PS20148 Biological Psychology Dr Claire Gibson cg95le'ac'uk School of Psychology, University of Leic

1
PS2014/8 Biological Psychology Dr Claire Gibson
(cg95_at_le.ac.uk)School of Psychology, University
of Leicester

• This handout covers the key points from the
  following lectures (images not in this handout
  are available to view in the lecture slides
  available via Blackboard)
• Development and Plasticity of the Nervous System
• Drugs and Behaviour
• Biological Basis of Learning and Memory I
• Biological Basis of Learning and Memory II
• Biological Basis of Brain Damage

• Please Note Students should check module website
  for timetable of lectures and recommended
  reading.
• Those requiring a larger print version of any
  handout can print directly from the module
  website. However, if you have any problems
  please email (cg95_at_le.ac.uk).

2
Lecture 1 Development and Plasticity of the
Nervous System
The Neural Tube
Stage 1 Cell birth

• Neurogenesis birth of neurones
• At the peak of brain development
• 250,00 neurones born per minute
• Majority finished by 5th month of pregnancy
• But, can be switched on by injury?
• Formation of fully functioning nervous system is
  dependent upon connections

• 3 wks after conception
• Failure of the neural tube to close
• 1500 live births
• Folic acid (folate)
• Middle anterior posterior
• Anencephaly
• Spina bifida

Stage 2 Migration

• Cells need to migrate to an appropriate location
• Migration of neural stem cells away from
  ventricular zone
• Migration begins shortly after neurogenesis
• Radial glial cells, Chemical signals

Genes and Environment

• 100,000 genes
• 100,000,000,000,000 neural interconnections
• Epigenetic factors
• Timing
• Genes environment _______
• fully functioning nervous system

Stage 3 Differentiation
Stage 4 Maturation

• Differentiation, Intrinsic factors
• Immediate environment
• Outgrowth of axons and dendrites (and formation
  of synapses)
• Dendrites dendritic arborisation and growth of
  dendritic spines
• Axons

3
Lecture 1 Development and Plasticity of the
Nervous System
Stage 4 Maturation (ii. Axonal Guidance)
Chemotropic Guidance
Axon terminal
Filapodia
Gradient

• Growth cones respond to
• Cell adhesion molecules
• attractive or repellant
• Tropic molecules
• Chemotropic gradient

Target cell
4
Lecture 1 Development and Plasticity of the
Nervous System
Stage 5 Formation of synaptic contacts
Stage 6 Synaptic pruning

• Synaptogenesis occurs when growth cone contacts
  dendrite
• Two-way interaction between axon and dendrite
• Estimated to be 1014 synapses in human cortex

• Apoptosis accounts for death of excess neurones
  but does not account for pruning of synapses from
  cells that survive
• Synaptic capacity of dendrites varies through
  development
• Synaptic pruning elimination of inappropriate
  and strengthening of appropriate synaptic
  contacts
• How does NS distinguish between appropriate and
  inappropriate?

Stage 6 Cell death

• Normal
• 20 80 cells die
• Apoptosis programmed cell death (PCD)
• Connection with target dependency
• Neurotrophic factors
• e.g. BDNF (brain-derived neurotrophic factor),
• NGF (nerve growth factor)
• Apoptosis

Stage 7 Myelination

• Oligodendroglia myelinating cells of the CNS
• Born shortly after neurones (along with glia)

5
Lecture 1 Development and Plasticity of the
Nervous System
Synaptic pruning
Donald Hebb (1949) Neurones that fire together
wire together
6
Lecture 1 Development and Plasticity of the
Nervous System
Plasticity
Fetal Alcohol Syndrome

• The ability of the nervous system to change with
  experience
• Developmental phenomenon?
• External and internal events

• Vulnerability of developing brain
• Fetal alcohol syndrome
• Decreased altertness, hyperactivity, mental
  retardation, motor problems, heart defects,
  facial abnormalities
• Risk depends on amount AND stage of pregnancy

Experience

• Experience effects our behaviour
• e.g. rats housed in a complex environment vs.
  simple environment
• BUT, does it alter our brain structure?

Cerebral Palsy
Synaptic plasticity

• Long-term potentiation (LTP)
• Long-lasting strengthening of synapses
• High frequency stimulation of incoming pathway
  enhances post-synaptic response to subsequent
  pathway stimulation
• Increased numbers of glutamate receptors
• Long-term depression (LTD)
• Long-lasting weakening of synapses
• Low frequency stimulation
• Decreased numbers of glutamate receptors

7
Lecture 2 Drugs and Behaviour
Overview
Administration

• Definitions
• Routes of administration
• Drug effectiveness dose response, therapeutic
  index, tolerance
• What is a placebo?
• How do drugs act?
• Behavioural effects and mechanism(s) of action
• Cannabis
• Monoamine-related drugs
• Dissociative anaesthetics

• Route of administration determines (in part)
  amount of drug that reaches the brain and the
  speed at which it starts to act

Routes of administration

• Ingestion
• Tablets, capsules, syrups,
• Depends on absorption by gut
• Inhalation
• Smoking, nasal absorption
• Takes advantage of rich blood supply of nose and
  lungs
• Peripheral injection
• Subcutaneous, intramuscular, intravenous
• Central injection
• Epidural, intracerebroventricular (icv)

Definitions

• Drug
• Psychopharmacology
• Drugs have effects and sites of action

Pharmacokinetics

• Absorption
• Distribution
• Metabolism
• Excretion

8
Lecture 2 Drugs and Behaviour
How drugs act
Distribution

• Must enter blood stream
• Gastrointestinal motility, pH
• Blood flow
• Diffusibility
• Solubility
• To get to brain must pass through blood-brain
  barrier (BBB)

• Drug serves as a precursor
• Drug inactivates synthetic enzyme
• Drug prevents storage of NT
• Drug stimulates release of NT
• Drug inhibits release of NT
• Drug stimulates postsynaptic receptors
• Drug blocks postsynaptic receptors
• Drug inhibits synthesis/release of NT
• Drug increases synthesis/release of NT
• Drug blocks reuptake
• Drug inactivates acetycholinesterase
• Agonist
• Antagonist

Metabolism and excretion

• Metabolism
• The liver
• First-pass metabolism
• Excretion
• The kidneys
• Drug testing

9
Lecture 2 Drugs and Behaviour
Mind-altering drugs of abuse
Psychedelics

• mind expanding
• Enhance/amplify thought processes of brain
• E.g. LSD (acid), MDMA (ecstasy), magic
  mushrooms, cannabis
• High levels dissociative state

• Classification difficult
• Dose important
• Psychotomimetic psychosis-mimicking
• Psychotogenic psychosis-generating
• Hallucinogenic
• Neurotransmitter mimics

Dissociatives
Mind-altering drugs of abuse

• Reduce or block signals to the conscious mind
• anesthesia
• e.g. PCP (angel dust), ketamine, nitrous oxide,
  muscimol
• Also act as CNS depressants
• death

• True hallucinogens produce their effects without
  causing changes in the level of consciousness
• Share an ability to profoundly alter mood state
  and perceptual-motor functioning
• NOT common mechanism

Deliriants
Hallucinogens

• Acetylcholine receptor antagonists
• true hallucinogens
• Plants such as deadly nightshade, mandrake,
  henbane, and datura, high doses of pharmaceutical
  drugs
• Side effects
• toxic

• Term is mis-leading?
• Psychedelics
• Dissociatives
• Deliriants

10
Lecture 2 Drugs and Behaviour
Cannabis
Effects of cannabis

• Natural substance derived from hemp plant,
  Cannabis sativa
• Reported use as recreational drug for over 4000
  years
• However, since 4th century BC also employed as a
  therapeutic drug
• Today most commonly used street drug world wide

• 1 initial period of euphoria and relaxation
  followed by depressant period.
• Euphoria, altered time perception, dissociation
  of ideas, paranoia, motor impairments and
  occasional hallucinations.
• Alterations in various cognitive and behavioural
  abilities

Biological effects of cannabis
Cannabinoids

• Cannabis plant contains over 60 compounds
• Cannabinoids
• Marijuana
• Hashish
• Active component
• delta-9 tetrahydrocannibinol (THC)
• street potency of cannabis i.e. THC content
• 1974 0.35
• 1990 3.54

• Cannabinoid (CB) receptors CB1 and CB2
• Widespread distribution
• Highest in cerebral cortex, hippocampus,
  hypothalamus and amygdala
• Endogenous cannabinoids?

11
Lecture 2 Drugs and Behaviour
Endocannabinoids
Monoamine-related drugs

• Endogenous cannabinoids endocannabinoids
• i.e. anandamide, 2-arachidonoyl-glycerol, noladin
  ether
• Act at presynaptic CB receptors and decrease
  release of transmitters
• Physiological effects poorly understood

• Similar molecular structure to monoamine
  neurotransmitters
• e.g. MDMA, LCD

MDMA

• 3,4-methylenedioxymethamphetamine
• Ecstasy
• Amphetamine analogue
• Hallucinogen not stimulant
• ve effects (love drug)
• euphoria, tingling, increased sociability
• -ve effects
• neuronal damage, fatigue, insomnia, sweating,
  blurred vision, loss of motor coordination,
  anxiety, dehydration, psychosis

Cannabis therapeutic uses

• Treatment of nausea and vomiting
• Appetite stimulation
• Analgesia
• Anticonvulsants

Cannabis use and psychosis

• Theories
• Cannabis use cannabis psychosis
• May precipitate an episode of schizophrenia
• May exacerbate symptoms of schizophrenia
• Cannabis is harmless

12
Lecture 2 Drugs and Behaviour
LSD
Actions of MDMA

• ve effects
• Alterations in hearing and vision
• Hallucinations
• Subjective sense of time prolongation
• -ve effects
• bad trip
• Dysphoria
• Anxiety
• Depression
• Flashbacks
• Tolerance develops quickly

• Stimulate 5-HT release
• Increase synaptic concn. of dopamine
• Neurotoxic reaction
• Even limited use of MDMA may cause permanent
  neuronal damage to 5-HT neurones

LSD

• Synthetic drug, related to a number of compounds
  in ergot fungus
• First synthesised in 1940s
• Very potent

Actions of LSD

• Affects 5-HT function
• May affect glutamate transmission
• May increase dopamine transmission

13
Lecture 2 Drugs and Behaviour
PCP mechanism of action
Dissociative anaesthetics

• Novel PCP binding site found
• High densities in hippocampus and motor cortex
• Discovered PCP binding site within NMDA receptor
  channel
• PCP NMDA receptor antagonist
• Also
• dopamine agonist in nucleus accumbens, prefrontal
  cortex and basal ganglia
• enhances 5-HT activity
• blocks muscarinic and nicotinic acetylcholine
  receptors

• Induce profound anaesthesia
• e.g. Phencyclidine (PCP), ketamine
• PCP
• Synthesised in 1950s
• Ketamine
• date rape drug

PCP

• angel dust
• Smoked, swallowed, sniffed or injected
• Low level of abuse
• Dose-dependent effects

Hallucinogens and risks
PCP and psychosis

• Not necessarily addictive (still damaging)
• Social addiction
• e.g. Cannabis, Ecstasy
• Some psychological addiction if experience
  pleasant
• e.g. LSD, Magic mushrooms

• PCP exacerbates symptoms of psychotic patients
• Heavy PCP users report schizophrenia- like
  psychotic episodes
• Part of evidence for glutamatergic involvement in
  schizophrenia

14
Lecture 3 Biological Basis of Learning and
Memory I
Memory has temporal stages
What happens when we learn?

• Learning can produce new synaptic connections
• Animals housed in
• Standard conditions (SC)
• Impoverished (isolated) conditions (IC)
• Enriched conditions (EC)

• Iconic
• Short-term
• Intermediate-term
• Long-term

Processes of memory
Learning can produce (and strengthen) synaptic
connections

• Functionally, memory has three stages
• Encoding Consolidation - Retrieval

• EC animals
• More extensive dendritic branching
• Increased postsynaptic thickening of synapses
• Formation of new synapses
• Such increases in the size and number of synaptic
  contacts may increase the certainty of synaptic
  transmission in the circuits where those changes
  occur

15
Lecture 3 Biological Basis of Learning and
Memory I
What conditions induce memory-related changes at
synapses?
Remember Donald Hebb (1949) Neurones that fire
together wire together
16
Lecture 3 Biological Basis of Learning and
Memory I
Long-term potentiation (LTP)
Long-term potentiation (LTP)

• Stable and enduring increase in the effectiveness
  of synaptic transmission
• First discovered in the hippocampus by Tim Bliss
  and Terje Lomo (1973)

• Similarities to Hebbian synapses
• The tetanus drives a group of axons to fire
  repeatedly
• Because the axon terminals are all firing at
  once, they succeed in causing the postsynaptic
  targets to fire repeatedly
• The synapses were stronger than prior to the
  tetanus

• Long-term potentiation (LTP)
• Long-lasting strengthening of synapses
• High frequency stimulation of incoming pathway
  enhances post-synaptic response to subsequent
  pathway stimulation
• Studied mostly in the hippocampus, also occurs in
  other areas important for learning (auditory,
  visual and motor cortex)
• Long-term depression (LTD)
• Long-lasting weakening of synapses
• Low frequency stimulation
• A mechanism to remove old memories?

17
Lecture 3 Biological Basis of Learning and
Memory I
Types of LTP
Calcium

• Associative LTP
• e.g. associative learning
• Strengthening of the connections between two
  neurones that are simultaneously active
• Non-associative LTP
• e.g. habituation and sensitization
• Repeated application of one stimulus

• 2nd messenger
• Signalling and cellular proteins
• Levels tightly controlled
• Calcium calmodulin calcium-dependent
  protein kinase cascade
• Increases in intracellular calcium occur via
• Diffusion through ion channels
• Release from intracellular stores
• Calcium pumps

Synaptic changes

• Structural changes
• Formation of new synapses
• Rearrangement of synaptic inputs
• Physiological changes
• Presynaptic, postsynaptic, or both
• Changes in
• neurotransmitter release
• receptor number/sensitivity
• Inactivation of neurotransmitter
• Impulses from other neurones

LTP

• Two phases
• Early-LTP
• Late-LTP

18
Lecture 3 Biological Basis of Learning and
Memory I
Early LTP

• 1-5 hours
• Protein-synthesis independent
• Increases sensitivity of glutamate receptors

19
Lecture 3 Biological Basis of Learning and
Memory I
Late LTP- days-months- protein-synthesis
dependent- enhance existing synapses- new
connections
LTP - summary

• NMDA antagonists prevent induction of LTP
• Has been demonstrated in numerous brain areas
• e.g. cerebral cortex, cerebellum, amygdala
• Two types of LTP
• Associative
• Non-associative

LTP, learning and memory

• LTP can be induced within seconds
• LTP may last for days or weeks
• Shows a labile consolidation phase that lasts for
  several minutes after induction

20
Lecture 3 Biological Basis of Learning and
Memory I
1. Persistently active protein kinases
The molecular basis of long-term memory

• Experience-dependent alterations in synaptic
  transmission memory
• Changes in the number of phosphate groups
  attached to proteins in the synaptic membrane
• changes in synaptic effectiveness
• as long as phosphate groups remain attached to
  that protein

• Kinases enzymes that attach phosphate groups to
  proteins
• Permanently switched on
• Independent of second messenger
• maintenance of phosphorylation of synaptic
  proteins
• Maintenance of synaptic modification
• Limited time

2. Protein synthesis

• Required to form new synapses
• Inhibitors can learn tasks but fail to remember
  when tested
• Memories become ? resistant as ? time interval
  between training and injection of inhibitor
• New protein synthesis requirement during memory
  consolidation

So, does protein phosphorylation account for
long-term memory?

• Phosphorylation of proteins is not permanent
• Protein molecules are not permanent
• So, how does changes in synaptic protein
  phosphorylation lead to long term memories?
• Persistently active protein kinases
• Protein synthesis

The molecular basis of long-term memory

• Summary
• Memory formation
• rapid modification of existing synaptic
  proteins
• BUT would be lost as a result of molecular
  turnover
• New protein at synapse converts temporary
  change into permanent one.

21
Lecture 4 Biological Basis of Learning and
Memory II
Alzheimers Disease (AD)
Aging

• Impairments in memory
• Especially declarative
• Less cortical activation during tasks
• Mechanisms
• Loss of neurones/connections
• Cholinergic system
• Representation of information

• 1st identified over 100 yrs ago
• A degenerative brain disorder of unknown origin
  that causes progressive memory loss, motor
  deficits, and eventual death.
• Incidence ? as population ages

AD - occurrence

• Loss of neurones/connections
• Gradual loss of brain weight
• Shrinkage of hippocampus
• Age-related decline
• Decline in the acetylcholine system
• Impaired coding by place cells
• Place cells in the hippocampus
• Number of neurones responding the same
• But, neurones encode a smaller amount of
  information

• 18 million worldwide
• 1 million UK
• 7 aged over 65
• 40 aged over 80
• NHS, carers, support services

22
Lecture 4 Biological Basis of Learning and
Memory II
AD early signs
AD - symptoms

• Personality changes
• Apathy
• Most common behavioural change
• Decreased motivation, indifference
• Not related to depression
• Depression
• Depressive symptoms are frequent

• Normal ageing?
• Blunting of emotional responses
• Social withdrawal
• Coping with Forgetfulness in Alzheimers
  Disease

AD - pathology
AD - symptoms

• Memory impairment
• Progressive memory loss
• Initially
• Impairments in episodic and declarative memory

• Brain atrophy
• Histopathological features
• Senile plaques
• Neurofibrillary tangles
• Synaptic loss
• Selective depletion of neurotransmitter systems
  (e.g. Ach)

• Loss of function
• Memory
• Insight
• Judgement
• language

23
Lecture 4 Biological Basis of Learning and
Memory II
AD and amyloid
3. Synaptic loss

• AD characterised by amyloid plaques which contain
  mainly aggregated b-amyloid peptide derived from
  amyloid precursor protein (APP)
• In normal healthy individuals, b-amyloid peptides
  are present only in small quantities as soluble
  monomers that circulate in CSF and blood.
• However, in AD patients, their levels are ? and
  they begin to accumulate as insoluble, fibrillar
  plaques.

• Extensive
• Depletion of selective neurotransmitter systems
• Acetylcholine (Ach)
• Glutamate
• Serotonin
• Noradrenaline

4. Depletion of selective neurotransmitter systems

• Neurones that use Ach or glutamate are
  particularly affected
• Also, neurones that utilise serotonin or
  noradrenaline are affected

24
Lecture 4 Biological Basis of Learning and
Memory II
Early onset AD
Cholinergic hypothesis of AD

• Cholinergic neurones
• Learning, memory, certain aspects of sleep states
  
• Antagonists (e.g. scopolamine)
• Deleterious effect on learning and memory
• Alzheimers Disease
• Degeneration of Ach producing neurones in
  forebrain
• Deficit in Ach producing enzyme

• Caused by gene mutations on chromosomes

• Autosomal dominant inheritance
• If one of these mutated genes is inherited from a
  parent person will almost always develop early
  onset AD

Causes of AD

• Early-onset
• Hereditary
• lt5 cases
• lt60 -65 yrs
• Late-onset
• Majority cases
• gt60-65 yrs

25
Lecture 4 Biological Basis of Learning and
Memory II
ApoE and b-amyloid
Late onset AD

• Genes involved
• Apolipoprotein E (apoE)
• ApoE
• gylcoprotein, transports cholesterol in blood,
  plays a role in cellular repair
• On chromosome 19, the apolipoprotein E (apoE)
  gene has three common forms or alleles E2, E3,
  and E4. Thus, the possible combinations in one
  person are E2/2, E2/3, E2/4, E3/3, E3/4, or E4/4.
• E4 one allele of apoE
• Presence of E4 increases risk of developing AD
• Alleles - different forms of the same gene. Two
  or more alleles can shape each human trait. Each
  person receives two alleles, one from each
  parent. This combination is one factor among many
  that influences a variety of processes in the
  body.

• Normally b-amyloid is soluble
• BUTbecomes insoluble when aopE4 attaches to it
• Therefore, more likely to be deposited in plaques
• Presence of ApoE4
• Increases deposits of b-amyloid and able to
  regulate APP protein from which b-amyloid is
  formed

AD risk factors

• Most cases of AD are sporadic (i.e. not
  hereditary)
• So, what causes b-amyloid accumulation in those
  cases?
• Head injury, infections, excessive alcohol or
  other drugs, exposure to toxic substances

26
Lecture 4 Biological Basis of Learning and
Memory II
Treatment of AD
AD whats the future?

• Drugs
• cholinesterase inhibitors
• Psychological
• For example
• External memory aids, visual imagery, reality
  orientation

• 1. Lower cholesterol levels
• Two copies of the ApoE4 allele ?? low-density
  lipoprotein
• High levels of low-density lipoprotein
• Linked to risk to AD
• Shown to promote deposition of b-amyloid
• 2. Anti-inflammatory
• Inflammation of brain tissue may play key role in
  development of plaques and tangles
• 3. Antioxidant therapies
• b-amyloid increases number of free radicals
• Brain tissue especially vulnerable to free
  radical damage
• Studies investigating effects of antioxidants
  (e.g. vitamin A, vitamin C, selenium)

Cholinergic drugs

• Nearly every drug currently licensed for AD
  cholinesterase inhibitor (ChEI)
• Boosts activity at cholinergic synapses
• (Aricept) UK approved for mild to moderate AD
  in 1997, transiently improves clinical symptoms
  for 6-12 months

27
Lecture 5 Biological Basis of Brain Damage
2. Closed head injury
Traumatic Brain Injury

• Acceleration and/or deceleration
• Acceleration
• Significant physical force, propels brain quickly
  from stationary to moving
• Deceleration
• Brain is already in motion stops abruptly
• Impact injury or at its opposite pole
• Shear, tear and rupture nerves, blood vessels and
  the covering of the brain

• Physical Trauma
• Males Females (41)
• Car accidents, sports injuries, falls, violence,
  industrial accidents

Mechanism of impact

• Neuronal shearing, stretching and tearing
• Retrograde degeneration
• Anterograde degeneration
• Penetrating head injury
• Penetrating mechanism
• Closed head injuries
• Blow to the head but no penetration of skull

Head Injury - Consequences

• Glasgow Coma Scale (GCS)
• Edema, Intracranial bleeding, Skull fractures
• Post-traumatic epilepsy/seizures
• Symptoms
• Difficulties with
• Memory, concentration, attention,
• Alterations in mood
• Hugely variable

1. Penetrating head injury

• Effects cortical integrity of brain
• Location of injury
• Complications infection and hemorrhaging

28
Lecture 5 Biological Basis of Brain Damage
Prevalence
Brain Tumours

• 5 of all cancers
• Tumours morbid enlargement of new growth/tissue
  in which cell multiplication is uncontrolled and
  progressive
• Growth disorganised, often at expense of
  surrounding, intact tissue

• In the Western World
• 250-400 strokes per 100 000 people
• 3rd cause of death
• 1st cause of disability (in adults)
• NHS
• Social services
• Carers
• Family members

Brain Tumours - Classification

• Infiltrative
• infiltrate neighbouring areas
• Non-infiltrative
• Encapsulated, differentiated, compress
• Malignant
• Infiltrative, spread (metastatic)
• Benign
• Non-infiltrative, fibrous capsule, do not spread

Outcomes

• Death (20)
• Varying degrees of disability (60)
• Achieve neurological recovery (20)
• 2nd stroke

Brain Tumours
Risk factors

• Diagnosis
• headache, nausea, vomiting ??
• CT Scan, MRI
• Cognitive effects
• Depends on size, location and grade
• Neuropsychological evaluations (surgery)

• Too many!
• For example hypertension, diabetes, cardiac
  disease, hyperlipidaemia, smoking, family history
  of stroke, obesity, diet, oral contraceptive
  pill, previous stroke

29
Lecture 5 Biological Basis of Brain Damage
Clinical symptoms
Pathology of stroke

• Sudden or gradual onset
• One-sided limb weakness/paralysis
• Confusion, loss of speech/vision
• Headache
• Loss of consciousness
• results in dysfunctional cognitive and motor
  behaviour
• determined by size and location of cell loss

• Massive cell death
• What causes death of neurones following
  interruption of their blood supply?
• Are cells simply starving to death because they
  lose their supply of glucose and oxygen?
• No - primary cause of cell death is excessive
  amounts of glutamate
• ischemic lesion excitotoxic lesion
• Cascade of complex events
• cell death, inflammation, reperfusion

Cognitive impairment

• Amnesia, Inattention, Confusion, Depression, Mood
  and behaviour changes

Events following stroke

• Excitotoxicity
• Cell death
• Inflammation

Depression

• Common after stroke
• Not simply a consequence of physical effects
• Patients with PSD often differ from those with
  primary depression in that they have more
  cognitive impairment (memory and concentration
  problems), irritability, more psychomotor
  slowing, and more mood liability.

30
Lecture 5 Biological Basis of Brain Damage
Events following stroke
1. Excitotoxicity
? blood flow
Calcium

• Second messenger

Mitochondrial dysfunction
Damage cell structures

• Activate enzymes

disruption

• e.g. Phospholipases
• Endonucleases
• Proteases

e.g. components of cytoskeleton, membrane and
DNA
? ATP
Ion homeostasis
glu
glu
glu
glu
gene activation
glu
Ca2
Ca2
Ca2
Cell Death
Ca2
NMDAR
Ca2
Ca2
free radical production
inflammation
Ca2
Ca2
31
Lecture 5 Biological Basis of Brain Damage
Events following stroke

• 2. Cell death

32
Lecture 5 Biological Basis of Brain Damage
Events following stroke

• 2. Cell death - apoptosis

Intracellular signals
Extracellular signals
Several pathways NFkB, P53, Bcl
Caspases formed
Caspase 3
DNA breaking enzymes e.g. endonucleases
Energy consuming DNA repair enzymes e.g. PARP
DNA breakdown
Cell death
33
Lecture 5 Biological Basis of Brain Damage
Events following stroke

• 3. Inflammation
• Excessive glutamate excessive amounts of sodium
  and calcium in cells
• High levels of sodium cells absorb water and
  swell (edema)
• Inflammation
• Resident microglia
• BBB breakdown
• Infiltrating neutrophils, macrophages, T- and
  B-lymphocytes
• Phagocytosis (cell-eating)

34
Lecture 5 Biological Basis of Brain Damage
Current treatments
Why no effective treatment?

• Tissue Plasminogen Activator (t-PA)
• Thrombolytic
• Licensed for stroke
• 3 hours
• CT scan
• gt49 neuroprotective agents studied in gt114 stroke
  trials

• Pathology indicates obvious choices?
• NMDA receptor antagonists e.g. MK-801
• Anti-inflammatory agents
• Caspase inhibitors
• BUT
• Pathology is complex
• Animal studies often poorly designed

Current research

• NXY-059 free radical scavenger
• Developed by Astra Zeneca
• Currently undergoing Phase III clinical trials
• Stem cells
• Replacement of dead neurones with new ones
• Realistic?