit. NA deficit also occurs but NA is a derivative of DA therefore focusing on DA targets both issues.
What are the 4 therapies used in PD treatment?
Drugs replacing DA. Drugs mimicking DA. Drugs reducing DA metabolism. Surgery.
Which drug is used for replacement therapies?
Levodopa (L-DOPA).
How does levodopa work?
Substitutes DOPA in the catecholaminergic pathway. Increases DA release from alive synapses or floods them with new DA.
What are the issues with levodopa?
Only 95% converted. <1% enters the brain. Side effects: Involuntary choreiform, Schizo-like syndrome.
How has the levodopa treatment been optimised?
Inhibition of peripheral DA synthesis. DOPA decarboxylase inhibitors: Carbidopa/Benserazide. Inhibition of MAO-B (Selegiline) and COMT (Entacapone). Block of peripheral DA receptors.
Which drugs are used for mimicking therapies?
DA receptor agonists: Bromocriptine, Pergolide, Lisuride.
When are mimicking therapies used?
When DAnergic neurons are lost.
Which drugs are used for DA metabolism reduction?
Selegiline/Entacapone.
Describe surgical techniques used to treat PD.B91B89:B124B87:B124B85:B124B83:B124B81:B124B79:B124B78:B124B79B2:B124
Depolarisation block by deep brain stimulation or surgical ablation of Sub-thalamic nucleus/Globus Pallidus.
